Group b streptococcus vaccine

DESCRIPTION

GROUP B STRAPS

VACCINE AGAINST

TECHNICAL FIELD

This invention relates to streptococcus agalactiae (GBS) polysaccharides and their use in immunization.

BACKGROUND ART

Once thought to infect only cows, Gram-positive bacteria Streptococcus agalactiae (or group B streptococcus abbreviated to GBS (Ref. 1) are now known to cause severe disease, bacteremia and meningitis in immunocompromised and newly born individuals. two types of neonatal infection The first (early onset, usually within 5 days after birth) is manifested by bacteremia and pneumonia. It is contracted vertically by the baby as it passes through the birth canal. GBS colonizes the vagina in about 25% of young women, and about 1% of children born through a vaginal birth of colonized mothers will be infected. Mortality is between 50-70%. The second is meningitis that occurs 10 to 60 days after birth. If pregnant women are vaccinated with Type III capsules so that infants are passively immunized, the incidence of late meningitis is low but not completely eliminated.

OB in GBS refers to the Lancefield classification which is based on the antigenicity of a carbohydrate that is soluble in dilute acid and called carbohydrate C. Lancefield identified 13 types of carbohydrates C, designated A to O, which could be serologically differentiated. The organisms that most often infect humans are found in groups A, B, D, and G. In group B, strains may be divided into at least 9 serotypes (Ia, Ib, Ia / c, II, III, IV, V, VI, VII, and VIII) based on the structure of their polysaccharide capsule. In the past, serotypes Ia, Ib, II, and III were equally present in normal vaginal death and early sepsis in newborns. GBS DO Type V has emerged as a major cause of GBS infection in the US, however, types VI and VIII strains have become prevalent among Japanese women.

The genome sequence of a serotype V of strain 2603 V / R has been published (Ref. 2) and several polypeptides for use of vaccine antigens have been identified (Ref. 3). The vaccines are currently in clinical trials, however, they are based on polysaccharide antigens. They suffer from serotype specificity and poor immunogenicity, and therefore there is a need for effective vaccines against S.agalactiae infection.

It is an object of the invention to provide more improved GBS vaccines.

DISCLOSURE OF INVENTION

The inventors have realized that saccharide-based vaccines can be improved by using them in combination with polypeptide antigens, and vice versa, such that the polypeptide and saccharide each contribute to the immune response in a receptor. The combination is particularly advantageous where the saccharide and polypeptide are of different GBS serotypes.

The combined antigens may be present as a single combination, where separate saccharide and polypeptide antigens are administered together, or may be present as a conjugate combination, where the saccharide and polypeptide antigens are covalently attached to each other.

Thus, the invention provides an immunogenic composition comprising (i) one or more GBS polypeptide antigens and (ii) one or more GBS saccharide antigens. The polypeptide and polysaccharide may be advantageously covalently linked together to form a conjugate.

Among them, the combined polypeptide and saccharide antigens preferably cover two or more EGB serotypes (e.g., 2, 3, 4, 5, 6, 7, 8 or more serotypes). Serotypes of polypeptide and saccharide antigens may or may not overlap. For example, the polypeptide may protect against serogroup II or V, while saccharide protects against either serogroups Ia, Ib or III. Preferred combinations protect against the following groups of serotypes: (1) serotypes Ia and Ib, (2) serotypes Ia and II, (3) serotypes Ia and III, (4) serotypes Ia and IV, (5) serotypes Ia and V , (6) sera Ia and VI, (7) serotype Ia and VII, (8) serotype Ia and VIII, (9) serotype Ib and II, (10) serotype Ib and III, (11) serotype Ib and IV, ( 12) serotypes Ib and V, (13) serotypes Ib and VI, (14) serotypes Ib and VII,

<td>(15) serotypes</td><td>Ib e</td><td>VIII,</td><td> 16)</td><td>serotypes III</td><td>and is,</td><td> (17)</td>

<td>serotypes II and</td><td>IV, (18</td><td colspan="2">) serotypes</td><td colspan="3">II and V, (19) serotypes II</td>

<td colspan="2">and VI, (20) serotypes</td><td>II and</td><td>VII,</td><td>(21) serotypes</td><td>II and</td><td>VII,</td>

<td>(22) serotypes</td><td>III and</td><td>IV,</td><td> (23)</td><td>serotypes III</td><td>and V,</td><td> (24)</td>

<td>serotypes III</td><td>and VI,</td><td> (25)</td><td colspan="2">serotypes III and</td><td>VII,</td><td> (26)</td>

serotypes III and VIII, (27) serotypes IV and V, (28) serotypes IV and VI, (29) serotypes IV and VII, (30) serotypes IV and VIII, (31) serotypes V and VI, (32) serotypes V and VII, (33) serotypes V and VIII, (34) serotypes VI and VII, (35) serotypes VI and VIII and (36) serotypes VII and VIII.

Even more preferably, the combinations protect against the following groups of serotypes: (1) serotypes Ia and II, (2) serotypes Ia and V, (3) serotypes Ib and II, (4) serotypes Ib and V, (5) serotypes III and II and (6) serotypes III and V. Most preferably, the combinations protect against serotypes III and V.

Protection against serotypes II and V is preferably provided by polypeptide antigens. Protection against serotypes Ia, Ib and / or III may be by polypeptide or saccharide antigens.

Preferably, the immunogenic composition comprises one or more serogroup V antigens or fragments thereof, selected from the group consisting of the antigen of

<td>GBS</td><td> 80,</td><td>GBS 91, GBS 104,</td><td>GBS 147, GBS 173,</td><td>GBS</td><td> 276,</td><td>GBS</td>

<td> 305,</td><td>GBS</td><td>313, GBS 322, GBS</td><td>328, GBS 330, GBS</td><td> 338,</td><td>GBS</td><td> 358,</td>

<td>GBS</td><td> 361</td><td>, GBS 404, GBS</td><td>656, GBS 690,</td><td>GBS</td><td> 691 .</td><td>In</td>

preferably, the composition comprises a composition of at least two of these GBS antigens or a fragment thereof.

In one embodiment, the immunogenic composition comprises a GBS saccharide antigen and at least two GBS polypeptide antigens or fragments thereof, wherein said GBS saccharide antigen comprises a saccharide selected from GBS serotype Ia, Ib and III, and wherein said antigens. GBS polypeptides comprise a combination of at least two polypeptides or a fragment thereof selected from the group consisting of

GBS 80, GBS 91, GBS 104, GBS 147, GBS 173, GBS 276, GBS

<td>305, GBS 313, GBS</td><td>322 GBS</td><td> 328</td><td>GBS 330,</td><td>GBS</td><td>338, 358 GBS,</td>

<td>GBS 361, 404 GBS,</td><td>GBS 656,</td><td>GBS</td><td>690, and GBS</td><td> 691</td><td> •</td>

<td>Preferably the</td><td colspan="2">combination</td><td>understand</td><td>GBS</td><td>80 or one of yours</td>

<td colspan="2">fragment. In a form</td><td>in</td><td>realization</td><td>r</td><td>the antigens</td>

GBS polypeptides comprise a combination of two GBS antigens or fragments thereof selected from the group consisting of antigen (1) of GBS 80 and GBS 91, (2) GBS 80 and GBS 104, (3) GBS 80 and GBS 147 , (4) GBS 80 and GBS 173, (5) GBS 80 and GBS 276, (6) GBS 80 and GBS 305, (7) GBS 80 and GBS 313, (8) GBS 80 and GBS 322, (9) GBS 80 and GBS 328, (10) GBS 80 and GBS 330, (11) GBS 80 and GBS 338, (12) GBS 80 and GBS 358, (13) GBS 80 and GBS 361, (14) GBS 80 and GBS 404 ( 14), GBS 80 and GBS 404, (15) GBS 80 and GBS 656, (16) GBS 80 and GBS 690, and (17) GBS 80 and GBS 691.

Even more preferably, the combination is selected from the group consisting of antigen (1) of GBS 80 and GBS 338; (2) GBS 80 and GBS 361, (3) GBS 80 and GBS 305, (4) GBS 80 and GBS 328, (5) GBS 80 and GBS 690, (6) GBS 80 and GBS 691, and (7) GBS 80 and GBS 147. Even more preferably, the combination comprises GBS 80 and GBS 691.

In one embodiment, the composition comprises a combination of at least three polypeptide antigens.

GBS. Preferably, this combination comprises GBS 80 and

GBS 691.

Preferably, the immunogenic composition further comprises a GBS polypeptide or a serogroup II fragment thereof.

The polypeptide antigen polypeptide is preferably: (a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ IDs 2-10966 pairs of Ref. 3; (b) a polypeptide comprising an amino acid sequence having a sequence identity to an amino acid sequence from (a); or (c) a polypeptide comprising a fragment of an amino acid sequence of (a).

Within (a), preferred SEQ IDs are those encoding GBS1 to GBS689 (see Table IV of Ref. 3)

Within (b), the degree of sequence identity may vary according to the amino acid sequence (a) in question, but is preferably greater than 50% (e.g. 60%, 70%, 80%, 90 %, 95%, 99% or more). Polypeptides within (b) include homologues, orthologs, allelic variants and functional mutants of (a). Typically, 50% identity or more between two proteins is considered an indication of functional equivalence. Identity between proteins is preferably determined by the Smith-Waterman homology search algorithm as implemented in the MPSRCH (Oxford Molecular) program using a related gap search with open penalty gap = 12 and penalty extension gap = parameters. 1.

Within (c), the length of the fragment may vary depending on the amino acid sequence (a) in question, but the fragment is preferably at least 7 consecutive amino acids from the sequences of (a), e.g. 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200 or more. Preferably, the fragment comprises one or more epitopes of the sequence. Other preferred fragments are the N-terminal signal peptides of SEQ IDs 1-10966 from Ret. 3, SEQ IDs 1-10966 of ref. 3, without the N-terminal signal peptides, and SEQ IDs 1-10966 of Ret. 3, wherein up to 10 amino acid residues (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 residues) are deleted from the N-terminal and / or C-terminal, for example. N-terminal amino acid residues can be deleted.

Polypeptides may, of course, be prepared by various means (e.g., by recombinant expression, GBS purification, chemical synthesis, etc.) and in various forms (e.g. native, fusions, glycosylated, unglycosylated, etc.). . They are preferably prepared in substantially pure form (i.e. substantially free of other streptococcal or host cell proteins) or in substantially isolated form.

Preferred polypeptide antigens are: GBS 80, GBS 91, GBS 104, GBS 147, GBS 173, GBS 276, 305 GBS, GBS 313, GBS 322, GBS 328, GBS 330, GBS 338, GBS 358, GBS 361, GBS 404 GBS 656, GBS 690, GBS 691 and, including polypeptides with amino acid sequences having sequence identity therewith, and the like.

The nucleotide and amino acid sequences of GBS 80 in Ref. 3 are SEQ ID 8779 and ID SEQ 8780. These sequences are set forth below as SEQ ID NOS 1 and 2:

SEQ ID NO. 1

ATGAAATTAÍCGAAGAASTrAI ^ rGTTTTOGGCTGCTGTTTTAACAATGGTGSCGGGGTCAACTGTTGAACCAGTAGCTCAGTrTGC

GACTGeAftreA &lt;JTATTSTAAGftGCTÍ3C &amp; SBAGrGTCACA &amp; G8ACeCCCAeCC3AAAAC3kACASTAAATATCTATAAATERCaAGOT »

ATAGTTATAAATCGGAAATTACTTCT &amp; ATSGTGGTATCSAGAATAAAGACGGCGAAGTAATATCTAAÇTATGCTAAACTTGGTGAC

AATGTAAAAGGTTTGCAAGGTXyíACAGTTTAAACGTTATAAAGTCAAGACSGATATTrGtGTTGATGAATTBAWiAATTOACAAC

RGXTGAASCAGCAGATGCAAAAGTTGGAACGArTCTTG &amp; AGAZi.GGTÔTCAGtCTACCTCAAAAAACTAATGCTCAAGGTrrSGTCG

TCGA'rGCTí2TGGA'nçaAAAAG'IAATATGASAracJrTGTATí3TAGAAGATTTAAAGAATTGAÇ'ETCAAACATTACCAAAGC3TAT

GGTGTACCOTTTSTGTTGGsArrACCAGrTGCTAACTCTACAGGTACAGSTTTCCrrTCTGAAATrAATArTTACCCTAAAAACGT

TGTAACTGATGAAGCAAAAACAGATAAAGATGTTAAAAAATTAGSTCAGGACGATGCAGGTTATACGATTGGTGAAGAATTCAAAT

GGTTCTTGAIATCTACAATCCCTGCCAAn ^ AGGTGACrATGAAAAATTTGAAATTACTGATASAATTTGCAGATGGCTTGACnAT

AAATCTCmGGAAAAATCAAGATTGOTTCGAAAACAC-reAATAGAGATOAGCACTACACTATrGATGAACCAACAGTTGATAACCA

AAAIACATTAAAAATTACGrTTAAACCAGAGAAAI-TTAAAGAAATTGCTGAGCTACTrAAAGGAATGAeCCTTGWAAAAAyCAAG

ATGCTCCTGitTAMGCrACTGCAAATACAGATGATSCGGCATITTTGGAAA-FTCCAGTTGCATCAACTATSAATGAAAAAGCAGTS '

ITAGGAAAAGCAATTGAAAATACTTTTGAACITCAATATGACCATACTCCTGATAAAGCTGACAAICACASACCATCTAATCCTCC

AAGAAAACCAGAAGTICATACTGGTGGGAAAGSATTrGTAAAGAAAGACTCAACAGAAACACAAACACTAGGTGGTGCTGAGTTTC

ATTrGTTGSCTTCTGAT ^ GACaGCASrAAAAISSACACSATGCTCTTATTAAAGCGAATACrAATAAAACTATATTGCrGGASAA

GGTGTrACTGGGCAACCAATCAAATTSAAATCACATACAGACGGTACeTTTGfeGATiaAAGGTTTGGCTTATGCAGCrTGATGCGAA

TGCAGAGGGTACAGCASTAACTTAGAAATTAAAAGAAACAAAAGCACCAGAAGGTTATGTAATCCCTGATAAAGAAATCGAGTTTA

CAG'rATCACAAàCATC »ATAATACAAAACCSACTGACATCACGGTTaA'rAGTGCTGATGCAACACCTGATACAA'rTAAAAA, CAAC

AAACGTCCTTCAATaCTAATACTGGWSGTATTGGTACGGCTATCTTTGTCSCl ^ TCSGTeCTGCSGTGKTtJGCTTTTSCTGTFAA

GGGGATGAAGCGÍGGCACAAAGATAAC

SEQ 10 NO: 2 «ΚΤΒίίΚΡ &amp; Ρ8Α.ΑνΑΪ ^ ΚΑβ3Τ ^ ΡνΑ &lt;ίΕ% ^» 2ΓνΕΑΑ &amp;^τ$ 0έΚΡΑΚΤ ^ Α'Νϊχίφ0ΑΙϊβΥΧ3Ε: ΐτ8ϊ (ί3δΙ®ΪΪΧβάδνΐ8 ^ ϊ'ΑΚΒΟΕί

ΝβΚξ ^ 50Ϋα ^ ΐήΐΚ \ ίΚΊΡ33νβ31ιΚΚύΤΤνΕίΑ &amp; ΠΑΚν0ΐίΑ ^ εβΫβΙ ^ 9ΚΊ ^ (3άΑννΒΑΣθ3ΚδΝνΚΪΑ ^ ΒβΙ&gt; ΚΗ3? 3ΝΙΤ5ίΑϊ '

AVPF í ^ ^ ^j IVAVAVAVASTSTSTSTGGGGGGGGGiy G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G GÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇÇ

^3νβΚΙΚίάδΚΤϊΐΒ ^ ΕέϊΤΐθΕΡΤνΒί ^ ΊΪ, κ1ϊΡΚΡΒΚΓΚέίΑΕΑ1ΚβΜΤω ^^ ΑΡβΚΑΤΑΚΪΒβΑΑϊ'ΑεΐΡνΑ3ΤΙίϊΕΚΑν

LGK &amp; lSKTFELÇYDSTPnKAGSSteGSPPÍíK GGPIKrKSBTÚGTPStKSIAyA ^ ^^ ^ SrvaTGGKSFi.nCKGSTEIQTtGGAEFSL.I.ASeGTAVJGíTDALíKAimmiYIAGS The rnSKAEGCTAVTYKijKETÍíABEGWXPOKEIEtrVSOTSYBTKSTDIWPSASATPWKSN KRPSIPHTGGIGTAIFVAIGAAVMAPAVXSÍÍKRRTKDK &lt;. · '

The nucleotide and amino acid sequences of GBS 91 in Ref. 3 are SEQ ID 8937 and ID SEQ 8938. These sequences are shown below as SEQ ID Nos. 3 and 4:

SEQ (Õ NO. 3

ATSAAAASAGSACAACrAftATGATACTSAGCAATCTT &amp; CTCTCTACGTAAATATAAATTTGGTTTAGCATCAGAATTATTT &amp; GGGPC

ATTttTAAIXSGTC &amp; CAAGTCCTOTTTrTGOSSATCASACE &amp; CATCGGTTCBAGTISlATAATCAGACAGSC &amp; CrAGTGTOSATeCTA

ATAATTCTTGCAATQ &amp; GACA &amp; GTSCGTCAAGYGTGATTACTTCCAATAATG &amp; T. &amp; STOTTC &amp; AGCGTCRIAT &amp; A &amp; GYYGTAAAYAG '!'

CAAAATACGGCAACAAAGSACA? TACTACTCCTTT'AG7'AGAGAGA &amp; AGCCAAT &lt;3GTGGILAAAAACAXTACC^lrGAACftAGSGAA.TrA

YGTTTATAGCAAAGAAACCGAGGTG &amp; AAAATACAGCTTCAAAATCAGCCCCAGTAGCTTTCTATGCASAGAJas.GSTiSAYAAAGTTT

TCTi.TGAC ^ ÍAGTATOTAATAAAGATAATGTGAAATGGATTTCATATAAGTCTTTTTGTGGCGTACGTCGATACGCAGCTATTGAG

TCACTAGATCCATCSGGAGSTTCAWÍWCTAAAGCACCWCTCCTBTAACAAATraMSGAASCAATÃATCfflAQAaaAAAriGCAAC

GCAAGGA &amp; ATTATA &lt;3lTrrTCACAWys.®rAGAAGTAAAAAATGAAGCXAAGGTAGeGAGTCCAACTC &amp; ATPTACATTGGAC &amp; AAG

GAGACAGAArTrTTTACGACCAAATACTAACTArrGZiAGGAAATCAGTGGTrATCTTATJiAATCATTCAATGGTGTTCGTCGTTTT

GTYTTGCTAGGTAÃAGCATCTTCAGTAGAAAAAACTGAAGATAAAGAAAAAGTGTCTCCTCAACCACAAGCCCGTATTOCTAAAAC 'IJGGTAGACTSACTATTTCrAACGAAACAACTAC &amp; GGTTTrGATATTATATATAGTATAGTATAGTATA

TTAAGGTACCGGTTrGGACIfGAACAAGGAGSeCAAGATGATATTAAASGGTATACAGCTGTAACTACrGGGGATGGCAACTACAAA

GTAGCTGTATCATTTGCTGACCATAAGAATGAGAAGGGTCTTTATAATATrCATTTATACTACCAAGAAGCTAGTGGGACACTTGT

AGGTGTAACaSGA &amp; CTAAAJSTGACfeGTA ^ TGGA &amp; CTAATTCTTCTCAAflAACCTATTtSA &amp; AATGGTTTAGCAAAGACTGSTGTTT

ATAATATTATCSGAAGTACTGAAGTAAAAAATGAAGCTAAAATATCAftGTCAGACCCAATTTACTTTAGAAAAAGGTGACAAAATA

AATTATGATCAA3TATTGACA &lt;KAGATCSTXACCA0TGGArrrCTTACAAATCTrATAGTGGTGTTCSTCeCrATATTCCTGTGAA aaagctaactacaagtagtgaaaaagcgaaagatgaggcgactaaaccgcataactagaccata

CATTIACTAAAACTtSTAGATGTGAAAAGTCAà CCTAAAGTATCAAGTCC &amp; GTGGAATTTAATTTTCAAAAGGGTGAASAAATACAT ^ AtGAYCAAGTGTíAGíAGTAGATGGGGATCAGTSGATrTGATAÇAAGAGTATATTTTTATA

SEQ 10 NO. 4

MKKGQWDTKQSYSIjRKXKFíSlASVIIGSFIMVTSFVFADOTTSVQVWQTGTSVDAWSStíETSASSVJTSHNDS ^ ASDKTOiS

OSTATiíDIlTPrVETKPfWEKTLPEQGirr / YSWEVKm ^ SKSAPVAÍYAKKGOKVyWQVFKrKUNVKWISYKgPCGVKRYAAIE

^ ^ ΒΡ3 (^ 8ΒΤΚΑΡΤΡνΤΝδ35 ^ 0ΕΚΙΑΤ0 £ 39ΥΤΡ5ΚΚνΒνΚ »ΕΑΚνΑ8ΡΤβΡ^,¡₁ΟΚα3ΚΙΡΥΕ0ΙΙ.ΤΙΕσΚ01 «ϋ8ΪΚ8ΕΙ! Κ3νΗΚ?

K ^ &amp; VIAGK SSVBK2 KVSPQWkaimOIO.riSSBTTTGFDIl &lt;IOT KI&gt;? DH &lt;3IAAVXVPVWTEQGGaDDIXWyTAVTTG33GNYK νΑνδΡΑΜΚΜΒΚβ ΥΜΙΗ ^ ^ ^ ΥΪΟΗ 6ΤΑνενΤ ΤΚνϊνΑ ^ &lt;3ΤΗ380ΕΡΙΕΝ6ΙΑΚτανΏίΙΙΘ3τΒνΚΝΒ &amp; ΚΪ880ΤΟΡΤΙ »^ ΕίϊΒ0ΚΙ imíOVI TSOGYQWISYKSYSGVItKrrPVKXLTTSSEÍÍAfajEAlKPTSCTKLPKTGTYTPTKTVDVKSQPKVSSPVEFÍÍPQKGEKIH

YlXJVLVTOSEQWISYKSYSSIREYIEl

The nucleotide and amino acid sequences of GBS 104 in ref. 3 are SEQ ID 8777 and SEQ ID 8778. These sequences are set forth below as SEQ ID Nos. 5 and 6:

SEQ ID NO. 5th

ATGAAAAAGAG ^ ACAAAAAATATGGAGAGGGTEATCAGTTACTTTACTAATCCTGTCCCAftATTCCArrrGGTATATTGGTACAAGG

TGAMCCCAA &lt;aTACCAATCAAG £ aCTT8GAAAAGW &lt;TT8TTAAAAAAAC © 3GAGACAATC3CTAC &amp; tXATrA®3CAAAGCX! ACTT

TTGTSTTAAAAAATGACAATGATAAGTCAGAAACAAGrCACGAAACGGTAGAGGGTTCTGGAGAAGCAACCTrTGAAAACATAAAA

CCTGGAGACTACACATrAAGAaAAG &amp; AACAGCACCAATTGGTrATAAAAAAACTGATAAAACCTGGAAAGTrAAAGTTGCAGATAA

CeGAGCAACAATAATCGAGCGTATGGATGCAGATAAAGCAGAGAAAGGAAAAGAAGTÓTTGAATGCCCAAXATCCftAAATCAGCTA

IfTTATGAGGATACAAAAGAAAATTACCCArTAGTTAATGTAGAGGGrrCCAAAGrTGGTGAACAATACAAAGCATTGAATCCAATA

AATGGAAAAGATGGTCGAAGAaAGATTGCTGAAGGTTGGS-rATCAAAAAAAATTACAGGGGTCAAYGATCTCGATAAGAATAAATA

TAAAATTGAATTAACTGTTGAGGGTAAAACCACIOTTGÁACGSAAGAACTrAATCAaiCTAGATGTCGTrG ^ GCTAITAGATA attcaaatagtatgaataatgaaagagccaataattctcaaagagcattaaaagctggggaagcagtatasaa

ATTAdkTCAAATAAAGACAATAGAGTAGCTCTTGTGACATATGCCTCAACCATTTrTGA.TGGTACTGAAGCGA.CCGTATCAAAGGG

AGTTGCCGATCAAAATGGTAAAGCGCTGAATGATAGTGTATCATGGGATTATCATAAAACTACrTTTACAGCAACTACACATAATT

ACAGTrATTTAAATTTAACAAATGATGCTAACGAAGTTAATATTCTAAAGTCAAGAATTCCaAAGGAAGCGGAGCATATAAATGGG

GATCGCACGCl ^ TATCAATTTGGTGCGACATTYACTCAAAAAGCTCTAATGAA &amp; GCAAATGAAATTrTAGAGACACAAAGTTCTAA

TGCTAeAAAAAATrTrTTTTTCACGTAACTGATOGTGTCCCTACGATGICRTATGCCATAÃATTrTAArCeiTATATATCAACAT

CTTACCAAAACCAGTTTAATTCTTTTTTAAATAAAATACGAGATAGAAGTGGTATTGTCCAAGAGGATTTTATAATCAATGGTGAT

GATGAYCAAATAGTAAAAGGAGATGGAGAGAGTTTEAAACTGTTTTGeGATAiSAAAAGraCCTGTTACTGGAGGAACGACACAAGC

AGCTTATCGAGTACCXSCAAAftTCAACTCTCTGTAATGASTAATGAGGGATATGCAATTATAeTGGArAT &amp; TTT &amp; YCTCTATTGGA

GAGATTACAACTGGGTCIATCCATTTtaTCCTAAGACAAAG &amp; ÁAGTÍTCTGCAACGSAACAAATCAAAACTCATGGTGAGCCAACA

ACATTArACTTTÁATGGAAATATAAG &amp; CKTAA &amp; GGTCATGACATTTTrACTGTrGGGATTGGTSTAAACGGAâATCCTeSTGCAAC

TCCTCrrGAAGCTGAGAAATTTATGCAATCAATATCAAGTAAAACAGAAAATTATACTAATGTTGATGATACAAATAAAATTTATG

ATGAGCTAAATAAATACTTTAAAACAATrGTTGAGGAAAAACATTCTATTGTTGATGffliAATGTGACTGATOCTATGGGAeAG &amp; TG

ATTíSAATTCCAATTAAAAAATGGTCAAAGTTTTACACATOATGATTACSSTTTTGGTTSQAAATGATGSCAGTCAATTAAAAA &amp; SGG

TGTGGCTCTYGGTGGACCAAACAGTSATGGOTGAATTrTAAAAGATGTTACAGTGACTfATGATAAGACATCPCAAACCSTCA &amp; AA

TGAAigATTTSAACTXAGQAAíSTÍ CAASAÃSTASTTCTTACCTATSATGTACSTTTAAAASATAAOMTA.TÁAOTMCAAATtT -TAOATÁC ^. ^ &amp; TAATCeTaGAACGCTÃASTCCÇAAGAeTGA ÃMGAÃCCÃO.TACTÃTTÇSTSASTTeçCSAOTÇCÇÁAAATreG Tffi · T ^ ^ ^ CGTf STTTÇCSGT &amp; ttAACGATCASTAATtÁGM tókíiATiSÔGWSSTÍSAATTTATr ^ ^ ^ GTTÁATAAACACAAÃC atTcyiG TCGCÍWS8ÔAGGTÃaGTTTCtoCTrC &amp; SRtAGSAAÀASAT^,5'TrTÇT &lt;3. A &lt;3TATÀASC &amp; ÃTrréTTCCAÇAGG &lt;3ftai3T &lt;TOTTAC &amp; ^ SS ^ (^ ^ TSATGGTÁA TTTATTTrAAABCSCÍTGÍaSATG5TÃACTATAAÁTTATA GftAÃ.TÍ'ÍCAAâTCCAGA TGGCTATAtÁSASGTTAtócGAAftCCTSTTGfGÀGATTTAGAÃTTCAAAATSGAGAAGTTACSAACCTSAAAGGASATÇCAA &amp; CTAAíkAA.WcaAAT TG &lt;^ t ^ £ ^ TATCTT SGAAATeQTAAA0ATCfTA'TTAàCAACAeTC &lt;: CÁAA6GCCGACCAGGÍGTSTTTeCT MAÃCAGE3âGt ^ ^ TTGGTAC AÍXGTCTATAW'TÃ0TTróTTCTac^rrrTTATGS'PÂCT'i'AGCATrTGÍ'ferT'reCGTeST &amp; A &amp; '3i ATtô:'. · ...

SEQ ID NO. 6th

MKKnQKXWRGLSVTUilLSQIPFGILVQGETQDTITIO.GKVÍVKKTSDSATPLGKATFVLKMOlíGKSBTSlíETyEqSGEATFEfíIK.

MQKDe8SEXABG ^ mTOV »» u «KSKXKJBbTVBGKTcmiW! IBU&gt; vvvi» ii »msifflmwBrac» aai8aeBKW®Kt »a3E» c^:

ITSSKEmVAI.WyÊiaPOGTJmVSK «mDQ» (5KJUifflWSWDXHmrPAraHireS ¥ IáHZt38E «MESWXldKSRXPKEAraIise mrLYÔE ^ TFTQKALMKABEII ^ rQSSNARKXNYKYNJKXNYKYNJKXNYY

DYQJVSGDGSSPKLFbORKVPVTGGTTQAAYSTOCaKaSVMSSBGYAISSSlfrsriiYWSXlíaSWYPFDPKWSVaÃTKQIKTaaBPT

YOU_JYFÍGSIRP! O3^,j '&amp; IFTVGISVSrGDPGA'rPl, EAEKl^íMOSISSK'rE5JyTBWr) D'rHKIYDKtoHKYFKTIVEEJAJSIV £ J £ »n? DPMGEH ΐΕ? ΟηκΝσο8Ρτκηβγνυνα8ϊ) άβιωΗντντρην

SSTSHRTTIjSPiraKKamTlEOFPISKIROTREPPVX.TZSNOKKMGSVBFIKVHKDXHSESI.WSaiWOliOIBKDPâSYKOPVPSGS

DVrTKiroGKiyF} ÍQ.CaiIYKI_íYEISSJ'DGYIEVÍXr \^&gt;yTPnQííSBVT81 &lt;K &amp;!&gt; PWA! ÍXlíQIGYI_íEGSGI &lt;HLITNTPKS? PSVFP

Ι3Ι &lt;3ΤΐνΥΙΙίν58 $ Ι ^ ΙΪ »ΤΙΟ3ΡΪΙΚ» δ1 (

The nucleotide and amino acid sequences of GBS 147 in ref. 3 are SEQ ID 8525 and SEQ ID 8526. These sequences are shown below as SEQ ID Nos. 7 and 8:

SEQ ID NO. 7th

GlXKSATAAACATCRCTCAAAAAfiSQCTATETTAAftBTTAACACCTJCTAACAAUtitóTATtTrATTAÁTÚCRraGChATtAAOTGlAATSCAGAGQAG

CAASAATTAMAAACCAAQAÇCAATCACCEGTAATTGCTAATGTTOCTCAAGAgCCATCGCCATCGaTAACTACTAATACTGTTSAAAAAACATCT

GTAAÍ ^ CSeCTTClWrACTAATAaiGCGAAAGAAATGGEfGATACATCTGTAAAASATGACftAAACAGAAGATCWirrATTACAAGAOTT &amp; TCT

AAAAACCrTG) ^ ACGTCTAATITXSKSGGCTOATCTTGAAGAAQAA * rArcCCTCTRAÁOCAGaGAC &amp; ACCAACAATA7togoGAAABCAA3G23M3TAB.CA

AATGCTrCAAOTeCPATA &lt;KA £ AG.MAGTTCCCTCAGCATÀTCAAGAGSTGAAGCCAGAAAGCSA &lt;3rCATCGePrGCl^!aCTCl^,'RACTAC'C,' TMA

^ ^ TAACAAAATEACAAGCCATAACCGAAAGSaGAAAGGGAAATGTAGTAGCTATrATriSATACTíJSCTTTOATATTAACCATOATasrKCTOOTTTA fiATAGÇCCAAAAGATGftTAAGCACAGCn ^ SAAACTAAfiGATAGATAGATAGATAGATAGATAGATAGATATA

GAÇAASATrSTITrTgCACATAACTACGCCAftCAATACAGAAAajGTGGCTGATATTGÇAGCAGCTATGAAAGATCGTTATCGTTCASAAGCAAAG

AATATWCGCATOGTAC »CAa3tSGCKK) TAmTK3TAa3WWASTAAA {S7TCOWK ^ TCAATOOTCrrCWTÍJ« 3SAGG3S3CAGa3CCARAT

GÇTCAAJSTCTTAnAATOOJTATrCCAG &amp; TAAAATTaATrCGaACAAACT ^ CTaAASCATATGCrAAAGf ^ ATOACAGACGCTGTTAATCTAGGA

GCMAAAC &lt;aTTAATATOftGTATrGaAAAAACASCTGATrCTTTAATr3CTCTCAATÇATAAAGTTAAArrAGCACTTAAATrA5CTTCTaAGAAG

SGCSTTGCAGTTGTTGTGGÇTSCCGCAAATGAAGGCGCATTTaGTATOGATrATAjSCAAACCA-TTATCAACrAATCCTGACTAOGGTACGGriAAT

AGTOCaGCTACTt &lt;TOAAGATaOTTeASTeTTGCTAaCIATOAATCACTTAAAACTATCASTGASGtCGTrGAAAeRACTATTSftAGOTAAGTTA

GTTAAGTTGCCGATfGJXòAClTCTAAAGCTTTTtàACAAAíSCTAAGGCCTACGAJOTGGl ^ TTATGCCAATTATGSTGCAAAAAAAGACTiTGAAíjGT

AAQG &amp; CrTTAftAOSTAAGATTOCATTAATTGMSCGTGOTGSrCSGACrXGATrTrATGACrAAAAICACTCATGCTACAAATGCSISGTGTríSrrGGT

ATCCTA.TTTTTAACGArCAAeAaAAACOTGGAAATTTTCTAATrCCTrAeCGTGAATTACCTarGGGGATTATTAGTAJiAGTASATGGCGAtGCer

ATAAAAAATACTTCAASTCAOTTAACATTTAACCAGAGTTTTKAAGTACTTaATAGCCAAGCSTSCITATACSTATQCTGGAACAATCAASTTgGGGC tnxaCHGCTGAAGSAGeMTCAAGCCKaTffrAACAeClTCTGGTATATCATATCATATCATATCATATCATACTA

ACAAGtATQaCTTCACCAGATGTrGCAGSMTAATGACAATCCTrCAAAGTCATrTGGCTGAGAAATAYAAAGSGATÍftftTTTAGATTCTAAAAAA

TrGCTAGAATTCIVfAAAAA ^ TCCTCATGASCTCa.BCAAeAGCATTATATAGTGSAjaAGSATAASGCGTTTTATTCACCACGTCAOCAAGGTGCA

GSTíGAGTTGATCCTGftAaAAGCTATCCAAGCrCAATATTATATrACTSGAAJlCSATGSCAAAGCTAAAATTAATC ^ CAAACGAATGQGAGATAAA

TTTGCCCTTAAACCAcaAGCCTTGCTAGATACTAATTGGCAGAAAGTAATTCTTCGTCSATAIAGAAACACM.GTTCGAIT-rACTATTOKrGCrSST

CAArrtaGTCaGaAAUUU «aAAa ^ TGSCAAAT« nTATrrCTlAGAaEK3TTTmiACGTTTEAAAGAaaCCTAOGATOSTAATCW3aAGTTA

ATGSnTAWCCTTrTGTAGGATTTAATCGTGATTTTGCSAACTTACMGCACTrGAAACACCGKrTTATAAGACGOTTTCTAAAGeTAaTCTCTAC

TATAAACCAÁATt ^ TACAACTCXTAAA ^ CCAATTSaAGTACAATCAATCisGCrCCrrrrGAAAGCAACAACTATACTwCCTTaTTAACAtSkATCA

GOTrcTTGGQSCTATGtTESATTATCTCAAAAATMyrGGGGAGrTASAATTAGCACCGSAGASTCCAAA &amp; AGAAnATTTrAGOAACTTrrGAGAAT

AASGTTACATATTAAACAATTÇATCNT ^ Tq®Uy «? AGATCCASCQAATAATCX ^ ATTTTSCCATTrCTCCAA &amp; TAAACA3XK3ftSATO &lt;3eSftC (SBA)

ATCACTCCCCAatJCAAOTTCTTAAaAAATESTTAGAGATTTCTSCTCAACSTTCTAGATCAAAATGGAAATTYTATTGaCAAACTAAGGTTTTA

CCATCTTATCGTAAAAA7 “rT'2CATAATASTCGAAASCAAAGTGATGGTCftTTATCGTATOGAB3CrGT^,3'CAQTGSAGTGGrrTA.A '? A? SGSftTCSC

AAAGTIGTAGCAGATQOTTTTTATACrTKrCacrrACGTIACACACCAGTAGCfiOAAGGAQCAÁATAGTCfeGGAGTCAGACTtTiAAINACAAGTA

AGTACTAAGraCCAAATCTrCCTTCACSAGCTCAeTr-TSATGAAACTAATCGAACATrAASCTTAGCaTGCCTAAGSAAAGTAGTTATetTCCT

ACAI &amp; TCGTTJ% CÁTTASTTITATCrCATOriOTAAftAGATC5 &amp; A &lt;SAATATGGGÇTSTS &amp; CPTCTTACCATrATTTCCftTATBQATCAAGAA &lt;3QT

AAAGTGACSCTTCCTAAASCGSTTAAGATAGGAGAGRGTQAGGTTGCGCSTAGACCCTAAQGCCTTGACftCTTGITGrGâAAeATAAAÔCTGjTAAT

TTCGCAACGGTAAAATrGTCTCATCTCTTGAATAASGCAGTAGTATCAGSaAAASAAAaCaCrATAGTAAlTTCTAACAGTTrCAAATArrrTaAT

AACTTGAAAAAAGAASXTATGTTTATTlOTAAAAAAGMAAAGTAGTAAACAAGAATCTAGAASAATAATATTAGTTAAGCCGCíyiACTACASTT

ACTACTCAATCATTeTCTAAACAftATAACTASATCAGGAAATGAGAIAGTCCTCACn ^ TACAAACAATAATASTAGCAGAGTAGCTAAGATCATA

TCACCEASACATAA ^ C ^ TTCTGWAACCATACCrrACCrAOTACATGAGATAGAGCAACGAATeQTCTATTrGTTGGTACTTTGSCATTSTTA

TGTÍffiTTTAGTOCTTTATTTGAAACCCAAAAAGACTAAAATATAT.STAAA

SEQ »0 NO, 8 \ T&gt; KaHSOAIX, KXzTLITOSl W8eSCVWASBQ ^ KNQ ^ SWIW / A &lt;K3W ^ VTtin / KK'rSS? RARSASHTAK®tQBTS \ T &lt;i! InKTSDBl₍t.SEl_íS rattDTSBLGAOLEEEyP3KPETTÍWKESffW ^^ STA3AQ? WPSAYEEVkP3BKSai &lt;AVLD-ESKIT5 «, OAITQ} FIGS33WW! tBTGFDÍHtcaiFRL

<img file="PT1551357E_D0001.tif" />

δΡΑΙδΕσΓΙ ^ ΑεΥ ^ ΙΚΤίεΒνν ^ ΙΕΰΜ.νΚΙ, ΡίνΤδΚΡίΕβίάΚΑΪΟννΥΑΝΥαΛΚΝΟΡΒβΚΟΡΚδΚΙΑΕΙΕββΟβωΟΙΤΚΪΪΗΑτΜΑαννδ

IVIWC! 2BKRG «Fl&gt; IPYREl.PVGlISKVDGB8 * i» rt'aS (JI_JTPS (GSFB \ GroS) GG SMI, EeSSWGVTAEGA'IKPSV^,ÍASí3-FEj.ySS7'n®QYQTMSe

TSKAS {^:HVAGX «T« 1&gt; 0Sf! IAEKYk (3MN'W-'iSKKbL-El, SS®IH &lt;SSATAX »ySESBKAFySPÍlí» C »G'-^r'/3ftEXAH3A(3Yyrr®íweight3K3w:rSi.KBW3OS

ΓΟΙΊνΤΙΒΚϋ \ 'Κ2 · «ΕΜΪ (3Α.» ΝΑτ2 £ 2ν8ΚΟΚ? ΑΕΚί^!35? Η »0Κν'ΙΙ« ηΚΕτ5νκΓΤΪΒΛ? (35^!8ΟίχΚΕΟΜΜ} ΟΥϊΊ. · Εδί''νκΡΚΕΑΚΙ&gt; 3ΜΟΕ ^

KVB »KTIBI.I * BROASNNt&gt; yFAISPKKOG» BOBITPí '!' Fl.R «VKniSAGVIí5QííSí!! VXSQSKV4_ípeyRKBP) »NPK, 2SW5ffySMDALQWSf5LOKa3

ΚννΑΠΰΡΪΤϊΚΕΚϊΤΡνΑΕαΑΝ5ϊ (Ε £ ΕΡΚν ^ ν3τΚ3ΡΝΙ / Ρ3ΗΑ0Ρ »ΕΤ» »Γ13ΙΑΜΡΪίΕ33ΎνΡΤΎΤ11.Ι3Ενΐ.8« ννΚβΕεΥΟίίΒα'δΥΚϊΡΗΐηΟ3; 3

KVTbPia ^&gt; KtGESBVAVDPKAVÍI.VVEDKRGiIFATVKI.SDbE_J8K &amp; WSEKi5NaiVISSSEàfP £ 3NI.KKSPMFjaf; ifEKVl'Í &lt;»í!_JEEI: LV&gt; tI&gt; O'TTV

Ί ^ ΟΒΕ «κεΐ1ϊ; 5ΟΜΒκνί₁ϊ3ΤΒ5 «Ι3ί; κνΑΚίί8ΡΚ · 3Κδ £&gt; εν!_&lt;· ΗΤΕΡ8'ϊ5ϋΡΑΪ1ϊδΙ₎? νθ · ΠΛίΛ, 381_ι1, ΐ_ί· ΪυΚΡΚΚΤΚϊΙΚ3Κ

The nucleotide and amino acid sequences of GBS 173 in Ref. 3 are SEQ ID 8787 and ID SEQ 8788. These sequences are shown below as SEQ ID Nos. 9 and 10:

SEQ ID NO.9

ATGMiACSW ^ TACTCTATTCTEAATACGCTCaiCGGrrTTAAOGTrAGa.OCTSCAATGAS.TACrAGCB.GTATCTATCCTAATAtyrACTGAGACA

AGTGCTOCAOrAGTrcCTBCTAaUUSrACTATGGTTCW ^ CTMTGA ^ GTAATCCTAKasCAAAATTTGTATCAaSATCJi ^ ACAftTCTGTAATA

CfGTC ^ erAMACC ^ GATAArrCraaKaxrOTrAACIGTrr ^ CACGCCyVATCATATrTCAecrCCAGATGCTTTAftAAACftSCrcAATCAAGT

CCTBTC53Ta »» GW ^ CTTCTOOT «tmAACTGASGAGACrTaCAaA. ^ AftftGAIWrCRR) 3aTTT» SCCAftCATGGTaAGJ »®rQGTCAACa? T, ACT? ®TaAGaAACTCCOTAATATTAGCATATCATATCATATCATATCATATCATATCATACATATTA.TTATA.TATA^,n'ACrACTAG «? GOC5lAC» .AGCTA'ET

GAAGAeGCTAGAAAACrTAAAGATACCAATa ^ GCCGríTrrftGGTSTTCCCTTGTTAC-TCAAGGGSITWjaGC &amp; CAGTATTÍSAAtSGrGGTGAAACC

AATAAlWCrnSATCTATecASATQBftBAAAWSGCACftieTTt ^ CAWAeCTAWrauUWAaTATSW ^ lTraA ^ TWArWWrTTTffSGftCft '.

Aa ^ CTITCOAGWAT ^ GSTGGCCTAAWMCASaTTCTAAATrATAISSSGlWAACeaTAATCCrnXSGRTCTrGCTCAWaxSCTOGTCSJC

TCTTCTGSTGGRAGTQCAGCftOCCATTGCTftSaSGAArSAGGCCARrYGCTAGCSGTftGTOATaCTaGTGarTCTATCCGTATTCCATCTTCTrGG

J ^ aGCTTGraTÃGGTTTAftftACÃ CAaiaAGGATraGIGAGTAATaAAftAeOC ^ ftTTCGTATAGTACACKaGTPCaTTrTCCRTaAraftaGTCA

TCTAGSSAO3CAG.WkC ^ WATrftA &lt;^ Upto? TAAAaAAAAGCC®'t3tAACffiCTAaT * TCAm ^ AATeATOTA_í\ Aft'rCT'fTAr.CfiA^,rTGCn'ATÃCT

TrGAÃATCACCAAlGGSAACACMa ^ AGTaAAGATGCTAftAAACGCTMTAXSGACAACCTCACTTTOTTAAeAAAftCSAGGArfCAAAarAACyv

OASATAGACTT * CCftWTOATS5T »CaWCATOUTGC £ H ^ TTATOaW! OT'eGCTaTTGOtaTGSGAC5e» SCTlTrrT &lt;^ C ^ TraAAAftSGAC

ΤτΑΑΑΑΑΑΑσΑΊ «ΪΓη ^ 'ΑΧΪΑΜβΑΑΟΑεΰΤ · £ ^ Κ: 0ΤΑΤΙΑα ^ Ύ30Β &lt;ΛβΤΓΕΑΤ'3'Γ1 · ΑΪΪΪ · Ατ &lt;» ΑΑΑ ·' αΐαΑ '£ ΑΑ3βστβΑΑ &lt;.Τ1'ΑΑβΑΑΑ

TeyATTAT «ÍAAGCCCAAAAACAraTC; GATaA7TA-rCÕTAAGGCAATGGA ^ GCTTWC» AâCftATrTCCTArtTTCr? A'i'CGCCAACGACCt3CAiGTTTAaCCCCTCTAAATACRSATCCAGGATATAGTAGTAGATA

GTCTTrAAWGaaaKKGAGOTATGTTCOGTAGAAGACCra ^ AWa ^ MTPGCrAATAl ^ CAÍWACTCCCAGCTATÇASTATCCCCACWAC

OATGGTrTTAATG-rrAASTGGCAAAOAATAATftGATAAAGATyrGIAACCATCTACrGeCCTAATACAGCCTACTBACrCCCTCTTEAAftGCTCAT

TUATCATTAGTAAATTOAGAAaAAAATTCACAAtSTTOCrcaAtSTATCrATCTCTAAAAAATGSATSA &amp; ATCGTCrG-I-TAAAAATAAAC.TCCGrA

ATGGCATATCAAAAAGCACTTCCTrAMAa ^ TSATACAGAATCSAGCCTATirrCCAGTTTTAGirAíyrflACCCTrTTATTAGCrTSTTTrSGCTTT

GTAACAAAAAAOAATGACAAAAGT

SEQ ID NO, 10

KKRKYTII ^ fTVrvl ^ IAAAM ^ SIWOT ^ SASWPTTNTTVQTKOSNPTAKFVSBSOOSyiOQVKPMJSMXirrWrOTAPIA.KrrQSS »ννΕ5η? 3ΪΚίίΤΕΕΤΪΚΟΚΟ35Β1ΛΜ · Γ.^,ΚΕί3 &lt;3 '6ΕΕ3νϊ' Μ 'ΙΙΑΚΕίίΡΒ] 3®.νΐ'ΤΊ'ΚΚΟΕΑΙΕΕΚΚΚΙΑΤ5ΤΗΟΡΕΒθνΡΕΙ &lt;νΚ0Εα! Κ3Κ (5Βδ'ϊ' BKGíjIYAWSKISTFDBSY '/ i KKYKDLGFI ILGOTNEPETOBRiílTOSiajyGLWtNPímLSSNAGGBBGGaAS.AIASGWrPIASGSOAGOS KXPSSW TSBVGLfCPTaGl.VSN5SXPOSYSTAVHEPbTKBBRa AETU.TO.KKS ÍXy.ftVSVKCMtíSU&gt; iAYTLKSm. yCEVBÇEAKN &amp; IMDNVTFLRKjGFKUT BIDM¹IUGRAl, il3BYS^,NAII »! OGAFCTISií! 3Ma &lt;: KGP'A^r'KEDTOprTWA \ iBVIYÇ' S! 3S! AK £_JKKSÍMEAQKBtCfDYRS, WlEKW [KQFPXFASPT'ra BtAPUJT »PYVTBBS&gt; KRAlYf» IBKI &lt;SOESRlX, raiHOiSPI ') LKRTPK.'C! JSl®frGBPAtS'JPTYLSSSG_fPIGTM!_J«A®U5YOMVl.IKE'A'IFPBKH HSEMWJWCRilBKEVKPSTGUIOFríJSlíFKaitóSLVaLBBRSQVTOVSlSKíOíMKSStfKBXPSWMAYQIai ^ irroSOTBSSLSPVIjWTLUKUGPI

The nucleotide and amino acid sequences of GBS 276 in

Ref. 3 are SEQ ID 8941 and SEQ ID 8942. These sequences are set forth below as SEQ ID Nos. 11 and 12:

SEQ ID NO: 11

TTGCGTAAAAAAC ^ AAACTACCAn ^ GATAM.t ^ GCCATTGaSCTTATATCtAOSAaCMCT ^ CrUAATGCACAATCACiACATTAAAGCAAAT

ACTGTGACAGAAGACACTCCTGCTACCGAACAAGCCGTAGAACCCCCACAACCAATAGCft.GTTÍ'CTiSA! 3GAATCACGATCATCAAa:) AAACTAAA

ACCTGACAAACKÍCrAGTGATGTÍvGtWGAAACAGTAGÍXGATGACGCTAATGATCTAGCCCCTOiAGCTCCTGCrAAAACTGCTGATACSCCAGCA

ACCTCAAAAGCGACTATTAGGGATTTGAACGACCerTCTGATGTCAAAACCCTGCAGGAAAAASCAGGCAAGGGAGCTGGGACCG-rTSTTGCAGTG

AnX ^ TGCXGCTTrrQATTLAAAATCATOAAGCSTGGCGCTTAACSMffiCAAAACTARAGaCCirTRCCBATCSiAftAeAAAATCTTGSRAAAGCTAAR

AAASftfiCACGGTATWCCIATGSCGAGTGGGTCAATGATAAGGTTGCTTATrACCACGACTATftGitesAGATGOTAAAftACGCTGTrSATCAAGfiA

CACGGCACftCftC ^ TOiGGGATCrTGTCafieAAATSCrtxarCTGAAATQAAAGPACX ^ ACCOCCTaJ3AAGGTGCGATGCCTeAGGCrC3SATrG

CTMTGATOCGTCTC &amp; AAATTGTAAATG ^ CTAGCR &amp; ACTATGCTCGTAACTACGCTCAAGCTATC &amp; GAGGATTI ^ GAACYTSÔI ^ GCTAAGGTG

ATTAATATGAGCTTrGGTAATGCTeCACTAGCrrACG-CCAACC3? TCCAGAa3AAACCAAftA »AGCCT! 'ReACrATGCCAAATCAAAAC-GTeTT'AaC

ATTCTaACGrCAGCTGGTAATGATAGTAQCTTTGGGGGGCAAGCCÇCGTCTACCTCTAGCASATCA-fOCTGAlTATGGGKKRGGTTGGGACACCTSCA acGGCAGATTraACATTQACAGTTeCTTCTTAC &amp; GCCCAGATGATACATAGACTACTACTA

ATGCerGTTA'mCAACAAACa5W? RGftGCCM ».C» AGaCTTACGACTATGCOTATGCTAATGGTGGj'AGGAAAGAGGATGA'iTOTAAGGATCS^rfC

SAASGTAACSATTSCeCTTATTGAftCaTGGCGATÍTTGftTTCACAAGATAAGftTrGCAAACGCTAAAAAAGCTGGTGGTGrAGGGGTClTGATCTftT

GACAATCMaACA ^ XÍOCTTCCGaATrGAArrGCCAAATG-rrGACCAGA-rGCCTGCGGCCTrTATCAGTCGAAnAGACGGTOTCTTATTAAftAGAC

AATCCCCCAAAAACCATT &amp; CCTTCAATÍJCGACACGIAAGGTAi-TGCIMACAGCAAGTSGCACCAAACTAAGCCGCTTCTCAAGCTGGGGTCTGACA

QCTGACSeCftATATtAAACC (^ TAWSCaqCA &lt;XCGGC \ 3 «\ GA1! ATrFroTCRTCAGT6qCraACaACAACTATGCCftRACrrTCrGGAACT? M3T

ATGTCTSGACCKITCGTAGCGGGTATCATGGgaCtGWGCAAAAGCAATATGAGACACAGTAÍCCTGATATSACACCA ^ CAGAGCGTCTTGATTTA

GCTAAaAAAGTArTOATGASCTCAX ^ CTGCCCfATATGATGAASATGAAAAAtSCITArriTTCrCCTCGCCAAGAGCiGAGCAGGfteeAGTCKAT • GCTAAABAAGCTrCAGCAGCAACGATGTATOTAGATACATAGATACATAGATACATAGATACATAGATACATACTAG

îG? AACAGTTCACAACAAATCTGATAAACCÍiiAlíAGTTe'rATrACCAAGTAACTGTTCAAACiGAT7sAAGTAGATt5CAAAS, CAC'tTi'GGCTTG

GffrCCaA »&lt;K» TTOTATGAGACATCftTG! K3UU «^ TCftCAATrCCAGCC» ATAGCAGCA »ACABSTraECGrrcC» ATCS3A'P3CX »GTa5ATrT

AGTI ^ t ^ eiTCCl ^ GCCaAÃATfMAAAMGGCTAmtTrrAGAAGCTITTGTirGSTraaiACÀAGATCCTACAAAAGAAGAGCTTATCAGCATT

CfATA'3'A'n'GG^,3^;TTCCC; AGG'I'GATT'rTSGCAATCTGTCAeCCTTASAAAAACCAATCTATGKrAGC &amp; AAC ^ CGGTAC3C ».acrACÍ'A'rCA^-SAS.GCA

AATAffJXiMGCCAARGACCMTOAGATGGUIAlWATTACfiGTTTTACaCTCTaAAAAATAACTTT &amp; CAGCACTTACCACAGAGTOTAACCCA-ree

ACGATIAACTAAAGCTGTCSASaAAGGGaiTOAAAACATAGAGGATATCGAATCTTCAGAGATCACAG / VIACCATTITTGCAGGTACTTTTOCAAAA

C »AGA &lt;^ TOAWWCCACraCTATAT (XACCGT &lt;aa ^ AATCSCAAJW: CATATGCTGOeATCTCTCCAAATGGGaAC1GTAACaaAGATTATGTC

C ^ TTCCAAGfiTACTTTCrrGCGTMTCCTMAMCCrKnWCTCjAAGTCTTGGACAAAGAAGGAAAIirrGTTTOGACAftGIGAGGTAACCGAa

CAAGTTGTIAAAAACTACAACAATGACTTGGCAAi3CACACTIOGTTCAACCCG3TtlSAAAAAACC3CGrR3GGACQGTAAW3ATAAA &lt;3ACGSCAAA

BTrGTTGCTAAOGGAACCrACftCCTATCeTGTTCGCrAíaCSCÇTOTTAGCrCAíMTGCAAAAGAACA &amp; CIAACTGATrrTGRTGTiarrGTAGAC

ARACGAÇAÇCTGAAGTCGÇASCATCíyJCAACATTCTCAACftC-AAGATAGTCGTfTaACACTTGCATCTAAACCAAAftACCAGÇCAACGG-rrTAC

CWeAGOSYATIfiC CTTATATGGATGACSATCTCCCAACAACAGAGTATA-rTCTCeAAATSAAG.AIGGTACCWTserCITCCTGAAGAG

GCTíSAAAC ^ TGGMGGCCCTAC-SXSTTCCATTG.ViAATGTCAaACTTTACTTATGTTaTrGSAGA-rAJXXjCroGTAACATCACTTATACACCAGTG

ACrAAGCTA'i'rGGAtKGCCftCTCTAATAA3CCAGAACAAGAC ^ STTCAGATCAAGCACC3iGzVAAGAAACCAGAAGCTAAACCAGAACAAeACXKIT

TCA ^ TCRAACAOCRC »TflRAAAftARAGAAACTAAAC &lt;MAAAAAGATftSrrCftSSTCftAaCACC &amp; fi5TOAAACrcc1'CftAAAIU38TCAATC't'TCT

CGTACTCTAGAGAAACCarClT.'CTAAGCGTGCTrrAGCTCAAAAGCATCMCAAGAaATCAeTTftCCAACGACTAATaACAAGaATACAAATCGT

TTACATCTCCTTAAGSTAGTTATGACGACTTTCrrCrfSaGA

SEQ1DNO, 12

Κ8Κ! «? Χ1ιϊ^ίΡΟϊα34ΙΜιΣ8Τ3ΙΙ (υϊΑΟ3ΟΙΚδΝΤνΤΒΕίΤΡΑΤΒ &lt;3Αν0ΡΡζϊΡΧΑνδΕΕ5Η53ΚΕΤΚΤ3 &lt;3ΤΙ&gt; δΙ) νβΕΤνΑηΠΑ! Ίφ &amp; ΑΚ}

Ai'Aíà'AOl^,PÁ7SKftTrílELSaPSSVKTI »QEKASKSA6TWAViaAGFDKSHEAWRI, 'rDKTKAK ¥ CSKE {S₁EKAKKEHaiTyGSWVH

DIP7AYYHCySKOGKaAVD! 2BHGTHVSGILSGSA''SEH5CEPYELKSAMPEAQhI.li&gt;! RVEIWGlAOyARKyAQ?₁.IROAWLGAíWII3 '

WWWtitle «a« t ^ ffll ^ ft »^» imiVT ^ ® ^ SPGGt®W ^ hMfflCmW ^ AÃ ^ K »WMygPOKQhTETATVK

TDDHQD! ®H&gt; VlSTKRPEPBKÃYDYA ¥ M !! KGTKEDOFKIIVEGKIALiERGDIDFKIíKIAifAKKAGAVGVI.IYQKQDKGFPSEIiPEV

0ΟΗΡΑΑΡΪΕΚΚΰαύΛ «Β.'5ΒΡΚΉΤΡΐΙΑΤϊ&gt; Κν) 4ΡΐΆδεΤί5Χ3ΚΡ38« 3Ι,^ιΕ) 6Ε [ΙΚΡΟΙΑΑΡ09ΏΪΕ33νΑΗΙ · ίϊςΥΑί ^ 3Ώτ3 «3ΑΡ ίν &amp; 0ϊ! &lt;50Ι₁1, β {«ΪΥΕϊΟΥΡ5Κ'1'Ρ3Ε8Ι₎ΒΙ₁ΑΚΚ'7Ι ^ β5ΑΤΑΙ.ΥϋΕΕεΚΑΥΡεΡΚΟδΟΆ &amp; ^ νΏΑΚΚΑ3ΑΑΤΜΠίΤΟΚΙ) Ι · ίτ83ΧνΗΪ »ν

8ΩΚΡΕντντνΗΪΠί3βΚΡ0Ε ^ ΥΥΟ \ · 'Τ · \' · ςιΤΒΚνηΐ3ΚΗΡΑΙΑΡΚΑΪ, ΪΕΤ3Κζ} ΚΧΤΧΡΑΜ38Κρνη '· ΡΙΟΑΕΚΡ £ ΧΓ) ΕΪ_ΙΑΟΜΚ1ίδϊΡΪ, Ε5

FVRPI ^ FSSmiNsrmSPSCSDPSínjSaiEKPiníSKDGSSSXBSÃMSaAKDQIítJSCíGbQPXAIKKSFTAL.TTESEiPWTIIKAV

KESVEí41EO3: ESSSXTETIPAGTFAP32DDDSIirYIHRHAHGKPYAAiSÍBSDÍ3KIDYVQWrPI_í8aAta '4VAEVLDlíEGíVVi'í'íS

ΞΧ^&gt;ΐΕδνν81β1Ιί®ΙΑδ · Πίσ3^,ΠίΡΚΕί'Κ «Ι36ΚΙ&gt; ίΦβΚννΑΚβΊΎ^,ΓΥΚνΕΥΤΡΪ803 &amp; ΚΕί3ΗΤΟΡΒνΐνβΚ · Π'ΡΕνΑτ3ΑΤΡ8ϊ3η3Ε

1.1ΊώδΚϊ&gt; Κ'ί3ΟΡνΥΗΕΚΙΑΥΤΪΚΒΕΣ&gt; Ι_ίΡΤΓΕΥΙδΡ5ίΕΪΧ3'ΓΡΤ1, ΡΡΕΑΕ'ΓΗΕ «ΑτνΡΕΚΜδ» ΡΤΥ · 7νΕΒΜΑβίίΓΤΥΤΡνΤΚΤΕΕ3Ηά írKPE: QS5G.'3E &lt;eAPKKKPEA] íi^;EDSGC7PDKKKETKPE®®SGQTPGKT.PQKGO3SR'rbt3KRSSKI 'UAl'KASTRCQLP'fTÍDK' T

ΝκΐίήΐίίύκυνΜττρρ ^ ε

The nucleotide and amino acid sequences of GBS 305 in Ref. 3 is SEQ ID 207 and SEQ ID 208. These sequences are set forth below as SEQ ID Nos. 13 and 14:

SEQ 10 NO. 13

AeSW'Q7TA0CTAA6TrAeGSGCftS.'i'AGTSACASTrÂATGATG'3eaSACCAT'n'eATGAAftATCCAACAGCACAQTC * ITeTF0G

AAGAGGOTAlTrAA &amp; ST8GrrlCTeGTAeTCATCCTTTAeAAWmíAGaTOA »ATM1 ^ TTAC &amp; TSAWS6AA &amp; TCCftGSAATA

CSra &amp; TAACAATCCTA ^ GGTCAAAAAAGCATTASAAAACAAATCCCTerfTTGACTGAAGTCJGAATIAaGATACTTiffeASA

ATCTCAÔCTAATASGÍATTACASGCTCTAACISGGAAAACGACAACGAeAACGATGATTGCAGAAOTGTIAAATSCTGBAGSTGAG »

GASGTTTGTTAGCrGGGAATATCGGCTTTCCTGCTAGTSAROTTQTTCAGGCTtJCSAATGATAAAGAT &amp; CTCTASTTATGGAATTA

TCAAGTTTTCAGCTAATGSGAGTTASSGAATTTCGTCCTCATATTGCAGTAATTACTAATTTAATGCCAACTCATTrASATTAICCA

TtASGTCTTTTGAA ^ TTAySTTGCTGCAAAATGGSATATCCSaAATCAAATSTCTTCArCTGATTrTTTGGTACTrAATTTTAATC

AAGGTATTTCTAAAGAGTÍAGCTAiJlACTACTAAAGCAACAATCGTTCCTfTCTCTACTACCGMAAAGTrGATGCTGCTrACGTA

CAfiGACAAGCAACTTrTCrATAAAGGGeAGAATAT-rATGTCAGTAtSATGACATTSGTSTCCCAGGAAGCCI-EAACGTAaAGAA-rGC

TCTAGCAACTATTGC®3TTCCTAAACTGOCTQGTATCAGTAATCAAaTIATTAC3AGAAACTTTAAGCAA7!? TTGaA (3GTaTTAAAC

ACCGCrrGCAATCACTCGGTAAGGTSCATGGTATTAGTTTCTATAACSACAGCAAaTCAACTAATATATTtJGCAACTCAAAAAGCA

TrATCTSGCTTTGATAATACTSAAGTTATCCTAATTGCAGSAGGTCTTSATCGCGGTÃATSAGTTTGATÍSAATTaATACeAeATAT

CACraQACTTAAACATATgGTTGTTTrAQGGSAATCSGIATCrCSAGTSAfiACGTGCTGCACAAAAAGCAGGAGTAACrTATAGCG

ATGCTTTAGATOrTAeAGATGCGGTACAAAASCTTATGASGTGGACCAACAGCJGCGArGTTATCTTGCT ^ ​​AGTCCTGCA &amp; ATCCA • ICATSGGAeATGTATA &amp; SAATTTCGAAGTCCSTSGTGATGAATTCTATTAATAATAaATAATA

SEQID NO. 14th

KGRyMKÍ: iVFBínCKVi_JVLGIAi? SG: 3.-V?, R '_J! '. A: \ I.GAi: VT' /? FfiGK^lFDEíre^,T.AQSl_iiEaGi: &lt;VVO33KÍ^,L-SLLK3DÍ^;'C'!: KIjaí'PGI

PYKHPKVKKAÚEKQIPVl.TEVBLAYl.VSESOLlGiyGSSGKTTTrTMIKEVlílAGGQRflArAGínGPPASEVVQAANDKSTLVMSI.

ssyoi «GVKjmíraAviTWímu» H &lt;fôpsOTVAwmçíwss £ nFLvi «F! s ^ sKEumímTJWFSTrsxvDGAYV

QOKCAPyKSSW-iSVCDIGVPSSHKVEKALATIAVAKLAGISiQVIRETLSSFGGVKHRAQSAGCTHGISFyKDSKILTQKA ω υ ^ΤΚ «ΚΉΉ «ΑΑΑυΤΧΤΧΤΧΚΚΤΧΚΤΧΚΤΧΚ

SWOMX ^ BVaSDEPIDTSESIiRGS

The nucleotide and amino acid sequences of GBS 313 in Ref. 3 are SEQ ID 4089 and ID SEQ 4090. These sequences are shown as SEQ ID No. 15 and 16 below:

SEQ fD NO. 15

ΑΓ®ΑΆεστΑΤΓβίΏΐ3? ΤτΓΑΑετΑστοετοσΤβΑεχ εεσΓδ0ΤΑτβΑΑ® ^ £ 3 'ίΓΑταε6ΤδίΑ6ηΐ τχ ^ ^ ΑΑΑβΕΣ! Μ.τϊτσΓΒΑΑ0 &lt;3ϊΑΤ3 &lt;5AAtSTTACBeCÃTCaACCRAGGTTACTATGCnATQOTGACA (AK3 (^ T &amp; TTTl'CCCTTTGGA'rGCTUlTrCrGTTõGGGft'EACTATCABCCQTGÍSA

GGMCGTTTTTACG'ri'ÇAGOACCTTATCCrGAAaTO3OTG. ^ CTTGAAGGTCAGCTTAAAGS3A'I? GAAÇAGCn'AAAAACCÍ3TATrGAAGGT

SICACTftGTTATCGGTCSSTiSATaGTTOTTATCATSaTGCTàTGCGTCTAACTGASCACfiCT-rTCCCAaCTGTTSSTTKSCCGGTACAATTGATAAC (^ TAWSTTtKCACmCTATACrAWSSrrmACACaCgCGAtCaTTCTaCTGTCaCTa

AACCGTACTTTTGTTSTTC ^ GGTrATTrSSAAGAAATGCAGGAGRTATCSCTrCJrTrGGTCAGGTATaSCTGCAGWSWAfiATCAAATTATreTTCCT

GAA®AGAt ^ CAATATrGATSAAGTTG7CT&gt; 3AAATGTra.GAGCTGGC7ATGCAGC3'GGTAAACATGACCAaA'rCATCGTCCTTi3CAGAAGGT! 3TT

ATSAOTGaTGATGAeTTTGCASAAftCftATQAAftGCAGCAGGAGftCaATAGGGATCTTCGTGTGAÇGAATTTAGGAGATCTGCrCCGTGGTGGTAGT

CCGACG®: TC ^ GATCGT®K ^ A3CATCrCGTA «^ AGC &lt;^ ACSKní? RTCAATT &lt;mGABAeAAOeTOSTQGTG®fTO« 3CCGITGGITGtCCAC

MO ^ QWWTGGTTGAj ^ ^ ^ CCAAOTlTAa ^ WiGCASAAGAÃGOTSCTriSWCASCITE &amp; CyGATeAAGÔAA &amp; ftTCffnV ^ TÁTAATCÇG

CATAAAGCGtSACCrrCGCl-rGGCAGCftCrrAATCGTSACCTTGCCAACCftAAaTACTAAft

SEQ ID NO. 16 {• «ΙΑ'βίΤ33αε · ΑΪ&gt; αΜ} ΑΑ1ΚΑ \ '\ ΦΧΑΪ8Ε &lt;3Κε ·« β1ΝΟβΥΎ &lt;ΪΜνΤΟ £ 3ΙΡΡυίΑΒί5ν0ΟΤ3ίίΡ, · 3ϋΤΡ ^ ΒδΑΚ * ϊΡδΓΖ_ΐΞΑΕαθΙιΚ) ί3ίΕΏί₎: &lt;ΚΗβΙΕΟ

WVIGGOGSYSGAMSLTEHGFPAVGLPGTOWI ^ ayTIGSOTAVATAVESi.ÇiíL.SITESASHSSTPWEVKSRSIAGMALKSGIAAGACQirvp

«Δ «8ίΛΦΑ6 ¥ ΑΚβΚΗΗ0Ι1^,ΛιΑΕσΐΛ433η! ΪΓΑ! ΣΜΚΑΑΰηϋ3εΜίνΤΚί.3Η1, ί.ΚΟ33ΐηΑΚύΑνΧΑ3Κ »5ΑΪΑνοΐ.Ι.Κ8ί3Αβ5ίΑνβνΗ

KiSHVESPIieiABBSAI ^ STITDEGKtWMPKKAESiKUAAXiKCIANQSSR

The nucleotide and amino acid sequences of GBS 322 in

Ref. 3 are SEQ ID 8539 and SEQ ID 8540. These sequences are set forth below as SEQ ID Nos. 17 and 18:

SEQUED HO. 17

C ^ rftCTOTTCAGA &lt;3GTAAftGGCT3ATTTÓGTAAAGCAAi3AC ^ rAAAT0AK? ATÁTÓTTOTaAftATATC ^ T ^ TACACTAAGCGTTATi: TCAGAA qCAATGTGAATTGATftTS ^ TG? CrrAGCAAA ^ TAGAGAAC ^ TACAGAAC ^TA

CAGAfti ^ Gl ^ TAClOtX: &amp; CTrCAA'iY&gt; &amp; A &amp; ATA &lt;yVAAEX ^ CCAGCAAC &amp; AAT ^

TCTTC ^ C ^ CCAtX ^ W ^ TCAAAAí ^ GTATrAGCAí ^ CAG &lt;^ GCTGTrAGTeAAGCAGCIAATGAACAGGTArC ^ CAG ^ OCTG7G ^ τσοΑττΛΟττο ^ ΑΑΰΑΑΰί ^^ττΑΑτΑτΑΑ ^ ση '

GCC ^ CWAMC ^ CC ^ ÒerCCA ^ AÚCrZv \ AGTAGCACCGOTAftether ^ 5 &lt;^ GGGa ^ Ae2X3GGAA &lt;? ReTTAAAGTAGTCAerCCTAAAGTA

GAAACTGGTCCArCACGAGà ^ ATGTATrAGÒ ^ r ^ CAG ^ TCCTGTGACT7K &lt;^ CrTCACC ^ CTACAGAC ^ GT / VkGTTACAAÒCC ^ CTí3AAG'ri '

AA (&gt; GCGTTC^fCGGTAGCACAAA. ^ GCrCC ^ CAGCAACACL ^ TAGCACRAC ^ GCrTCAAC ^ CAAA ^ GCi ^ AàCTGCAGATCCTÍ3AAAArGCÀ • &lt;3S83CrCCWX ^ C ^ &amp; TTGCftGC ^ ATTA ^ CTAATC ^ GCLACrrG ^ TAATAAÁGTTCA ^ CTACT ^ ACAa ^ A ^ ATGGCACCAAAT

AA ^^ CATATGrrATCRAGe ^ CAAAAGTTÍTAACATAÇÃO ^ ACA ^ f ^ mATGGACCTG ^ rAATACTT ^ WÍTGCftATGCCAGATCGTGGT ^ CC ^ ACTGGCAACrACTATC ^ CCACGTTCAC ^ A ^ GATTlATAAAAA ^ T^,rQCCTi^,GAA.T

SEQ 10 HO. 1S

MKKI ^ l ^ TST $ lAASX_tUVA5V ^ AQ ^^,IzrTWTARWSEVKADLVKeGf3KSSYTVOGi ^ I ^ VISEAMSIOMNVLAK2iJIADXKa4irPE^,mt'rVT: in

QKSHTAT ^ KIE ^ ATWAAGQTmVOijKTNQVSVAXíQKVSUTrJSSGíOT ^ SAAlTIVSPMKTYSSAPALKSí ^ VIAAQSQAVSQftAANSQVSPAPV

KSITSSVPAAK ^ VKFlOT-SVSQSTrvSPASVAASTPAPVAKVAPWTVAAPRVASVKVVTPKVETGASPSHV ^ PAVPVTTTSFATDSKhQATSV

KSV ^ A ^ Qfô ^ ATPVAQFASlWAVAAHPÉ ^ GÁC ^ VAAY ^ ífVASTIGV ^ PSTY ^ GBP ^ ^ ^ KfilAWFZVSTMOAtCH ^ AOVSTQÍBWyff ·

[8] [3] [3] [3] [3] [3] [3] [3] [3] [3] [3] [3] [3] [3]

The nucleotide and amino acid sequences of GBS 328 in Ref. 3 are SEQ ID 6015 and ID SEQ 6016. These sequences are set forth below as SEQ ID Nos. 19 and 20:

SEQ ID NO. 19

ATGAAAAAGAAAATrATTTraAAAAOTAOTCSTrCTTGGTrTAGTCSCTGGGACTTCTATrATGrrCTCAAGCGTGTrCGCGGACCSAGTCGGTGTC

CAAÔTTATAGGCGTCAATCMcrTTOVrGGTGraCTTGACAAYACTGi ^ CAGraAATATGCCTGAPSGAAAAtSTTGCTAATGCrGSTACTGCTGCT

E3yKTO &lt;®TGCTIATATGGATGACGCTCWAÃAi? ATTTCAA®.CftAACTAftCCCTAATGGTGfiASGCA.TTAaiSrrCAAGCAGGCGATATf3 (3^,r^,] K3GA

GCAAGTCCAGCCAACTCTGGacrrGTTCAAaA ​​GAACCAACTGÍCAAAAATTTTAATGCAATGAATeTrGASTATeGCACATTiSSGTAACCAlOAA ^ '^ ® jfTTSATGAAeGGTTsàCRGAAÍATAATCCfrATCGTTACTGSTAAAGCCCCTCCTCCAGATTCTAATATTAATAftTAlTACGAAATCX.TACCCtfiCAT crecStíw' c! '\ &lt;3AAATTeTAaqmcwuvmTRTTSATAAAaTTAftcwcwvrrccmcaATTOcmGO (awx3ci% TTftAAí! ATATT (XTGTAAATAACAAAACmSTÍ ^ CGTTGGCprTATCGaGATTOTCACCAAAGACATCCCAMCCTOTCTTAOSTAAAAATTATaAACMTATÍSAA

TrTOAGATSAAGO «3AAACMTCetTAAA% CBCX3UWaWim &lt;^ SCTAA3iÁATÇTCAftft8CTAM®a« »TCTCSCa ^ T ^ CCTâCaACA

SGTAAAAATQftTA'3'TOCTGAÃGGTGAAGCAQCftG &amp; AATGATGAÃAfiAft! 3TCAATCffl.C? Rcn'CCCTGAAAATAGCGTAGATATTaTCTTrGCTGaA

CAC ^ TCATCAATATACW ^ TGGTCTTS1TrisSSAAACTCGTATTCTACAAfSCGCTCTOTCAAGtiaAAAGCCTATGCrGATGrACGTHCTGTCTTA

G.VfACTSATACACAAGftTTTCATrGAGACCCCTrcAGCTKAAGTAATTe ^ TTÍKTCCTGGOTKAABAAGftGGTAgTGCCCATATTCAAGCCATT (TrTGACCAÀGCTAATZtCTATCGTTAWiCAAGTAACftGAAGGATATATGATATGATATAGAGATTATGATATAGATTAGTGATATAGGATTAGTGATATGATATGATATAGATTAG

AATCTTAGTCCGGTA &amp; aCASCCÍCATCACJs.aAGSCTCAACTAGCAftTJOCTCGAAAAAGCTGGCCaSATATCGArrrTSCCATOACAAATAATGGT

GGCATTCOTGCTOAOTACTCATCAAftCCAESATGGAACÃATCACCTGGGGAGCTGCACAAGCACTTCAACCjrTTTGGTAATATCTTACAÃGTCGTC

GMUWlRCTOOTASASATCrTfATAAASXaClXMCaftACAATAC ^ CCAAaftACJSSAÁTTTCTrCCTTCSSATÍtàCrQGTCTGOBATAGACÍCIA

ACAGATAATAAAGAe &lt;^ G &lt;3aGM.aAftACacCATrTASAGTTGTAAAAGCTrATAAAT (3yiATGGrGAi53AAATCAATCCTSATGCWAATACAAA

TTAGTrATCMTOACrrrTTATTCGGTGOTGCTGATGGCTrTGCAAGCTICAGMKroCCAAACTTCIAOGAGCCATTSAC ^ CCGft ^ ACftCSAGGTA

TmTSGCCTATATCI ^ TCMrn ^ aAgGTGGTAAWtóGTeAGCSITKWnTUamO ^ AAAimriAtGTCACTATGAAQATGGTTAAT

GAAACTATTACACAAAATGATCSTACACATSavingTATTAAGAAACTTTATTTAGATCSACMGSASATATTGTAGCACAASAeATTaTATCAGAC

ACTTÍAAAGCAAAí ^ ftAT ^ WlTCTACÁAAAAATCAACCCTGTAACTAGftATT ^ -CWíAAAACAÁTÁACÁACÀTRATÁÇAÁCTâTrAÁqGCTATG Α0ΑΑΑΤΤΑΤσ3ςΑΑΑ0 {ΛΤΛΤΛΤΛΑΤΤΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑ^&lt;ΓΤεσίΤΑ '[· Β7 · εϊ · &lt;3ϊ (: ÍTTGGTtTIC ^ ACtTS.TAeGAAWGCTCTAAATACAAAGASAAACAÇ.ATGAAA' '&lt;·?

SEQ »NO&gt; 23« 8KKriiaCSSV ^ WST ^ M ^ 9WraffiQV8VeWItanroBSraftií »rtCTA ^ M« KW ^ OT »8QU» Wl »» ig «SPRQIJ®H« ^ lRifl »VSDMTO

ASPANSGLLQDS? TViÍFIFIs&gt; 3in'EYGTtGSílEPOKGUKSíHS.tVK5KAPAPl! SNIWITXS'íPHKAAKQSIWAíWIOmJXÍ3iFY! Í «í«^!yAlia «

ΒνΝΚΚ3νκναΡΙΟΐνΤ! ΊΒ1Ρ®ί, 'Μ.Β! «ΓϊΕ0ΫΕΡΑηΕΑΕΤΐνΚγ ΑΚ3Ε &lt;} Α? 3η'ΚΑ5ννΐΑί! Νϊ'Α^ι!3ί! ΝΟΙΑΕβΕΑΜ: ΜΜΚΚνΝΰΙ_ιÍl2ΒΕΓνυΐνΡΑΟ jílíHQYTfKÍLVSRraiVQALSQGKAVADVRGVI.aTOTÇpFISTPSAKVIAVAPGKKTGSAOlOAIVpCiAMTIVKQVTEAKIQTASVSVMITRSVOQD

ΝνΒΡν «; 5ΜΪΕΑ0'ΑίΑ.'5Κ3ΗΡΟ3ΒΡΜί®3 ': 3δΙΚδβυ_ίΪΚΡη5τΐΤ! · ®ΑΑ (3Άνζ! ΡΕαϊΙΙΑ0ννΕίτ3ΕΟΒΥΚΑΑίϊΕ &lt;3Υβ0Κζ) ΗΡΡ · ΑαΧΑ! ΪΙ..ΗΥ '; Ύ

,Ννί! ΑΥί {, 5Ν6ΕΒί8Ρ £) ΑΚΥΚΧ.νΐ! ΦΡΙ.Ρβ36ϊϊεΓΑ3ΪΤΙΗΑΚΙ ^ .ί3ΑΙΗΡ £ ΪΓΕνΡΜΑΥΙΤΟ! ^ ΚΑί3ΚΚν5'ίΡΪ '? Ί33ίΙ^ιΤΗΕυΤΗΕ? ΊνΝ

ΕΤΙΤΟΗΟβΉ3ΙΙΚΚΑΧ1Ε · Κζ3ΗΚΪ »Ά5ΕΣν3ΕΤΜζ) ΤΚδΚ8ΤΚΙ (3Εν'ΓΓΣΚΚΚ'21.ΗΰΕΙΑ.» ΊΡΚΜίΟΚΕ'8Μ81 «'Κ6Κ0Π'Κ.Τϊ333Υδ03ΡΙ3ί55ν

PSWBCilOIALNTKKKHMK

The nucleotide and amino acid sequences of GBS 330 in Ref. 3 are SEQ ID 8791 and ID SEQ 8792. These sequences are set forth below as SEQ ID Nos. 21 and 22:

SEQ) D NO. 21 errOAOUfrAGaAGCTTCJWKatóWWWASTTGCTÇ ^ OTiaTTftAfta ^ GTGCEftACffrrTTCXMTÇreCAACTrCTCftCftTOOASATCRTGCTaAC

CAftCMftSercGraTaffiTACTíarcCTftJaGCfteRAGA &amp; ^ TrQaCreACAAAAQ ^ GGCTTOTCCTTOATiCTAftGGACCTCASArrCCrACA

GAACrTrrraARGAlWTeC ^ ArWCCArrCATM'ACMCAGGTACAA.WrACSTGTTCCTACTAACCAA &lt;5GTATCASATCAftCrCCS, GAAÔTG

RTTGCKrrGÃATSTTGCT «GTGSACriOACATCTTTGAT3ACTOT'GJtò (5Tl ^ WiAGCAAATCCrrí3TO3ÃTGATGGTAAACTftGafCTTACTQTG

TTrGOVRaftGftT »AftQftC ^ T? CGTWUaOTaA * ÔraCTTeTTG * eAATOa'RK [XTr» TTaGT * JUiC ^ AA &lt;^ TÓTA ^ QmXCTTATACTRAA

ATrcCTrrccrasoACTTGCftG ^ AcacGRTAft ^ GCTOftTAYccffn ^ -TOGAcr ^ SAGCaAaGACTTAACTTrArTGCTATcrcAiTiroyACGTAcr

GCTAA.A3ATOrTÃATOÃrfiTrCGTCCTATrrGTGÃA (3AMCTaGSKATOGACA »3G'A. ^ TC &lt;rgxAAAACTGAAAATCAi: jiAea'J^,ATCGA-r

ÍATATTOATOaGkTTATCGAAG &amp; AGC ^ GATXIT.WTATGATTaCTCGWGTiaTATfXKTATroAAGTTCCATTTGAAATGGrrCraSrrrACCAA

ÁAAAM &amp; TCftTTAOTAAAGTTaATSCAGCTOgTMAGCAGTrATOACAGCAAe.SGkATATGCrTGAAACA &amp; TSACTGAlAAACCACGTSCGACTCGT

XCS &lt;mOTftTCTCAWCTK ^ SG &lt;3WrAT1®ATCOTftC ^ WT &lt;3WACAATqCTTTCR &lt;XK «ftOTCftGC! RAftTGOT^-AftATA &lt;X: CSiGTTC »0TCA

GTr &lt;KTACSATaGCTACTATFGATAWtf4TCCTCftAACAT7'ACTCAfi'Tí3ftGTA'rS &lt;3TaJC? Rr * GACTCftTCT &lt;3CATTCCC &amp; CGTAATAACR.AAM? I '

GAl ^ rATTgCATCTGCGGrrAAJ ^ rGC ^ CAOiCTCAATeeA-TAyCAftACrrGTrGTAACAATTACTGAAACAGGTAATACAGCTCGTGCCA-TT

TUTTAAATTCCST £ XASATOra.GACATÍ ^ GCWrTA £ »TrraftlXlAAAAAGTAÍ ^ CCTTtATTGATGATTAACr®3gtJIGTTATCCCT3TCCr^,r

CAAAC &lt;J1GCA7'CTACAaATQATATGTTTCaGGTTGCA! MCS7GTACCACrmAAGCAGC-A'm'C3 'TGAATCAGSO3ATÍA'.^lKQ'n^,A'TC

Grffiía £ ®I'GTTÇCIffrAGGTACaGeTSQWTAACAÇAS'K3CGTG'rrCGTAGTGTTA 'A:

SEQ ID NO. 22

MSiía \ nCIV.ATI6PAVBKKaGKKFGSSi3YWGESLEW8aSAS: KIAQÍ.IKE (3AMVpRFf '' SHGaHASQaA5WrVKKSWAGQSVGFíiLmKGPEIET εΐιΡ30Κ ^ΚΚΤΡΤΡΤΡΤΡΤΡΤΡΤΡΤΡΤΡΤΡΤΡ^,Ι3ΚΙ; βΙ.Τν? Α: '®ΚΕ (ΤΕΕΡΕννν £ ϊΐ! Χ3Ι_&lt;iaαΚ0Κ2νΝ1? ΪΤΚ lPFPAIASRD »ADiaFGLSQGLlSÍFIMSSVRTAKDVHEVRAICSETGX®EVKJ.FAKIS! i (QeSIMJI» SIIESAC! 3JWJ: AIIIADÍ (iCIB^í/ ^ PFEMVPWQ KMIITKTOAASKAVITATÍWnSTMTDKPRftTRSEVgCVFSAVjnCiTDRTOSiíiGESAWGIWPVBSVRTKATltJKNÀÍJTLLNEYGRl.DSSAP PHSNKT DVXftBAVKnaTOMDIKlVVTITÍCrCSOTA ISKírHPaSIÍIiJiVrroEKVORSIJIXSWGVIFVTADKPASlWBFEVAESVAI.BaíSFVSSGCaflVI WSVRSGXGGTOTMRWVÍE

The nucleotide and amino acid sequences of GBS 338 in Ref. 3 are SEQ ID 8637 and ID SEQ 8638. These sequences are set forth below as SEQ ID Nos. 23 and 24:

SEQ ID NO. 23

TTGTCTGCTRTAATAeACAAAAASGTGSTGATATTTATOTATTTAeCftrrAATCSGTGATATCATIÃ ATTCSAAACAGATACraSA

ACGTGAÃACTTrCCAACAGTCTTrTCAGCAACTAATSACCGAACTATCTOATGTATATGGTGAAGGCTGATTTCTCCATTCACTA

TTACA.GCTGGTGATGAATTTCAAGCTTTATTGAAACCATCAAAAAAGGTAlTITC &amp; AATTAÍTSACCATATrGflACTAGCTCTAAÃA • CCTGTTAATGTAAGGTTCGGCCTCGGTACAGGAAACATTATAACATCCATGATTGATACTAGTGATAGTCTGATAGTGATA

CTACTGGCATGCTCSCTCftGCTATTAÃTACATATACATGATAAAAATGATTATGGAACSiGTTCAAGTftGCTATTTGCCTTGATGATG

AAGACCAAAACCTTGAATTAACACfAAAT &amp; GTCTCATTrCAGCTGaTaATTTTATCAAGTCAAÃATGGACTACAAACCATlTTCAA

ATGCTTGAG &lt;^ CTTAATACTTCAAGATAATTATCaAGAACAAT. ”ÍTCAACATCAAAAGT1? AJ3CCCAACTGSAAAATATTGAACCTS.G

TSCGerGACTAAACGCCTTAAAGCAAGCGGTCTGAASATTTACTTAAGAACGAGAACACAGGCAGCCGATCTATTAGTTAAAAQTT

GCACTCÃAACTAAAGGGGGAAGCTÀTGATTTG

SEQ ID NO. 24

MSAXIDKKWIFMYIAIíIGDX IHSKQILSRETPQQSFaQÍ.KrSI.SDWCEELI SPJ-TITAGDEFQALbKPSKlWEOI IEMIQUU4CPV »raF®WSIG BXITSINSKESIGADGPAYWHARSAIKHXHOKNDYGTVQVAI CIOTBDQN1®I, TU! SI.IS ftGDFIKSKWTINHFOMLBHI · I LQDNyQEQFQHQKLAQ LENXEPSAX / TKStUfflSGIjKXXLRTSTQAfiSlitíVKSCrQTKGGSYDF

The nucleotide and amino acid sequences of GBS 358 in the

Ref. 3 are SEQ ID 3183 and SEQ ID 3184. These sequences are set forth below as SEQ ID Nos. 25 and 26:

SEQ ID NO. 25

ATGTTWAJ ^ CAATTGAftGftGCTGGTimCAAOCWlTAGCCWaT &amp; AGGeTAACATASCftGftOCTCATeATCCWKtoGAAJmSAAKrGACr

GÖnWMGTOSTGAAJir ^ TTOGTCSTATlATffrCOGGAAATCrTrWiGrCATGAAAGCTrCrGTTAT ^ GATGGATTAACCCC-FAGTASATCAATC

ASIOGTÍTAACAGGCGGTâATeCÍGTCAAOÃTSGATCAATATTTACAATCAGGAAAATATAOOGACACAATCÇTAGCFGCCGTrASCiAAT

GCTATGSCTOTj «TGR (OT» iR1! QCTAãGATG (^ CTGGnTO5TCC ^ CACCAftÚreCftGC ^ ACnXXStoÔ »TGTTTÀCCftGCII3TGATTTCTftCR and CCITTGAAAAGCrrAArTrAaCAATTAGATTATAGAGATACATTAGAGATACATTATAGAGATACAT

TCÁ &lt;X3TSCA5ftMO ^ TT &lt;3CCR »SCTCftAeTTôesTC« K? RACTCCrATGGOTXSGCTeCTTTft5rrftTGGCTSCTGGAGejRCTCCSTTCt3tó

GCTj «CCAAGCTATASC &amp; TrT8TTATTWmTOTGCTTGeACTOkTCTGTGACCCTGTTGCA0 ^ rTTAQWGW« 3TCCCTTGIGreAAGCGaAftT

OCTCrTGGATCtóGriTrGCAeTTGTOCTGCrGATATGGCCTTGÕCTCGTATtGAATCGCAAB.-rrCCAGTAGATeAAGIIATTGATCCA.ATGTAT CAAGOTGGATCAABTl-TACCGACTCCTTTTCGTGÁeACTGCAaAftGGAGGAt ^ · raCrGCCftCGCCeACAGGAÁGACGTTATACrrAAAGAAATTTn GQGGAS;

SEQ! D NO. 28

KFmBakVEC ^ 30WGNÍABL! A ^ IEMTGRS »SIRYÍHSm ^ WCtóVXt« t&gt; Ti¹SKSXSGItfGGDAV &amp; '! 0 &lt;r7WWmaOTTIU »VR»

«Ν «ΒυΐΑ5Ο« Ι.ναΑΤΡ7ΑΟ3Α £ 5ίΧΡΑνΤ5ΤΑΙ8ίαΑ ^ ΤΕΚΕ0ϊ43Ρυ ΤΑβΤΑσΐ · νΐθ »ίΑίίΙ8 &lt;3ΑΕβε € 0ΑΒν5εΑεΑΜΑΑΑΑ1.υΜΑΑαβΤ £^!Ρα

ASQAIAmmU3GXCDm.SI.VBWCWMAI.GSSFAl, V3iRIiMALAGIESQIPVDEVinAMYQV (5SSI, t&gt; TAPRETABGeiAATPTGRRISKEIP

GB ''

The nucleotide and amino acid sequences of GBS 361 in Ref. 3 are SEQ ID 8769 and SEQ ID 8770. These sequences are set forth below as SEQ ID Nos. 27 and 28:

SEQ ID NO. 27

ATGAGCeTA3'AlOT 'AGTa3AATA'; ArrATT3 ^^ 'CTTK3 © 3SASGAA'rTATAeCGAGCATAAAeAGGATCTTI^,Ge.ACTTAÀAASARG6ftATTT

CTAAACATTiATfiTAAAAOTCACXSACIVrATTTTAGÃATCTrftTACABGAAGCftTAACTAerGACatAGAGGTTCCrGaGCftATACASAiaA ^ rGAGAC

AC6TftOTrrrmTTT &lt;SiriCXOCTT3mAftSfiiCKÇrfOTQOTm (^ STOTTAATTOUU «GCTEATCRTAftTSTrGCTerGTGTrTA &lt;3GG

ACCTCAC7KO3GGAAAGA £ 3T &lt;K: i »GTCAAAATGCCTTGTATCAATrr0ftAGAAGeA^f3AGCt3TC ».M; TAC! A'5? GCrAOTTrArrAC« AABAGCA't'erG

TTTACCATArmCTGATeAATT &lt;3AT »3CTTATC3t'rGATA'rrGTGO3ftGCrTCG^,Í'TT 'ATTTCAP. (' CGCC'rQTTCTaCAAG 'AATAA^,CCCCTAAT

AYTAGGAACACAATTACTTCAAGATâGCGATTeaOATTTAGCTATPrGTGSTGaCTGTCATGAGTTAACrGATATTrCTTTAGCAGtjetTCACATCA

CTAGSAGCTATTAATACASAAAlWCATGTCAeCCCTATTCrrCTIGAAftAGGSATCAATrTGSGmAGeaasCf-GCfmTOTTCTCTTOrCAAAG

ATraGTCCrrAeraAAATAT &lt;MAAAAA3 ^ AK: GCT &lt;3TC ^ ATTACTTC?_sSA'TOGITA'rCATATAACAGCACCrAftGCCA.ACAe3IG &amp; AG &lt;3GGCGGC

ACftGArrGGAAASCAGCTZfiTGACrCAAQtAGíjATTOACTACAGTGAGATrGACrATATrSACGGTCACGGTAaAaG-rACTCAAGCTAATGATAAA

ATaGAAAWATATmATGGTAAÔCTTrTCCCGACAACSACATTGATCAGCAGTACCAAGGGGCAAACGCKir-ÍA-rACTCTAGGGGCTGCACÍGTATrA

TCGSATFSAiTSAATlOTTTAGCGGCAATAaAGGAACAGAerGWCCAGCAACTAAARATGAGAITGGGATAGAAGCTTTTCCAaAAAAtrTQTCTA

TCATCAAAftSMSJVSAATftxXCAATAASUUaxXIOTAAATTrTTCOTTTCCrrTroGTCKSAUCTAATRGTSGTBTCTTaTTGTCATCTrrAGÍKrfCA

COTCTAGftA.WATTACX? RGCTAGAGAAÃATCrrAAMTGGCTATCTTWCATCTt3TTGt3 ^ aAlT ^ CXAA / aAYaftATCAÇ^,rrTCTATAACCTATG

AAAÃffrTGCTASTAATTTCAACaACTTeAAGCAríÇGCTTTAAAGGGGerAGACCACCCAAAACTGTCAACCCAGaCAATTTSGGftAAATGGA

T ^ OTTTTUGWUÍTGGTTrKCGTAACAACAt ^ CAAGCftCTAATAGAAAGCAATATTAATCAAAAACACAGATACTTCAAAASywSGAArTGrA

TTTSCAACACTTTrTrtSSACCAGTKACJGTTGTTCSAAGaTATTGARAÁGCAAATCACAACAG &amp; AGGATATGCACATGrTTCTGCTTaKOSATTCCCGT

TrACAOTAAtKJAATGCAGCaGCTGGTATC ^ CTcrATCAWTTAAAATAACAGGTCCrrTATCTCT1-TrCGACAAATACTGGAGCGCTTGATGG

TATAOUtTATGCCSAGGSAATGATÍCSSAACGAÍTCTCTAGACTATCTSATrCTrGTTTCTSCrAftTCWnGtSACAGACATCrAGTTTPATCàTOSTGG

GftACAATrAftACrATGA'mSTCAAATGTTTGTCSGTTC «3ATTATTGTTCAGC» rA &amp; GTCClCTVrCGTCASGCB.TrGGATAATTCTCCrATAA^,t'AT

TftGGTACTAftfidAATTAAAAGAXSSCX ^ AAAAWTTiaCASATaTOATGACTATTTTrCATGCTGOGCETCAAAATTTATTATCBaACrCAGSftCT

AACCATAAAftSATATCAARSaTTTCSfmGeAAlQASCtSGAAaAAGGCaGTTAGTTCAGATTATCATTTCTTAeCGAACTrarCTGAaTATTATAAT

ATGC &lt;yAACGn^,GCn'TCríOmX »GT-TrâaATTTKATCIAATeGr8CTeeTGAAeSACrGGRerATACTGTTAA'i'GAAAG'IA'rA3AAAAGSaC'I'ATr

ATTTASTCCIKFCTTAlTaSATeTWSGIXSOTATCTeriTTSCTATTA.TTHAABASAiSG

SEQ ID NO. 28

MSVyvSGIâMBSLSh2IYSEaKí3It &lt;POtKSGlSKHLYÍa-®OSIt.SS '/^,TG5ÍTâD »EVAEÔYK £; ETHiSfFK? SP7AFSBMASSGVNLKfl'íUB3AVC! JG τ31, βδΚ3Α! 3®! Α1, Υ0ϊ^,ΚΕ 'ΚΚ (3νΏΑ3', ΒΚΑ8νγΗΙ.Α0Βω® · · ΪΗΟϊνδΑ8 ΛΊ8ΤΑα3Α3Ι®ΙΑνϊΑβΤ (2 ^ ξίΚ3ΠϋΟΙ.Αϊσα50! 3ΕΙ) 3ΗΧά1ΑαΚΤΒ Wals P-rEiííACOPVSSSKGrtEGBGAGmmVÍCBQSIAKyGKIIÍSSL-ITSDeyíilTAPXPTÍaiGAAClíAKQLVTOAGJKySAlOXIKrGSHGTGTOAtiOK! BKmffiKFpmTLISSTK a'W © £ 'l'bGftAGirELIHCIAAIEBl2WPATKtíBTeJK &lt;^ ii 3PP^fVY! IQKSEyPLÍÍSALSÍ'SFAFGGía5SGVAÍ.SSllos Ρ1 ^ Τί.Ρ »^ ΚίΙΚΜΑΙΪ.ΒδνΑΒΙ8Ι8ΪΒ31, ΒΙΤΪΒΚνΑ35!^;τνΜί · ΪΑΑΑβ&gt; ίΐ23ΙΪΡΚΪΤδΡΑ3νί8'3.'ί390ΑΙιίΜί0ΎΑί $ Μί «ί» ΟΒ1.ϊ&gt; Υνΐΰν3Μϊι31 "Βι'ί3ΡΜΚΒ ®2Β ^ ΤΙ3 (3Κ!? ν335ΥσΒΑ9ν3&gt; 3Κ0ΑΜ383ΡΙ ILGSKGAKYSKKOTTDVMTI FPAAIJ3KLLSDU3LT1ΚΒΣ Κβϊ ίΕΚΧΚΑνεδΟ ^ ^ ΡΙοΑΚΧ, δΕ ΥΪΒ» PBIAS £ X&gt; I © RaaJSim8UWTOSSSI ^ SXIi «US» Simi-SFAtIBS®

The nucleotide and amino acid sequences of GBS 404 in

Ref. 3 are SEQ ID 8799 and SEQ ID 8800. These sequences are set forth below as SEQ ID Nos. 29 and 30:

SEQ ID NO. 29

STGAAAATÃGATGAKTWtóamfteCGAC ^ TGTl ^ Acara ^ raKn ^ CWSTAGCBaAGtSKtTCArrCTCTAGCQSftGGWGTCGATTACCISAaif

CTCAACT ^^ ArmCTGC &lt;aGGa% GTT &lt;3Stò? AC &lt;^ GClT? GTGSrRITA «TCATC»^,AC'TO0TOC.'rKSGCGaaC5GGaACT?! ACCft'3CATrTTT

AMSW ^ tXOTCCTCSkCCTTCTftGTTftCCAATCrGBGftATCTCTCftCSTTCTGTOWTAATAGCGCAACGSGSGAACfiAATCtffiT ^ TCGTrAftTAAA &lt;TrCCTOSGCTC3 «CTt3»! ^ TrTCTSafrCACTTCACAATTCCATCACAAA

ATTQ ^ ACTOTJl ^ QTOTAGGTOAftWrGC ^ CRGSACXàTTTTÓTOrrCAfi ^ gATAAKrAAftTCWJCTTGATATi ^ / CTrTOTACAATGflA

TlATCACAlWtóTATGGTSCTACTGOTSATriWCTAXGGCCWXyrCATCGCCÇACSAAGTTí ^ T ^ GCACf trrCAAaiGAGTTAGGCATIWTG «aTASOTATWftS ^ TSÓSACiVaSOTCW ^ ARWtATGTCAGAGATATCAGATA

TCGGCTCACrACOT ^ GGG &lt;M? IAAATWCTTAt3AACAAGSAi3AC'rETeAftGAfiSCai'rCAA'rGCTeCCCACGCCCTCG

ATGCAACAGGGTGATACT ^ TCTCCSSTAGfiAGBTCTA

SEQ (D NO. 30

ΜΚΙ »θηβΜ3Σ®ηίΕΟΗΚ33 &amp; 53ΒΓ83Ο28αί, ΡΙ1, Οί.εΛΧ.Αβ® ·» ΓϊίΙ.νΐΛίΙΑϋΙ, θ3α6ΑΤ3ΙΡ !! ΐΟ583Ρδ3νί33ζ3ΪΛ · 5Ρ, δνΐ »13ΑΤΗΒΟΙΟϊΎΝΚ .VU3STSDPWSQEF®rô3FG WXS KUaiYTSSIQTCCSIGESRSB FfCSA3iaayi.OIBFYOT:?!? LS3KlfaATCDFJi" The VI /? aiBVSHaiQr [SXX! lM

OKmH ^ LTKKB »3ttiiVTa« y3ftDY1 «OVW» HyiSOKta, l ^ QG®FSfi »l« »MAMIL« 3t »HMiiCSTVía, Vpi5SFrBffrASaRQRWFBia3PQyGD

ÍQHGDTFSVSffil ·

The nucleotide and amino acid sequences of GBS 656 in Ref. 3 are SEQ ID 9323 and SEQ ID 9324. These sequences are set forth below as SEQ ID Nos. 31 and 32:

SEQ ID NO. 31

ATGAftAAGATTÁCATÍAAACTGTTTATAACCGTAATTGCTACATTAGGTATGTTGÍGGGTAATGACCrTTGSTCTrGCAACGCAaCCGCfiAAACGTA

ÃCGCraATAGTACATGCTGAIGTC iATTQATCTXSlTÔZffAOSAGC ^ ^ ^ GG.WriTCAAAATARTOAAAAAATGCrATTqGTMÇCTACCA MCAA tATGTTAATCGT 'TrTAT &lt;^ ^ tTAMaAATftATC3W3ACASAWTAAAT TSftTt5rCAATGTrAA' GCeTATGTrC7 'mi' CSATTGACAATCBA caAAGACTATCAAcrGtaftA raATGCTreATAGAAccArrcâic ^ / ^ ATATCAAftKPcsscRLQAGÃTAccji.CTcrrceeeícrGGjwaví GKAftncA

TTAGGTTCKCÁTCAAOTASCTJ ^ ÁATGRCíamTCGRÍ ^ TOCSSTtW ^ SGaGCmTMTTOCCTATOt ^ íAeCtWSftWvrTrCBAaGG-r

TOG (»TSClTCCGTClX3 ^ TCCTCAAAaT ^ TG? CftCAOWiCftGCTCATTC &lt;AACCÁAK3UVrtCAAAAAATf3iS.TCG'rGi5ACAW&gt; ATTA'rTAT

BAAAXKTTAGTTCOTftAGGCCKnTtàRCCBAJUWSVWCGTBTTCGTTJWJCBTOTAACTCCATTGTACCSTAKI ^ ATACTGATrrSGTTCCATTTGCA

ATgCACCTASAAGCTAftATCStCAGA3? T3GCACA^,n'ASAftrrrAATeTTeCTATTCCftAAC.% CACA, AG-CA'rCA'l'ACACTATGGftT3^,ATGCfiACftGG ^

GÁATAAÇAÇTíSAAT

SEQ ID NO. .Ν ^ 32 ^ ΰΗκτριτνίΑΤΗ ^^^^^^ ρίοχϊΝυτρι ιοιβίδδνητδδΕΓΰΝΚί, ΚΗΑϊ ΒΐίΡΓίίϊ'νΝβιΥδίΛββίΟτΝΜΑονίΓ ^ / κΑϊνοΝίΊΰ '®LSTM ^ ^ ^ LI TIRQYQSKaOTIJ' ftmíKPLGWVATmÍy SHAVDKGiíX.IASAIj £! 'Aím5WiaeVSiSIPQHVVTQTAaSMC! Sli (QÍCXB3' 3QMYY

ESLVRKAVTKÍKKVRyBVTPWfRSDTDI.VPEftMHKaAKSQTuBEMVAXESTQftSyíMOXA ^ GBITIilS

The nucleotide and amino acid sequences of GBS 690 in Ref. 3 are SEQ ID 9965 and ID SEQ 9966. These sequences are shown as SEQ ID Nos. 33 and 34 below:

SEQ 10 NO. 33

ATGAGTAAfiCC ^ CW ^ mAi ^ AJVrTAGWJiAAAGCSAGCftATTATATCIGGICTCAGTGGCACTARTTGTAGTMTAGGTGGCTTTTTAfCKJ

GTA. «ATCTCAACCTAATMGAS^,reCA &lt;3TAAftAACTAAC '? ACSAAGTTTTTAA'rGTrAffliGAAGC3AAGTBT3? TaSTCCTCAAOTC''riT? T (3ACASaA /' SSC ^ 3U 'WCrWCSA5aaCWTATQTGraTr?

CMTWI ^ a ^ .AGrrCAA-rATGATA &amp; AACSACTOCACftAGCAGCCTACGACACTGCTAATCCTC &amp; ASTA &amp; ATAAAGTAGCGÓSTCAGATTAATAAT

CrAAAOACAÁCAHi ^ GTCTTCSMJCrATCGAATraAGTGATCMTCrrrfTCSTCftTraCftASGACAAGGESGACTCAATCGACTIGGBa-rGCGACG

AATC ^ TCTAC ^ CAAAftTTATCAAAGTCAM; CTAftTSC? RTeATACSACC ^ Cft.ACTTCAAGATI'TGÃA'rGATaC? RTA'i ''? SGATGCA.CaGGCAGM.

GTAAATA, W &lt;3CACAAAA3 ^ &lt;ArrGAAlT ^ TACTCTTA? TACAAGTGS.CGTATCAG'3GAfaGTrt5'riGAAG'r £ 'AATASTGATÁTT®' 'CCAGi? TrCA

AAAACTAGTCAACTACrTGTCCATGTASCAACX'aAAeGTAAAC^,rçaiAaTAeAAGGAAC3SAT8í «3TGAGTATGATrTGGCTAA'SQTISAAA.AA3AC

CRGGTTrSTTAAAftTAWWlTCTAACX ^ CTATCCTC ^ CSWSQftATeSGftAGÍAAATWcaTÃrATCrCMATTATCCaeAASCftOAAGCftAftCBAC

AATOACTÇrAATAÈCGSC.TCTASTOCTGrSMTTATAÁATATAAAGrAGATÍTACTAGCCCTCTCaATGCATOVAàACAAGGTrTiACCGTACA

GTTGAASTAGTTÃATSGAGÃTAAGCACCTTATrGTCCCTACAAGTTCTSTGATAAACAAAGATAATAAACACMTTCTITGCiCfrATAGftATÇMTrOT

MTCGTAAMTTTCCWiGTrcAAGTCAftAArrGTAAAGClVATCGTAAaACACMGA &amp; ATTTrATC.VSGTTTGAAAecAGGACAAftTCGTOGTT

ACTAATCCAAGIRAMKSnTGftftGGATGCKCMAftW®TI ^ TA &amp; TATX5AATCAATOSS.TCTTAACrCTAATAASnSATCROSÍ! GTGAAA

SEQ ID NO. 34

MSiWO ^ ISXXGAIISGXfSVJ ^ XWIGOEMíVQSOPHKSAVKTlinrKVFMVREGSVSaSrriTGKRKftlJÇKQXVYFnaKKSMRATVTVÍWGDKITAS

QQliVQYD^,ITIW3RAYinMBlQLSttV ^ QISMbICTTSSI, PflNE83DQSSSSBOBQGTQSTSGRTOKI &lt;3Q! ÍYOSQHíA35WQ! SiQn ^ Brai.YADftOaBVK

KAQ AMBTViTSDveGTVwswTSDinpftSJçrsQviiVHweíEGiciiavaGTíJSErDi.ANVKKriQAVKiKSKVYPDKBMEGK.jsYigtfSPKASJWiHKDs ίΜ03ΒΑ ^ ^ ^ ΥΚΪ ΤΙΤ3ΡΙιΙ ΚΏ6ΡΤν3νενΐη ^ 0 £ ίΚί! 1.ΐνΡΤ33νΐ 'ΐσ3ΝΚΗΓΛίνϊΝΙ53ΗΚΚΙ5ΚνΕνΚΐαΚΑΙ! ΑΚΤΟΕΙΏ36ΪΛ'Αβί3ΐννΤΝΡδ

XTFKDGQKIDNISSIBUJSBKKSEVK

The nucleotide and amino acid sequences of GBS 691 in Ref. 3 are SEQ ID 3691 and ID SEQ 3692. These sequences are shown as SEQ ID Nos. 35 and 36 below:

SEQfDNQ, 35

A ^ AAJWAAATT ^ MTTATTOTCCTCACWrACTGACCTlTCrTTTrGGTATCT ^ CG ^ CAACAAACW ^ CAAGAAAeCACaiàAACAACTATT

TC ^ W ^ ATGCCTA ^ VlTTGMGGCTTCACCTA ^ ATGGAAAAATTCCTGRKAATCCGAAfeA ^^^^^ f ^ n ^ CftT ^ n ^ rrACACrGGGTAT

71ATTAf: .AA ^ A3GTCT? KAT £ I'TrCAfr3T7ACbAGTTTAG ^

ACiOCTGATC ^ TACAGAAC ^ Al ^ GCCGCACJViJWiCCTGATTTAATCxATGGriTTCGATOkAC ^ TCi ^ ACATCAATACTCrGAAAAAAATTGCA

CCAAC? TTlAGrrA^rrrAAATAl \ 7mOCACAAAATTAITrAGATATC ^ rGCeAGCC ^ 3Â ° C ^ Sout &lt;TrATTCGGTAAAGAAAAASAAGCTAATCAGTGG &lt;5TTAGCCAA^,rGGW ^ CrAJ ^ ACTCTCGCT ^ ​​TCAAAAAA ^ ATTTAC ^ CCATATGTTAAAGCx; TAAGACrACTTTTACrftTTAT &lt;^ ATTrriATGAT

AAAftATATCTATTTArA * lWTAATÃATT ^ GIMMCGCGG? QGAGMemArCTATGATrCACTA &lt;3 &lt;OTATGCTGCCCCAGAAAAAOTCAAAAAAGAT

GTCI ^ TAAAAAAG'3Gb^í3X? L ^ .rrACCa'ríTCGCAAGAACCAAW3GWATl \ ACGrTGGACtATTATCtCCCTrGTrA ^ TAT? AACAAACGACrAAAAAA

GCAGCTT € ATCAOTTAAACkAAAGTGATGTCTGGAA ^ l ^ TACCAGa? GTCAAAAAAGISCCACATCATAGAAACTAàCTACGACCr ^ TTTTAITrC

TCrGACGCrCTATCTrrAGJyiGCTC ^^ AAAATCATTTACAAAGGCTATCAAAAAAATACAAAT

SEQ ID NO: 36 ^ QLX &amp; AK ^ TADI&gt; TE £ ^ 0KM: W ^^ WWW ^ OXAPTLVI ^

531ΚΕ30ν! ΊΚϊώΡΆνΕΚαΗΙ.ΙΕ3ΪΘΏνΡΥΡδΠΕ ^ 3 ^ έΐ.% Κ3ΡΤΚΑΙΚΕΪίΤΗ

Other preferred polypeptide antigens include: GBS4 (SEQ ID 2 from Ref 3.); GBS22 (SEQ ID 8584 from Ref 3.); and GBS85 (SEQ ID NO: 216 from Ref 3.), including polypeptides with amino acid sequences having sequence identity therewith, and the like.

The polypeptide is preferably not a C protein (alpha or beta or epsilon) or an R protein (Rib). The nucleotide and amino acid sequences of GBS 4 in Ref. 3 are SEQ ID 1 and SEQ ID 2.

These sequences are shown below as SEQ ID Nos. 37 and 38:

SEQ ID NO. 37

ATGAMCTGMAAATAAiSAITTTAACC-ATBSrAGC &amp; CrTAefaTCITAAaATGTSCrACTTATTCATCSATCSOTTATGCrSATACAAGTGATAASA

ATACTGAGaaSAGTGTCGTGACTACGACCrrArCTGAGGAGAAAAGATCAGftTGAACTiBACCIA-1-CTftSTACTGffrTCTTCTrCTGASSATCaaTC:

®GTTCATCAAGTaftACCAGAAACAAATCCffrCÁACTAATCCACCTACAACAGAACCATCGCM.CCCTCACCTAQTGAAC3AiSftACAAiSCCrGATGSr

AGMCGAA ^ CAGAAArf ^ t ^ TAATA) Wi ^ rwn'CT.% STS &lt;MACAABAaTWrrAi% TrTCAGSAGATAGTAI-rftAG.WTTTAGTAAAGCaSGTA

GIBATCAAGA ^ GAAGTBGATCGCSATCAATÍATCftTCTTCAJlAAeCAAATGATiSeiMaAAtCACASTAAeCCTAAAAAGGAACTTCCrAAAAC:

ACXSAGATAaCCACTCAGATACTGTAATftGCATCTACGCsGAeQGATrATTCTGTTÃ.TCATTAAGTríTTfvCASTAAQAAAATGSAACTTfAT

SEQ IO NO. 38

KKV.KJÍKJÍ, TMW.TUX.TÇATYSSlGYABTSDÍNT £ iTSWPTO.8ESKRSDSWeSST &lt;5SSSgSSSSSSSSPSTOT '£ T' PPTTapSQ? SP8BBNKpnG

»6® »'ΚΕ) ϊ3δ0ΤΚνΐ, Ι3Κβ $ Ι®ίΡ5ΚΆ33ίί (5εΕυηί1Ειε3333ΧΑίΦ0ΚΚΰΗ8ΚΡΚΚΕ ^ ΡΚ^,Κ; 03Η8Ι) ΤνΐΑ3Τ06ΪΙΙιΙι51ι3ϊΎΝΚί®ΧίιΥ

The nucleotide and amino acid sequences of GBS 22 in Ref. 3 are SEQ 8583 and SEQ ID 8584. These sequences are shown below as SEQ ID Nos. 39 and 40:

SEQ ID NO. 39

SmWiAÍ ^ TACSSWUWSCCTTATTTTrGTTCKKWSOTSamCCCmmocmTSTOCtTOTACrAíWaiAAGCCftSC ^ JUtfaAWrGGCT lOTCAtnrAGTGAmSCTOTaTaSVmTftTKXRTTATJTTTTTTTTTTTTTATTTTTTATTTTTATTTTATTTTATTTTATTTTTATTTTTATTTTTAT

TOweGrrrreAACCCTaTGRaSTeATarTGCTCCKATTTATOATOCTGATCTÃMTCTTTATCA-nOscYsCftíriAGAftGcrTOGscGAGACir TTGGAACCTAGTTTSCATCACrCTMAGtATCTGTAATWWTmAwmTmAwmTwAStmw^,UXa'IQSCrrAGftASATOT 'Sfi. &lt;K3CÍ' 3-MAMGSACTAGATCAGTCMCCTTGTATCACCCTCAOACTraeAftTGACCerGTAMÃGTAT CTGiiiSGAfkGCXCaACrCATCGCEÔCÍiCÃA-l ^ AeC TAAAAAGGA'TC &lt;^ PÍ AAAACGCTAAíjí3T'í'TATCAAAAAAATGCT3ATCAATTTAGTGAÇAAGGCAA^&lt;rGGCTA'rTGCAGAGAAGTA'i^JAAGCCAAAATT'f »» AGCiWAAaCTcrftBATActiTaACTTcacaTACKScaRT ^ ACTTAGcrAAGnsAT »CGGAWGacrca (mASOTATiecR« JTrarcr^yiGGA.GTCTC ftuCTÂArrAGerCjAAGC \ CTA &amp;.? TTeftCA? rAC7 £ G £ ^^^^

0A ^ mx ^ íy \ ACTAftTcn ^^ TACTTôTCAAftTC &lt;mw ^ TatòTA3

SÉGtB NQv 40

ΧβΧ »Κ81ΪΡν ^ 3νντΐ_ίΣε ^ ΰΑσΓΚ0δίίς ^ αΐ * &amp; ννΤδΕΪ- &amp; ν&gt; * δίτ ^ νδΟΙ&gt; ίίΙ? ΟΣΚΜΐί &lt;5030Χΐί5? ΒΡ58δθνΑΛΙΥΕ5ΑΟΪ-ΡΪ₍ι · ϊΗδίΙΤίΕΑ '«Α ^ Κ

W ^ SUiHSKVSVX ^^ GWTUJKWCLSQV ^ S ^^^ ST ^ YS ^ HTW ^ &amp; VKySS ^ C ^ iATC ^ KKIJPy ^ KV ^ Q ^ TmGFSnKWÍAIASKyKPK?

ΚΑ ^ ΚΥ ^ ΓδΗΤΑΡδΥ ^ ΑΚΚΥσ ^ ΤΟ ^ βΧΑθν5Τ ^ ΕΡ5ΑΚΚί ^ Ι02Ρ¹^ ΫΚνΚΤΧΡνΕ2θν3'ΡϊαΑΟΑνΑδΑΤΡ.νΚΐΑεΐ&gt; 3ΡΣ4ΧΑνρΚίίΚΧε3Υ ^

E ^ sm&gt; mvKs «?

The nucleotide and amino acid sequences of GBS 85 in Ref. 3 are SEQ ID 215 and SEQ ID 216. These sequences are set forth below as SEQ ID Nos. 41 and 42:

SEQ ID NO. 41

ATGCCTAAÍSAAGSAATCAGATACCCCAGAAAAAaftAÍjaaSTTGTCTTAAÇGtSAATSGCAAAAGCOTAACCTTGAATTTrfAAAAAAACGCAAAGAAG

ATGM, GAA3AACSAAAAO3TATTA.AWAAAWTTACSCTTASATAJtóAt5AAGTAAATTAAATATTTCrTCTCCTGAAGAftCCrCftAAA'rACTACTSA

AATT / AGAr ^ CCTCATrTTCCftWGATTTCAA &lt;SACCTAASAT? SAA ^ eAAACfe3ABAftAãAMAAATAGTCAACAGCTTAGCCRAAACTBATCQC

ATTAGSACrGCACCTATACTTGTAGTAGOATTCePACITAL ^ TAGTTTCCGTTTrCCiaCTAACTCCTTTTAGTAAGCAAAAAACIVATASCAGTrA

GTíSSftAATaecATSeACCTGATTATRTGATA ^ iSAftAAeeMTATTCAABAAAACGATTATTTerrTTCTTTAATTTTríaACATAAAGCTAT

TGAACAACGTTTAG ("rGCASMSA" OtATQ ^ AAW ^^ GCTCA &lt;^ TGACTTATaUTRrcCCAATAA &amp; 'TTJ'CATA'i'rCAAGTTCftAGSAAAAG

A1TATTOCATATOCAaTAOAAGCSASGATATCXACC ^ TCTTGGAAACTCGAAAAW &lt;3CrGATCCTOTAAATAGrTCAGAGCTACCAAAiGCACT

TCrTAACSArrA &amp; COT &amp; ATA ^ Q &lt;^ GATAGTATTAAGCrATrAATTMAGATTTA &amp; ACOCrTTAaACCCTGAyrTASTAASTGAGA'ETCA &lt;S3TC5AT

AAIM ^ AGCTGATTCTAAAACGA ^ Ce ^ ACCTCCTfWCTATGGAAlGCACGATGGAAATAGTAWAGftATACCATTA-rCTAAATTTAAAGAAAGA

CrrcCTTTTTACAMCViATrAAGAAGMCCTTMeGAACCITetATrCTTGATATSmAGTGSGAGTTTAaraACAACWiATACCS.TOSAATCAA

'3CAGAASATAC' SUPPLY MAAAW ^ TCAACTGATAAACACAAACACAAAATGGTCAOGTTOCaGAAAATAGTCAAG &lt;3ACJiMCAAATAA

CT &lt;»AATACTAATCAACRAGS» GAACASATASaUM2ft! SAS £ AGGCSCCW «XX3K3U« ATGTTAAT

SEQ IDNO.42 «pSQOtSOTPEKESWLTEKàKMLÈFLíàÁSOSBEQkRIt ^ KIjRLDKRSiâNISSEEÈPQtjTrKXiOajHFPKISEiPKIEkKgKKEKIVNSlAKTKR

IRTfiPIFW'Fi.VlLVSVFLLTPFSKQKTI'rtSGlfOaTP &amp; BIi.ISKTickle: &lt;NI&gt; 1fPPSIIPKHKÃLEQKIAàfô3WVjÇrAQWreQFE! '(KFHH5VQSKK

ΪΙΑΪΑ] ΐτκ0δΥ &lt;3ΡύϋΕΤάί «Μ) ί^,νΒδ8Ε ^ ΡΚΗΡηΤ1ΝΣ ^ ΚΕΒ3ίΚΙ₁ί, ίΚήυΚ «ΤΟΡΒΙ« Ι3Εΐςνΐ31Α.ΰ8ΚΓΤΡΩΙΛΙίΓΟίίΚΟ5Μ2ΙΚΪΡΙί8ΚΓΚΕΚ ^ PFYKQIKKNUCEPSrVDMEVGVymOTIBSrPVKftBOTKlíKSTBKTOrQlíGQWAESSCSGeTNIJAQQIQQIQQIQQIQQIQQIQQIQQIQIQQI

The GBS polypeptides of the invention may be present in the composition as separate individual polypeptides. It is preferable, however, that two or more (i.e. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) of the antigens are expressed as a single polypeptide chain (a 'hybrid' polypeptide). Hybrid polypeptides offer two main advantages: First, a polypeptide that can be unstable or poorly expressed by itself can be assisted by the addition of a suitable hybrid partner that overcomes the problem; Second, commercial manufacturing is simplified since only one expression and purification needs to be employed in order to produce two polypeptides that are antigenically useful.

The hybrid polypeptide may comprise two or more polypeptide sequences from the first antigen group. Accordingly, the invention includes a composition comprising a first amino acid sequence and a second amino acid sequence, wherein said first and second amino acid sequences are selected from a GBS antigen or fragment thereof. Preferably, the first and second amino acid sequences in the hybrid polypeptide comprise different epitopes.

The hybrid polypeptide may comprise one or more polypeptide sequences from different GBS serotypes. Accordingly, the invention includes a composition comprising a first amino acid sequence and a second amino acid sequence, said first amino acid sequence and said second amino acid sequence selected from a GBS serotype selected from the group consisting of of serotypes Ia, Ib, Ia / c, II, III, IV, V, VI, VII and VIII. The first and second amino acid sequences may be from the same GBS serotype or may be from different GBS serotypes. Preferably, the first and second amino acid sequences are selected from a GBS serotype selected from the group consisting of serotypes II and V. More preferably, at least one of the first and second amino acid sequences is from GBS serotype V. Preferably, the first and second amino acid sequences of the hybrid polypeptide comprise different epitopes.

In one embodiment, the hybrid polypeptide comprises one or more serotype V GBS antigens. Preferably, the hybrid polypeptide comprises a first amino acid sequence and a second amino acid sequence, said first amino acid sequence and said second amino acid sequence comprises a GBS antigen or a fragment thereof selected from the group consisting of GBS 80. GBS 91, GBS 104, GBS 147, GBS 173, GBS 276, GBS 305, GBS 313, GBS 322, GBS 328, GBS 330, GBS 338, GBS 358, GBS 361, GBS 404, GBS 656, GBS 690, and GBS 691. Preferably, the GBS antigen or fragment thereof is selected from the group consisting of GBS 80 and GBS 691. Preferably, the first and second amino acid sequences in the hybrid polypeptide comprise different epitopes.

Hybrids consisting of amino acid sequences of two, three, four, five, six, seven, eight, nine, or ten GBS antigens are preferred. In particular, hybrids consisting of amino acid sequences of two, three, four, or five GBS antigens are preferred.

Different hybrid polypeptides may be mixed together in a single formulation. Within such combinations, a GBS antigen may be present on more than one hybrid polypeptide and / or as a non-hybrid polypeptide. It is preferable, however, for an antigen to be present either as a hybrid or as a non-hybrid, but not both.

Preferably, the GBS antigen on one of the hybrid polypeptides is GBS 80 or a fragment thereof. Accordingly, examples of two antigen hybrids for use in the present invention may comprise: (1) GBS 80 and GBS 91, (2) GBS 80 and GBS 104, (3) GBS 80 and GBS 147, (4) GBS 80 and GBS 173, (5) GBS 80 and GBS 276, (6) GBS 80 and GBS 305, (7) GBS 80 and GBS 313, (8) GBS 80 and GBS 322, (9) GBS 80 and GBS 328, (10) GBS 80 and GBS 330, (11) GBS 80 and GBS 338, ( 12) GBS 80 and GBS 358, (13) GBS 80 and GBS 361, (14) GBS 80 and GBS 404, (14) GBS 80 and GBS 404, (15), GBS 80 and GBS 656 (16), GBS 80 and GBS 690, and (17) GBS 80 and GBS 691. Preferably, a two antigen hybrid for use in the present invention comprises GBS 80 and GBS 691.

Hybrid polypeptides may be represented by the general formula NH₂-A- {XL}_no-B-COOH_z wherein: X is an amino acid sequence of a GBS antigen or fragment thereof, L is an optional linker amino acid sequence; A is an optional N-terminal amino acid sequence; B is an optional C-terminal amino acid sequence; and n is 2, 3, 4, 6, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

If an -X- moiety has a leader peptide sequence in its wild-type form, it may be included or omitted in the hybrid protein. In some embodiments, the leader peptides will be deleted except for the -X portion located at the N-terminal end of the hybrid protein, that is, the X-leader peptide._lf will be kept but the leader peptides X₂ ... X_no will be omitted. This is equivalent to the exclusion of all leader peptides and using leader peptide Xi as -A- radical.

For each n occurrence of {-XL-}, the -L- linker amino acid sequence may be present or absent. For example, when -n = 2, the hybrid may be NH₂-Xi-X₂-Lil₂-ohhh no₂-Xi-x₂-cooh, nhz-xi-iu-xz-cooh, nh₂-Xi-x₂-l₂-cooh, etc. -L- amino acid linker sequences will typically be short (e.g., 20 or fewer amino acids, i.e. 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1). Examples include short cloning sequences which facilitate cloning, polyglycine ligands (i.e. comprising Gly where n = 2, 3, 4, 5, 6, 7, 8,

9, 10 or more), and histidine markers (ie His_no where n = 3, 4, 5, 6, 7, 8, 9, 10 or more). Other suitable linker amino acid sequences will be apparent to those skilled in the art. A useful ligand is GSGGGG (SEQ ID 1), with the Gly-Ser dipeptide formed from a Bam H1 restriction site, thereby aiding cloning and manipulation, and tetrapeptide (Gli) 4 being a poly ligand. -glycine typical.

-A- is an optional N-terminal amino acid sequence. This will typically be short (e.g. 40 amino acids or less, ie 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23 , 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1). Examples include direct protein trafficking leader sequences, or short peptide sequences that facilitate cloning or purification (e.g., histidine markers, ie, His_no where n = 3, 4, 5, 6, 7, 8, 9, 10 or more). Other suitable N-terminal amino acid sequences will be apparent to those skilled in the art. If X1 lacks its own N-terminal methionine, -A- is preferably an oligopeptide (e.g., with 1, 2, 3, 4, 5, 6, 7 or 8 amino acids), which provides an N-terminal methionine.

-B- is an optional C-terminal amino acid sequence. This will typically be short (e.g. 40 amino acids

<td>or less or</td><td>be 39, 38, 37, 36,</td><td> 35, 34,</td><td> 33, 32,</td><td> 31,</td><td> 30,</td>

<td> 29, 28, 27,</td><td> 26, 25, 24, 23, 22 ,</td><td> 21, 20,</td><td> 19, 18,</td><td> 17,</td><td> 16,</td>

<td> 15, 14, 13,</td><td> 12, 11, 10, 9, 8,</td><td> 7, 6, 5</td><td> , 4, 3,</td><td> 2,</td><td>D</td>

Examples include direct protein trafficking sequences, short peptide sequences that facilitate cloning or purification (e.g., comprising histidine markers, ie, His_no on what _no = 3, 4, 5, 6, 7, 8, 9, 10 or more), or sequences that increase protein stability. Other suitable C-terminal amino acid sequences will be apparent to those skilled in the art.

More preferably, n is 2 or 3.

The saccharide antigen Saccharide antigen is generally the capsular polysaccharide of a GBS or derivative thereof. Suitable derivatives include oligosaccharide fragments (e.g. 3-150, preferably 8-100, monosaccharide units) of polysaccharide (e.g. refs. 12 and 16), acetylated saccharides (Ref. 16), Nacetylated saccharides (16 ), saccharides with terminal aldehyde groups, etc.

The saccharide is preferably conjugated to a carrier molecule to improve immunogenicity (see for example refs. 4-23 etc.). In some embodiments of the invention, GBS saccharide is conjugated to a GBS protein as defined above, thereby giving a polypeptide / saccharide combination of the invention in a single molecule. In other embodiments the GBS saccharide is conjugated to a non-GBS protein, in which case the conjugate will be combined with a separate GBS protein to give a polypeptide / saccharide combination of the invention.

Non-GBS transporter polypeptides include tetanus toxoid, N.meningitidis outer membrane protein (24), synthetic peptides (25, 26), heat shock proteins (27, 28), whooping cough proteins (29, 30 ), H. influenzae protein D (31), (32) cytokines, lymphokines (32), hormones (32), growth factors (32), C. difficile toxin A or B (33), iron (34), etc. Preferred carrier proteins are CRM197 diphtheria toxoid (35) and tetanus toxoid.

saccharide and polypeptide are covalently joined.

This may involve a direct covalent bond between the saccharide and polypeptide, or indirect coupling through a binder or spacer through a B-propionamide binder may be used. Any suitable conjugation chemistry may (eg, reductive amination (21), etc.). .), preferably via a polysaccharide saccharide.

(e.g., (16), etc.). be used The connection is terminal on

A single carrier molecule may carry saccharide antigens of a single type (e.g. saccharides derived from a single GBS serotype) or may carry several different antigens (e.g. saccharides derived from multiple GBS serotypes all conjugated to the same carrier). ).

The saccharides may, of course, be prepared by various means (e.g., GBS saccharide purification, chemical synthesis, etc.), in various sizes (e.g. full length, fragmented, etc.) and may be derivatized to bind to the carriers. They are preferably prepared in substantially pure form (i.e. substantially free of other streptococcal saccharides) or in substantially isolated form. Processes for preparing GBS capsular polysaccharides are well known in the art (e.g. Refs. 36-39) and processes for preparing polysaccharide oligosaccharides are also known (e.g. hydrolysis, ultrasound, enzymatic treatment, base treatment followed by nitrosation, etc. (12 to 16)).

Y1

As an alternative to the use of a saccharide antigen in unconjugated combinations, a GBS capsular polysaccharide mimetic peptide (e.g. 40) may be used. Suitable peptides may be selected by phage display techniques using protective antisaccharide antibodies. As another alternative, an anti-idiotypic antibody may be used in place of a saccharide antigen (e.g. ref. 41)

Initiation / Booster Calendars

Polypeptide / saccharide combinations of the invention may be administered as a single dose or as part of an initiation / booster scheme. In a first initiation / booster schedule, the combination may be used as the inoculation dose, the booster dose (s), or both.

If a combination is used for both initiation and reinforcement, it is preferable to use the same combination both times. If a combination is used for only one of the first immunization and booster, it is preferable that the other dose should use the polypeptide or saccharide on which the combination is based. Thus, the invention provides an initiation / booster schedule where (i) one of the saccharide and polypeptide antigens is used to prepare an immune response and a combination is used to stimulate the response, or (ii) combined saccharide and polypeptide antigens are used. to initiate an immune response but only one is used to boost the response

Various immunization and booster ranges are suitable for use with the invention. In one embodiment, an initiation dose is given to a child and a booster is given to a teenager (13-18 years) or young adult (19-25 years). In another embodiment, an initiation dose is given to a teenager or young adult and a booster is given during pregnancy. In another embodiment, an initiation dose is given to a woman intending to become pregnant and a booster is administered during pregnancy.

Immunogenic Pharmaceutical Compositions

Polypeptide / saccharide combinations are formulated as immunogenic compositions, and more preferably as compositions suitable for use as a vaccine in humans (e.g., children or adults). The vaccines of the invention may be either prophylactic (e.g. to prevent infection) or therapeutic (ie to treat disease after infection), but will usually be prophylactic. Thus, the invention includes a method for the therapeutic or prophylactic treatment of GBS infection in an animal susceptible to GBS infection, comprising administering to said animal a therapeutic or prophylactic amount of immunogenic compositions of the invention.

The composition of the invention is preferably sterile.

The composition of the invention is preferably pyrogen free.

The composition of the present invention generally has a pH between 6.0 and 7.0, more preferably between 6.3 and 6.9, for example 6.6 ± 0.2. The composition is preferably buffered at this pH.

Other components suitable for administration to humans are disclosed in ref. 42

The vaccines of the invention may be administered in conjunction with other immunoregulatory agents. In particular, the compositions generally include an adjuvant. Other preferred adjuvants include, but are not limited to, one or more of the following requirements set forth below:

A. Compositions containing minerals

Mineral-containing compositions suitable for use as adjuvants in the invention include mineral salts, such as aluminum salts and calcium salts. The invention includes mineral salts such as oxyhydroxides), orthophosphates) such as hydroxides (e.g. phosphates (e.g. hydroxyphosphates, (e.g. see different sulfates or mixtures, chapters 8 and 9 of ref.

etc.

43}), mineral compounds, with the compounds having any suitable form (e.g., gel, crystalline, amorphous, etc.), and with the adsorption to be preferred. Mineral-containing compositions may also be formulated as a metal salt particle. See ref. 44.

B. Oil Emulsions

Oil emulsion compositions suitable for use as adjuvants in the present invention include squalene in water emulsions such as MF59 (5% squalene, 0.5% Tween 80, and 0 to 5% Span 85 formulated in submicron particles using a microfluidizer). See ref. 45

Freund's Complete Adjuvant (CFA) and Incomplete Freund's Adjuvant (IFA) may also be used as adjuvants in the present invention.

used a glycoside group

C. Saponin Formulations

Saponin formulations may also be as adjuvants in the invention. Saponins are heterologous to sterol glycosides and triterpenoids that are found in the bark, leaves, stems, roots and even flowers of a wide range of plant species. Quillaia saponaria Molina tree bark saponin has been widely studied as an adjuvant. The commercially obtainable (sarsapnlla), and Saponana saponina can also start from Smilax ornata Gypsophilla paniculata (bridal veil) officianalis (soap root). Saponin adjuvant formulations include purified formulations such as QS21 as well as lipid formulations such as ISCOM.

Saponin compositions were purified using high performance thin layer chromatography (HP-CL) and high performance reverse phase liquid chromatography (HPLC). Specific fractions purified using these techniques have been identified, including QS7, QS17, QS18, QS21, QH-A, QH-B and QH-C. Preferably the saponin is QS21. A production method of QS21 is disclosed in US Patent 5057540. Saponin formulations may also comprise 96/33739).

one

Combinations of sterol to form such as cholesterol (see WO saponins and cholesterols single particles called immunostimulating complexes (ISCOM) may be used. ISCOM typically also include a phospholipid such as phosphatidylethanolamine or phosphatidylcholine. Any known saponin may be used in ISCOMs. Preferably ISCOM includes one or more of Quil A, QHA and QHC ISCOM are further described in EP 0 109 942, WO 96/11711 and WO 96/33739. Optionally, ISCOMS may be devoid of additional detergent. See ref. 46

Evaluation of the development of saponin-based adjuvants can be found in ref. 47

C. Virosomes and Virus Particles (VLPs)

Virosomes and virus-like particles (VLPs) may also be used as adjuvants in the present invention. These structures generally contain one or more virus proteins, optionally combined or formulated with a phospholipid. They are generally non-pathogenic, non-replicating and generally do not contain any part of the native viral genome. Viral proteins may be recombinantly produced or isolated from whole viruses. These viral proteins suitable for use in virosomes or VLPs include influenza virus derived proteins (such as HA or NA), Hepatitis B virus (such as capsid or nucleus proteins), hepatitis E virus, measles virus, Sindbis virus, rotavirus, foot-and-mouth virus, retrovirus, Norwalk virus, human papilloma virus, HIV, RNA phage, QSS phage (such as coat proteins), GA phage, phage fr, AP205 phage, and Ty (such as like the retrotransposon Ty pl protein). VLPs are discussed in WO 03/024480, WO 03/024481, and Refs. 48, 49, 50 and 51. Virosomes are discussed, for example, in

Ref. 52.

D. Bacterial or Microbial Derivatives

Suitable adjuvants for use in the present invention include bacterial or microbial derivatives such as:

(1) Non-toxic enterobacterial lipopolysaccharide (LPS) derivatives

Such derivatives include monophosphoryl lipid A (MPL) and 30-deacylated MPL (3dMPL). 3dMPL is a mixture of 3-De-Oacylated monophosphoryl lipid A with 4, 5 or 6 acylated chains. A preferred small particle form of 3-De-O-acylated monophosphoryl lipid A is described in EP 0 689

454 Such small 3dMPL particles are small enough to be sterilized by filtration through a 0.22 micron membrane (see EP 0 689454). Other non-toxic LPS derivatives include imitation of monophosphoryl lipid A, such as aminoalkyl glucosaminide phosphate derivatives, for example, RC-529. See Ref. 53 (2) Lipid derivatives A

Lipid A derivatives include Escherichia coli lipid A derivatives such as OM-174. OM-174 is described, for example, in ref. 54 and 55.

(3) Immunostimulatory Oligonucleotides

Suitable immunostimulating oligonucleotides for use as adjuvants in the invention include nucleotide sequences containing a CpG motif (a sequence containing an unmethylated cytosine followed by guanosine and linked by a phosphate bond). Double stranded bacterial RNA or oligonucleotides containing palmdromic (dG) or poly sequences have also been shown to be immunostimulants.

CpG may include nucleotide / analog changes, such as phosphorothioate modifications, and may be double stranded or single stranded. Optionally, guanosine may be substituted for an analog such as 2'-deoxy-7deazaguanosine. See ref. 56, WO 02/26757 and WO 99/62923 for examples of possible analog substitutions. The adjuvant effect of CpG oligonucleotides is discussed in Refs. 57, 58, WO 98/40100, US Patent 6207646, US Patent 6239116, and US Patent 6429199.

The CpG sequence can be directed to TLR9, such as the GTCGTT or TTCGTT motif. See ref. 59. The CpG sequence may be specific for inducing a Th1 immune response, such as a CpG-A ODN, or may be more specific for inducing a B cell response, such as CpG-B ODN. CpG-A and CpG-B ODN are discussed in refs. 60, 61 and WO 01/95935. Preferably, the CpG is a CpG-A ODN. Preferably, the CpG oligonucleotide is constructed such that the 5 'end is accessible for receptor recognition. Optionally, two CpG oligonucleotide sequences may be linked at their 3 'ends to form immunomers. See, for example, refs. 62, 63, 64 and WO 03/035836.

(4) ADP ribosylating toxins and detoxified derivatives.

Bacterial ribosylating toxins from ADP and their detoxified derivatives may be used as adjuvants in the invention. Preferably, the protein is derived from E. coli (i.e. heat labile E. coli enterotoxin, LT), cholera (TC), or whooping cough (PT). The use of ADP ribosylating detoxified toxins as mucosal adjuvants is described in WO 95/17211 and as parenteral adjuvants in WO 98/42375. Preferably, the adjuvant is a detoxified mutant LT such as LT-K63, LT-R72, and LTR192G. The use of ADP ribolysed toxins and detoxified derivatives, particularly LT-K63 and LT-R72, as adjuvants can be found in refs. 65, 66, 67, 68, 69, 70, 71 and 72, each of which is specifically incorporated herein by reference in its entirety. The numerical reference for amino acid substitutions preferably based on the A and B subunit alignments of ADP ribolysing toxins is set forth in Domenighini et al. Mol. Microbiol (1995) 15 (6): 1165-1167.

E. Human Immunomodulators

Suitable human immunomodulators for use as adjuvants in the invention include cytokines such as interleukins (e.g., IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, etc.). interferons (e.g. interferon-γ), macrophage colony stimulating factor, and tumor necrosis factor.

F. Bioadhesives and Mucoadhesives

Bioadhesives and mucoadhesives may also be used as adjuvants in the present invention. Suitable bioadhesives include esterified (reference 73) hyaluronic acid microspheres or mucoadhesives such as cross-linked poly (acrylic acid) derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, polysaccharides and carboxymethylcellulose. Chitosan and its derivatives may also be used as adjuvants in the present invention. For example, ref. 74,

G. Microparticles

Microparticles may also be used as adjuvants in the invention. Microparticles (e.g., a particle of ~ 100nm to ~ 150pm in diameter, more preferably to ~ 200nm ~ 30pm in diameter, and more preferably to ~ 500nm ~ 10pm in diameter) formed from materials that are biodegradable and non-toxic. (e.g. a poly (hydroxy-α) acid, a polyhydroxybutyric acid, a polyorthoester, a polyanhydride, a polycaprolactone, etc.) with poly (lactide-co-glycolic acid) are preferred, optionally treated to have a negatively charged surface (e.g. with SDS) or a positively charged surface (e.g. with a cationic detergent such as CTAB).

H. Liposomes

Examples of liposome formulations suitable for use as adjuvants are described in US Patent 6090406, US Patent 5916588, and EP 0 626169.

I. Formulations of polyoxyethylene ether and polyoxyethylene ester

Suitable adjuvants for use in the present invention include polyoxyethylene ethers and polyoxyethylene esters. Ref. 75. Such formulations further include polyoxyethylene sorbitan ester surfactants in combination with an octoxynol (Ref. 76), as well as polyoxyethylene alkyl ethers or ester surfactants in combination with at least one nonionic surfactant. such as an octoxynol (Ref. 77).

Preferred polyoxyethylene ethers are selected from the following group: polyoxyethylene-9-lauryl ether (laureth 9), polyoxyethylene-9-stearyl ether, polyoxyethylene-8-stearyl ether, polyoxyethylene-436 lauryl ether, polyoxyethylene ether Lauryl, and polyoxyethylene-23-lauryl ether.

J. Polyphosphazene (PCPP)

PCPP formulations are described, for example, in reference 78 and 79.

K. Muramyl Peptides

Examples of muramyl peptides suitable for use as N-acetyl muramyl-LN-acetyl-normuramyl-Le N-acetylmuramyl-Ladjuvantes in the invention include threonyl-D-isoglutamine (thr-MDP), alanyl-D-isoglutamine (nor- MDP), alanyl-D-isoglutaminyl-L-alanine-2- (1'-2'-dipalmitoyl-glycero-3-hydroxyphosphoryloxy) ethylamine (MTP-PE).

L. Imidazoquinolone Compounds

Examples of suitable imidazoquinolone compounds for use as adjuvants in the invention include Imiquamod and homologs thereof further described in Refs. 80 and 81.

The invention may also comprise combinations of aspects of one or more of the above identified adjuvants, for example, the following adjuvant compositions may be used in the present invention:

(1) a saponin and an oil-in-water emulsion (ref. 82);

(2) a saponin (e.g. QS21) + a non-toxic LPS derivative (e.g. 3dMPL) (see WO 94/00153);

(3) a saponin (eg QS21) + a non-toxic LPS derivative (eg 3dMPL) + a cholesterol, (4) a saponin (eg QS21) + 3dMPL + IL-12 (optionally + a sterol ) (Ref. 83), combinations of 3dMPL with, for example, QS21 and / or oil-in-water emulsions (Ref. 84);

(5) SAF, containing 10% squalene, 0.4% Tween 80, 5% Pluronic L121 block polymer, and thr-MDP, either microfluidized in a submicron or vortex emulsion to generate a larger emulsion particle size.

(6) Ribi ™ (RAS) adjuvant system (Ribi Immunochem) containing 2% squalene, 0.2% Tween 80, and one or more bacterial cell wall components from the group consisting of monophosphoryl lipid A (MPL) ), trehalose dimicolate (TDM), and cell wall structure (CWS), preferably MPL + CWS (Detox ™), and (7) one or more mineral salts (such as an aluminum salt) + a non-toxic derivative of LPS (such as 3dPML).

Aluminum salts and MF59 are preferred adjuvants for parenteral immunization. Mutant bacterial toxins are preferred mucosal adjuvants.

The composition may include an antibiotic.

GBS polypeptide and saccharide compositions will be present in the invention in, for example, 'immunologically effective amounts'. Administration of this amount to an individual, either as a single dose or as part of a series, is effective for treating or preventing disease. The amount varies, depending on the health and physical condition of the individual being treated, age, the taxonomic group of the individual being treated (eg non-human primate, primate, etc.), the ability of the individual's immune system to synthesize antibodies, the degree of protection desired, the formulation of the vaccine, the physician's assessment of the clinical situation, and other relevant factors. It is expected that the amount will fall within a relatively wide range that can be determined by routine testing.

Typically, the compositions of the invention are prepared as injectables. Right delivery of the compositions will generally be parenteral (e.g., by injection, either subcutaneously, intraperitoneally, intravenously or intramuscularly or delivered to the interstitial space of a tissue) or mucosal (eg orally or intranasally [85,86]) . The compositions may also be administered in a lesion. The invention provides a syringe containing a composition of the invention.

Once formulated, the compositions of the invention may be administered directly to the subject. The subjects to be treated may be animals, in particular the human subjects may be treated. Vaccines are particularly useful for vaccinating children and adolescents, and more particularly females.

As well as GBS polypeptides and saccharides, the composition of the invention may comprise other antigens, for example, the composition may comprise one or more of the following additional antigens.

Helicobacter pylori antigens such as cagA [87-90], VacA [91, 92], NAP [93, 94, 95], HopX [eg 96], hopy [eg 96] and / or urease.

- a N. meningitidis saccharide antigen from serogroup A, C, W135 and / or Y, such as the oligosaccharide disclosed in ref. 97 of serogroup C [see also ref. 98] or the oligosaccharides of ref. 99 a saccharide antigen from Streptococcus pnenmoniae [e.g., 100, 101, 102].

- a hepatitis A virus antigen, such as inactivated virus [e.g., 103, 104].

a hepatitis B virus antigen, such as surface and / or core antigens [e.g., 104, 105].

a Bordetella pertussis antigen such as pertussis holotoxin (PT) and B. pertussis filamentous hemagglutinin (FHA), optionally also in combination with pertactin and / or agglutinogens 2 and 3 [e.g. refs. 106 and 107].

a diphtheria antigen, such as a diphtheria toxoid [e.g. chapter 3 of ref 108], e.g. the CRM197 mutant [e.g. 109].

- a tetanus antigen, such as a tetanus toxoid [e.g. chapter 4 of ref. 128].

- a Haemophilus influenzae B saccharide antigen [e.g. 98].

- a hepatitis C virus antigen [e.g. 110].

- an N. gonorrhoeae antigen [e.g. 111, 112,

113, 114] .

- a Chlamydia pneumoniae antigen [e.g. refs. 115-121].

- a Chlamydia trachomatis antigen [e.g. 122].

- a Porphyromonas gingivalis antigen [e.g. 123]

- Poho antigen (s) [e.g. 124, 125] such as OPV or preferably IPV

- rabies antigen (eg lyophilised inactivated [e.g.

126], such as virus 127, RabAvert ™]

- measles, mumps and / or rubella antigens (eg chapters 9, 10 and 11 of ref. 128].

- influenza antigen (s) (eg Chapter 19 of ref. 128], such as hemagglutinin and / or neuraminidase surface proteins an antigen from Moraxella catarrhalis [e.g., 129].

- a Streptococcus pyogenes antigen (group A streptococci) [e.g., 3, 130, 131].

- a Staphylococcus aureus antigen [e.g. 132].

- a Bacillus anthracis antigen [e.g., 133, 134, 135].

- an antigen of a virus of the family Flaviviridae (genus flavivirus), such as yellow fever virus, Japanese encephalitis virus, four dengue virus serotypes, tick-borne encephalitis virus, West Nile virus.

a pestivirus antigen, such as classical porcine fever virus, bovine viral diarrhea virus, and / or borderline disease virus.

- a parvovirus antigen, for example parvovirus B19.

- a prion protein (for example, the DCJ prion protein)

- an amyloid protein, such as a beta peptide [136]

a cancer antigen such as those listed in Table 1 of ref. 137 or in tables 3 and 4 of ref. 138

The antigen composition.

may comprise one or more of these other

Toxic protein antigens may be detoxified where necessary (eg, detoxification of pertussis toxin by chemical and / or genetic means [107]).

In case a diphtheria antigen is included in the composition, it is preferable also to include tetanus antigen and pertussis antigens. Similarly, where a tetanus antigen is included, it is preferable to also include diphtheria and pertussis antigens. Similarly, where a pertussis antigen is included it is also preferred to include diphtheria and tetanus antigens. DTP combinations are thus preferred. The saccharide antigens are preferably in the form of conjugates. The carrier proteins for the conjugates are the same as those described above for conjugation of GBS saccharides, with CRM197 being preferred.

Antigens in the composition will typically be present at a concentration of at least 1 pg / ml each. In general, the concentration of a given antigen will be sufficient to elicit an immune response against that antigen.

As an alternative to the use of protein antigens in the composition of the invention, the antigen-encoding nucleic acid may be used. Protein components of the compositions of the invention may thus be replaced by nucleic acid (preferably DNA, for example in the form of a plasmid) encoding the protein.

Patient treatment methods

The invention provides polypeptide / saccharide combinations of the invention for use as medicaments. The medicament is preferably capable of enhancing an immune response in a mammal (i.e. it is an immunogenic composition) and is more preferably a vaccine.

The invention also provides a method for enhancing an immune response in a patient, comprising administering to a patient a composition of the invention. The immune response is protective against streptococcal disease, preferably, and may comprise a humoral immune response and / or a cellular immune response.

The invention also provides for the use of the polypeptide / saccharide combination of the invention in the manufacture of a medicament for enhancing an immune response in a patient. The medicament is preferably an immunogenic composition (e.g., a vaccine). The medicament is preferably for the prevention and / or treatment of a disease caused by GBS (e.g. meningitis, septicemia, chorioamniotitis).

The invention also provides a kit comprising one comprising the compositions. The kit may further include a first immunogenic component of the invention, second component comprising one or more of the following, instructions, syringe or other delivery device, adjuvant, or pharmaceutical formulation solution. acceptable

The invention also provides a pre-filled delivery device with the immunogenic compositions of the invention.

The invention also provides a method for enhancing a mammalian immune response comprising the step of administering an effective amount of a composition of the invention. The immune response is preferably protective and preferably involves antibodies and / or cell mediated immunity. The method can increase a boost response.

Manufacturing Process

The invention provides a process for the preparation of a composition of the invention, comprising the step of mixing (i) one or more GBS polypeptide antigens (ii) one or more GBS saccharide antigens.

The process may comprise the step of covalently binding the GBS polypeptide to the GBS saccharide to form a conjugate.

Definitions Term comprising comprising means including as well as constituted, for example, a composition comprising X may consist exclusively of X or may include something additional, for example, X + Y.

term about a numerical value x means, for example, x ± 10%.

The word substantially does not completely exclude, for example, a composition that is substantially free of Y may be completely free of Y. Where necessary, the word substantially may be omitted from the definition of the invention.

METHODS OF CARRYING OUT THE INVENTION

GBS serotype III is grown in Todd-Hewitt broth as described in ref. 36 and its capsular polysaccharide has been purified. The polysaccharide is scaled down and purified as described in reference 14 to obtain the oligosaccharide antigen. Similar procedures are used to prepare capsular polysaccharides from other GBS serotypes.

The oligosaccharide is either covalently attached or conjugated (right or through a ligand) to the purified serotype V protein. Preferably, the protein comprises a GBS antigen or fragment thereof selected from 91, GBS 104, GBS 147 GBS 322, GBS 328, GBS 404, GBS 656, GBS 690, the group consisting of GBS GBS 173, GBS 276, GBS 305, 330, GBS 338, GBS 358, GBS and GBS 691.

80,

GBS

361,

GBS

313,

GBS

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