HUE032539T2 - Eljárás legalább két, alumínium-oxihidroxidra adszorbeálódni képes antigént tartalmazó oltóanyag elõállítására - Google Patents

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ObÉÜii&s&fs

Ittekvesikm rsfstsrW toli Si «aleae© thmsisdhf'# Ü* htfpiát i ik\Bs&amp;^mé*yMömi%>h!lm tyiumgmtyp® b vaienvs. ttmd&amp;dttg of its <s«j>sal8r:^i^m«Wd«, called piMytiixisylsMöi^hm^te^R?), whifcb iapi« má&amp;r U> he eifceUw w children t»tdér eoigagated mmmísf fawtein* fbrexmspk the tmimíjfre^is&amp;í·· :&amp;bh samfekstjosss ^ífekpssMi^sá^ls'^iminiaimfclfe ynnag ^Mt^.gei^^^í.ew^ÉgíiS^K^.sa^tg^ís: that «ifi :i:pi?ssi&amp;k dó:ysesstsaíd spfest s&amp;vsmi diseases its a skgfe oixsaSion,. ssiá stísss as aitimbmimbssss! adjuvant. iíafest apphítatkísis WO öabfObM5? sxmcems ihe pí<?l>iem oí vsomrc stsMIÍty ami teeomrooíKlst wh«a the hepatitis B arttfps is |MW%. «wtál^^^feg-tí öto stifcimlsmm byimside; &amp; is reeofmsemfei! is a<fesri H mm iiktmimmM0imyphm^mk or tust k· sdkssb b<

Pmmú appiiestot WO bWíSBCib cilsckíses a vaeeme eompossüon eoinpmmg, as k dssmhtd ott page O, antigens sifepisg líspstlls:© atsd ·%&amp;βι»ψΜίΜ -i0mmm type b te 1^ sáyoilssásRfe ss sltsmtotn salt is srder P> &amp; immsmogsiáis 'fhis is m: patt kkarifte ew:«itfe"8te Itepatkk É snrtfee anipn nrMSs Ag. ÜöWever, ss. is indicated sxi page 1?. of application \!!i$ö 9WK19Ö6, theiöih váláséit.. consisting ísiiiKe t^pssíiáF .pi^saccharklí txmjngated to ?he fctatsus proton, has a fandeaey tn io« its intmranogeaistty over time seben «is aliboBkíd onto almntnutn salts. 1« order to avoid thss drawback, the solution proposedtutilig prior art p asistd stsstady beets tecomtstended is the prior applies boti K'lVFRyet-'OÖ79I, to add anions aodiioípaftístdiaí ydsophaíe,; «ssbösale «a'ieltfsíe isssi: ítevvcr, tbc athbor» sí the present inveftiibrBin^toed üks!* khifedői»· addition of nms* iniprtiaolar oi: :phssphdtgs:pteersa?to?yiiísf atnsaiiy mak«&amp;i|:pössMfetö ps^vesttítheisílissppíiíts of tW-'í onto atomimat:! oKltSd hjnh oxide tAHHJHt. and sheredtrrdb .; maintain ii'1»«hrtí||^My'Stíy#atm«. this addhs^sÍj^vfe»S';''ÍÍ: terhsek of desorbmg the hepadris B sutllee autfgsst syhsn itbe MerflMt. fc<*lf. also hepp nisoihtd m®. atasÉhdn oxide hydros ide ftklkereíbrc necessary ts üsd a method tor preparing a vaccine coobbsiaiam csmspmhig nímiuatrm xixlin hedroaak so wlneh tt\ tiocxn v* R sbiHu e .-unpoo >*> kor 5 nhmtxd 0¾ xkiOH. ohxie.'S:dmBti> songén tg Isspí: ssmiKigmbed. Ίο this end, the subject <>i the presotsfíftsvaáitm: Is s:isethod for preparing a Snpttd vasc-ka esmbibsstlsn .Vv'tüptts'ngai least • ooebepatltss 0swtface^.stspesstUBsApi -.,· «»- ......—ππ:·ι·-·ιιΤΒ'ΐ8ΐ' - one /íi/Swwroe Svíx·. h (Bib) antikon eonsktiog of capsular poiysaecharsde XAnXgsted nt a cntrier protein. - aiunnmms oxide hydroxide (AiOOSii, la which tbc hepatitis B sártök anhgers te k«^t ΡΘ£Η| .$§: i$ ffitpf nonadsorbeds wherein: - the hepatitis B sorfa*. a antigén k adsorbed onto ÁH iOt t aj order to obtain ao AlDOH/HBsAg ίΧοοηΙον, ::» sasd AiOOiidlBsAg complex is mixed wish the Btb antigen in the presence of caskmtc otnirto add» «1 a vo>\'«»th»iO - <.H &amp;s teást töd ,ng I aad or phospoak κ n. .a a concentration of' s^ >H mMoi i

By 'íátoe of the method according to the invention, n k po-jdbie m achieve he desired balance ix iwe*. n looping the aasotption of the hopatUix it surface antigen on sire ahntsintsm aside hydroxide anti keeping the ixmmiiOr-pfh'O of the ihh <mm\o

According to one particular innhodhneas of the inventions the SiBxAg sohgars 1st adsorbed onto she akinlmiost bp nevnx ;'s 'itvrn.o ' r»f AKOB wxn ' s,ím esw »n of 1 B \g vor -nsta'g tot at icost 4 f»\ i' ptoterabh sttkwi 12 honeg preferably between 20 and 24 bonts,

According to one pamcuh» embodiment of she invetifiou the: etsijpslc asnlpp: stkidv are added.....to saM

AiiXIi'kXiBBAgcotnpicv before the mmag with the Hih antigen,

According to itt· aítentaítvecmhoái»^;iM^|w#^^^bfilc ssntösvtsdtdkWstktó topáid Bib antigen before She mixiog with the AKX>lbB§Ai|§ebtpgte

According to doe ftplmdiment of the ipphtiöö., ||^ phosphate Idas aid added ;Hfpi4ÉI^C^^Ág coipptek before the tnixing with the Bib antigen.

According to ppg dixtbrsdimem of site invention, the pH §f|^f:VgrP£>ipM^ sskhpioXhl the ÁlfhBfÉBSsAi complex k adjusted to 7.1 ·> (s. \ before the mixing with the Ihb antigen, lie subject of ihe: Ihvciihtn teteit ipcfPOTöbfesöMi id the snethod efahsted and conspri?;i:og at least - the· hepatitis B sortaco antigen» - the diphtheria antigen h the form s>f diphtheria toxin D, - she tetanus not igen in the fetid of tefastss tnkin T, ' die whooping coogi; antigens in the form of Pmifisd InsinfPfvd) and of Rksmentons Hemagghsttmts (FHAy - She Hwmopttilui Og/ocoroe type:h gntlgest> in pk«tphsík..«ö»iti^y-:-to the teMRos protein (Rif- 14> • the poiio antigens tit the form ot inscitvated type l, 2 amO vimses> terds íí: vatxdnP ípornghyjtsóh hte: thé stttiMli* öf Bájtig SS tlsslö: 1ss?sS: SsfefsSV: axdidmig Q|56;^Hös:ss: Is iíökö >%ψ xfhailyttpbtlisate. 8 has prove» to be teteietstly xtutsle to rem-iks immunogenie nodi bx·. buy sí iiw^iswii st> rrsstes after its date of msssaf&amp;cttire A««*^3Rg.--to f§&amp;'.vaeted pomflositioa comprise* a Ixepatitis 0 mííükí? assisges-s tsRSsAg). Ibis tetgds:r sssry ds prtetsjar be a hesteteB tette antigén ste as. tlw »8« present ws the Reoosuba»:·. HB** «vtódssá* teío assy pite hepatitis B teteé. b may is* partiadat be the reeombusaht: tesgnn entajoed by tteseisisstte xsf §. /termrte />ís/mi»fte! yeast which te tens nsxtesexl, a<-.«. s>í-.Hf v κ» she texbosungy teteoped by Crucall, ssseh as the ssrse preste in she Hepavax-Gesste voocte te stse purposes of the teteson, sSe .smooth of HBsAg present ás a 0.5 mi dxaasis sdvansoge-oasty stexveess a üshI i:> kg: abá is particular iö pg ,,Actor<h«g to she invention. the vaccine composition e:í>s«peB«ss S type fe iitib) antigén. 3 his antigen consists of ds« esspsste polysaccharide of she hae-terimo or lteysteo*y3Rit>iud Phospte* iRftR) umea s-< μ.'!''«'\ΡοΡ h« a smu< poneO 'he x.·«*ser psote srs oho S'e an* sutesr ,*sed os ttv- respsxt as te teem* flékl 3s tm> he, tor example. diphtheria toxin t>, isipMsis f, i.iaemophihss s^hemaa lipoprotein Ö, CRM 3 $7 ra she Λ?, meningitidis outer mombrane protein (OMVl Use *s preferably made of the ivtams* pi Site isi teles- tetette the PRR-T etette, fdf the ptesBgs MM® present invention, the PRP-T conjugate .:may be present in a proportion of from I to 30 gg of I-RR ptedJ ml dose; advteággteliy froth 5 so 2b up ol » per dose; preferably from 30 m 15 p§ ofPRP M.1»: dE>se} end more pamctdariy t a pg ot i'S ib conjugated to 22·· 3d gg.-oftote«s prs>s*sn.

Afeordlbg so she inventsos, ibe vaEC*n6 CE>mjH>5«i0S! cotnprsies alostsisusm oxide hydroxide ARK-Bi ihss idssptbssMfs Stv.< (s Eortmnís3s n«.<'nc%.»S* v^ilc-uab»' 'ixdts'Xtdc tu.v \RRds srbKis oats bo sisód kss-te fgis'posbb i-is'jsse pressnt inveinmn m&amp;\ be, idr example, the ΛΙΟΟΗ sail sxsRI by Brenntag AO, or R«hydrage3 |is \ i»os >·. h ivn (Uj^ies ><te' '·< Μ» eísK'ug** tb, >"i^ vd oi f \k tsxs' so v,sxh κί he two adjuvants diffets. l isa asnoant of AbdiH used is csüatlated so as to allow a satisfactory tsnmyne response us be ssehkrxad; ;s depends.:tn parsissular ess the nsnstbei assd snt she nature ot the sssssigetss ptesens in the tomposltldu end also on sins amount of eaelsiofthsms arttfaetw;· sb-sresy by \v;iv of suformanon, the oíSsíoíSos adsorption ot HBsAg onso Λ100Η is 3brass pg ot ps'oseas per sog of alnniiinssfs teorsviOititBi-idy. ihc arnysint of Atr.)OH ss expsessed as ararasiv; ot aluinininn AÍ s bof a v.;.'viS;> sb'···' í '''.ariis.a ' :st pe os'sss3'.s^ aba-^alae\ other sddit-ossei a-usp.esss, s ' pg os yjonuuent u<'sssd sees liSidVne ukius· a ,n> aniossns sSaP i: hesxvever isj4ufteii.'nt so «obtain the dessted ett'seaxy vvheo oshes' sasi gens are ssddeb. Thus, depersdiug oss she ssiktisiots of one or issrsos iutsSitisusat ansigxau. IÖ ng xs? HBsAg stay 3;e btoujdu stssx« aonts,; x« s«s« isxxssi 0 OS nsg So 3 mp xo siítanntotn "·χSo, Is o. OSx' ssao -usosn .sinosoa ',e,x>tranx teas by Shi itepfeatSi |íhsrts8és>te la s

For o\.mspk, « d,5 ob dose vt a gr 4' <ts r ^\s -e \ oevpi ssnrg diphibo as ses mm . OrfKOptm. o»ttí«ih ami mpaUOs B ; v ííís- mm m '.mioo' ath n óm s - ».' sí; y os am hí ο, p-o >. okik ayrm s‘sm.eh dt> rm: Ά aluminum.

According to the sttvontion, the hepatitis 0 «.urfctee antigen is kept a-terhed o« AKX>Fi, which means ihat at H:<ssí 60%, preferably at kast *5%, preferably as least ?U%, prefer&amp;hiy at least 7$%t |>tefcr&amp;bl>- at kast 50%, preferably at least %$%, preferably at kaas vo*·,», preferably at least 9$% of the total amount of this antigen preseat ie the composition is present so adsorbed fosat.

According to the invention, the Hlb asdigen is kept nonadsorhed s.>n AÍUOI1, which memo. that at least b5%, preferably at ices; 70%, preferably at least 75% of the total amoaot of this ant ige» present sís dm composition is : presentin nost&amp;dsorbodifhrrit;:

AuvOsJ-ap to she s os'so.o \ the period -Ί isme do* mg tv Inch hemmtss B sut'me osrí.v i is k>.pt s^otboo on she Ahkdt ,md tie 'tsh ontigut is kpt normAm he J se si leal 1 rc»x:h*. os e feral'v at kist A month , preferably ai least id nnmílm, prefemhk- at least 15 months, preferably at least .M month;,·, more preferably .0 •east 5b months start sop. fo>:o the dale of ιοηποίΧιοπ? of the composts ioo, o so··!', the storage- temperáimé ss 3 e 'X 1% „«abb lm Oil s sb'ski* is i ί e set Kd tt s>gei e ts B.be os O' S sue hm s s> o si ' ' *\ provided shat o remains onhin acceptable Homs i'kus, svhmi at least >555« of she tótat ásnom** of she IfRxAg present la the composition ο adsorbed on the AlUGH for 3 months starving from the elate of rmsmbiieture of she eomposikots stored at a temperature of 5 > 3Ό it is emirtdy possible that* after eme year arat still raider Pm xamv stoispeeshdiiiotis, 80% of she: total sipieioal: Of the HBsAgpfessm in the composition is kept adsorbed. io order to assess

Wish regard to tfeb siefsrrmissatkm ot sire percentage adsorption of the HBsAg. it is possible to use a swittakh 5 11\\ 'oeih'O ckomime s % ό d oied b·· ilv i οό'ν< « pixanaeope 1 3 ! A-χ-<1\ o, HA v> > ,φο,οΐΐ' 'Sin ÜHxAy p.i!-are O'Oses un,* ü i'u't O' LM >p, u weih o« « Am'I pan* loo HO-it s.s.' ssoiid ín <.oök'il with an ^oií-HBsAp seoesadar. monocli>o;-J aelibody, oilgG type, which is itselfdeierled by means of a peroJiidase-eonpierl artiklgt.» polyclonal antibody. A chromogeriK·: substrate lor peroxidase, íeirsaiedivlbosi/idiar t VMB), ^ives as a {Sevelopom egem. When st is added. &amp; color develops the tatensity of usooh i.i proportional so dm aoiomti of lIBsAe captured m the oeli the ivsoiis ore simlyaed accmsfing to she p(o.díel Iοic osotisocl elesi-nbod no tbc 1 uropean ptsasnmcopei&amp; Ihe pCKOougc adassrppon is öblhlPsd tan jise déteirsiiaalioíi of the tsrtaS HBsAg content mxiof the nooedsorlxal MBsAg content.

Wdh regard so she ammon of iK-soidsoBjed PdP- i the evalaaluxs can be earned out by ilPAl.-C-PAf1 (Ibgl*·· perfostsiaiiCe ion exchange chrorom-xgrophy - piilcsxl amperonk-irii. dettetion). x.,uiobog io ok-mcilonl vd tlx m\,ntiosi tk hepatitis ft i<mfmo anngeo ο. ,ηΧοΠνΒ onto bíOtílí Hns stop caB he carried oot by bringing the hepatitis B mMm aotigetríioíl iho AiGÖH inks contact to ibe abscsice of aoy „íher atóiprn ami allowing tóé hepatete B snsike nemem to tótónh mito tee AiüOH for o lenit 4 temt>, pipfembly s) Seató 13 hem's. entnoiy preiersbly betweee 20 ami 2.4 boom, m m< i&amp; okain a preparation i^mkmg m AléOM fiságeMgieió Ibisvafefpím «tói tó mrtM'-&amp;tá, -.seeing tó tóé tósotótók tó ;fe atóeace; of phosphide fees, -14¾ objective pmaeeó by mosna of»|5fö!«í3gí;d: eotóbeí ime betgen the hepatitis B suá&amp;«r:«tfifes -ától&amp;* : AfCTÖli grists:.·tó másMisiig d«íí«mtóffc Mmmíímm má tó : jtmmsf mg- #4 e laíetmtóos* wtótdt mn ihm rmiii tó wblíSBmsg,

Aseerdtegm ífe msíboitóf itó Invtóttóth tóé AMMWisAi Mipsat tó mised with ttó tílitsmftjftm 1» tós pnesesestófésífímiéami^iB acisfe: ásd or|tóosphafsJíss&amp;.: Föf tóé B«n>osestóf dtó ac«fc!i is. mtendetóio mm pHi is tógáé? tiuí« die giii of4lje-v»^te-eo^e«»tí«9»;^á'í3wfwch will therblfeee be sv ctóí<wtó IBssa et tóe pfiöí üie..v»ecine. these esc ile partteyí&amp;i Lyshte (Lysh Argmioe tArgt m idistiddis (His)· eseh örtóe^tóídhe iscids SiSfhtó-UM* n « i t nMm mt < lepi .ills ‘ Ve * i- He \ > |i\' ^<|. 'W*Vl? U'i * Vg íHis), Aecorbtóg tó s»te:pÉltófcmbtó|«»nB the eatksm·. smims ssids may be assobiitbd tó tósseptóeMm,· 'hlemtot*:«y :faÉfediaHy be rnsdb of die dipeptjdes tys-l.ys, :%s*Aíg. lys-Bis, Arg-Aíi, Idsd-lis.lltó-bysemf H»«At&amp; Alfemaite«4y; a dipepbde of i^elsrthe poroses of the presetó fnsetóitm stray tó *m$mé. alfa sísdohte «Imi asdb mtd of -est sísefsafietó^iesi seki sefetóed fftóv Áfa, ¥sf fka Jso. Pso, Me| Phe. Ίφ, Oly* dog Tht, Cys, ϊy>\ Asp aod xa»öf&amp;^::b:p^c%-»:|»^pmba:cMtó}i%;:«^*»ss»«-5aid^x ammo etid^s) in hoc amfor dtóeptide form may he esed. it % sf^i jmsslifg iomse stótóo setd timpomíiötss ;. isnps n '> o sn on, »iiJ » PtNoeriiam» « >*»» \ »te-wtáttmer:Mgfe;^^ifestó«^idptó*Re:: .too gr*a? a drop tó the pH dóriiig the addídsa efthe ammo acids,, i? tó possible is etiviskssi ímMsmg the pitóf the prepamtas eessipHsió|:4hesetd:tóo imíbtóbemre adtlsgiift tó Ató Aií>Of4d4B$Ág eompteig by msaes of a: base, ippt$i««fk:RidiömIliyiáro,Kklaí:.: Áeeoídsny to theloveotiöip: íheiemostóiAjfissttótae atóöo ittóds dlffssMdeiy pt^^f:.ötil.te;-:saoótego«tpas^öíV modi be iít teasí iCiif mgli*ptótóastggsousiy m fetói; lööisia^f,; iafcoiaf^^^váti&amp;así Λ mgl -m«é&amp; prefemldy at te-ast lett otg'h Them itittö'itófitói:masifeöm-i.dose,-.;Ö«wam^I:i:%pdlM6fe feritei-:«tax8fi«m .«tnornit to lx- at most 4 mgtóth more preferably at pmsl 1 .οιο*«:ρ?«Ι&amp;»%. af:-te'#!S' #00 jtgfmL eofbtdy pefembiy at snovt TOO ngdtd. \bhsm caiceiaaieg ihe aotoodt of ctómnlfe ámító acids toitó added, the oafteale iBbteo acids that >sm> be iaooiitKvd by the media it·· •^Wz:iWm\$’m:®Ém:· then SiBsAg áed tóé Hsb aot»gett nresceS a tend d in· mlu-o ode ^ocooati iAecotding lo a,ne sitemabm of-the 4«íÍife«»ÍKt-;fc-aws^d: #í tókmte reiative to the weight of she fiib-.eo|tó^ar4tóÍtel^3«.^-1«.iP«5fltteftó*11ih-:pi|p^«ia^iÉctó<tótó'tó?tó:

Otód vuvht f OiO ni ! 4 V 1 5«tó ο>Κη»ΐ<'<νοι«ιΚ of ϊ Bitot ftg pjeternbh ot 1 l>tot t,0. or peatn obi· te iprok-raidy of i. id isi I: Jo or 4ii<

According tfa Ihe method ofthe ktvsklbsg imAliKiBTtBKAg s^misls^ ila ^^^^wisSs t^Afib sndgertd&amp;Afes pmsmsi· Mmtikmfa tmtlito ««Ids, 'bt#sfe« fa sCpe^'»ta.:íi»»i AesmsAg te Qrs^sH&amp;mdímet» «£ Ι^ί^Α^ν^ίΑϊ^ϊΟί^.ΙΙ^^χρ^ΐίκρ^^ϊίί-.Ιίΐϊ^ϊ;: isr« :Jíiblg-b ;1:« tbb: A10ÖI ί>;|· 1 ϊί 1¾Atg: <ϊθΤ5ΐ|?1«5ί bieíbf« SÍ: ís |>^Kíg:h3?íίΐΐ wíííΐ :fc>lí!b 2jÉ%^jí:.:T^-:^tepto«4e!«s «a^rfe-b^npNí fee sss4fcw:ftssÍR»g«8. phosphÉe $r :píbsiam;l^áf!^|es phosphate, t«f ehmrrtMure öfife tw 'Wmmmmt of phosphate: tons is calndnlM so ihsi i8ie.:«wla5«myi8ísoam of hepatiks B swd&amp;og muigens reread ajilösrbud ok the AI£®| wfeiie at the Sasié lipid avíiding fe;atfeurpiion of the H?b tmigpn, 1¾¾ atwmnt vafiss; according to the auilgeos pr«^{%a«é'in particular atoetdidgipthoaoigoss otfeorthao the lIBsAg asitillífe sdtipös.

Thus, u>r.a':vamsvs oimihioaiios com|>mihg the aaiigens ppratalljr »É^1ó,p^^^-íKtóá^ ihat Is 1¾¾¾¾ id addition to. Hg IIIsAg and tiis W^nfegmjjEfee.^jiltiheria, tetany and whooping cough antigens, it titanic adyamageons to add phospbí8i'$É|K· -mfaiMgá tbt..phosphate km eo«eot#af|t>a Is the vacehie compfeslÖöft' íölimatehs obtained Is at leasi egoa! to 35 hthfoi/'k gob «wre particularly Is hetvveea 35 &amp;ικΙ4$ mM«1/l< hlhjis uncladed. ptvíeraidy betweea digltd 44 mtMbl/h IMIis kichided, srtitrdy preferably between 38 and 42 ttlMokL illMlis Included Wording to ood igrefeshk) eutfeodknem, the phosphate loo . ermomitcaison In the vseeidf family ojklrmed Is4d othfol/k

Apsordtng to ott .omniatn > "if-' '«htrem, «he px> phate mm an aided m-tm amount »uoh that tfrc\ ate p*e*e«!

Is the vaccine composition «t a tmal eonecaif&amp;tkm of jkdwssn 35 atsd 3S ksMPbk hokis included. This, ip «ipleted |>y uko adding «.athonote Ions, but in a limits M0MÍMMS&amp;Í idee it has in íaet lkam SpWdbid: an excessive amount of c&amp;thonate ions Is ufdavorabk. Advantageously, they may be added in an «.mount such ο η '\ \ m- present ϊ' te vaccine so* 4' "'>'i<n, ht> d <, veer’ruttoti ot loss than >« «-'gnai tu Hi m\kd i

In shock etdeh could destabilise the HBsAg and promote desinptum thereof, it

Is:tm*wtigt«feá lörftM$fe®:::$feö$ph*iu· ions η» several «exampk >n 2s dsstmet operai iim» tsteps). 1 feus, the phosphide kmsfsmtiy:lk added M st drst ooemtion,. I» a η.οιγ wl Jv ^tLis t p »' e to ae u \e a <nl mmmkfami of between 3$ timldO PtMoh. ΙοηΙκ Included; then, m a secood operaion, in an amount a huh makes ífpmsifelelQ-aeMfesfS^lrsáfewteieniiríttjeh 4 s specified dbbys:.

Acsordmg te- one, preferred emfeod invent «ft the- method according to the us yen; loo, the nB of the preparation oosa not s t 'do tn Jjusteu to 7 t + ! t Hostgtm Mn nogs « λ rh th« '5k4'tBBI"\> « > pies It has In fact been noted «hat such a pl I vine das a positive effect on keeping the Bin antigen in the nonadsorhed state. áecocdiítgto omipmu-'olar embodiment, the >>! i Is in addh Inn adjusted to ” I ± 0 Í a*et «he mo. ng ph^ce llnSj l%- vtttye of the meahod according to the invention, it k possibte to ofetalt» a HKome v»v;nposkioa in svhteh: - t (I; feast 60% <>r §0%. preferably as least total áSMstmf of (he-:i^iis:fö-:spte^«sii^ pi'CSOSt; fit Síi? vOOspOÍJhOSi H Uihorhfcd OSt Üfe AtfOfiHfeír Pf feSisi O SS!S®!S StSítíítg ÉtSift: Íli8 áate oí StOOiohí-Oni. <d Ú!é eOOspO'öSiO!! SÍOi vd .>S -.; tOüSpeoidiK' OÍ -'' i. 2Ά S -hid :||1| as jtefesí d$% ?ö% a- 711¾ %i:táiát:::8»tötó· ö$ Öfe'Hib·· hsoörn enmpöátfp ia nai sdsorhess os sin; A ti K dl tfe expresssoíí -‘AlOOt l/t l*UAg e o*tó<*·4 shöhlífbe sníeq:5Föíí3íÍI tiS intessí5tlí5¾¾ ífeö «|>íe?s s*s aifétó

Isti HBsAg antigén adsorbed on AKXJM. The antlgm^sitál^ ÜaÜ ksptólbá ar:: ttot.

One or snoro aíldsíiooíd antigén*: t»ay :-'m. srfdiífeo. &amp;m® t««« iSN«:..«o^>fex»· -Λρί staff «5 psssiferdfef te diphthem sóstóid fi», tetanus tötóá-fí)* eoasé itmaííalar aiti|em «tó lstef«xifies* ttóa tPTxd), isfesssessfoíss hesmgglsiinín (1 H ferfedfe φ Mit antigén) aná *^Mim>®em •(ftmhtínO of mit. *a«n bar* s .«tat, leetóÍRg;%:« p.assvui.jrfy aásssatagoíías ssnhodisseoi D* -)¾ pfxd sad VfBÁ tustigenis rosy 1« addod 10 orá^::ts-.femHfe««titJ5itex< 1 he additional ^m^mm^-bsmiSMá iwmémi-w%y&amp; ss^méU%Mbmíng öté htptóti ti isisen aasigvss preadsorbed ti) eisher onso the totói 8m<aost of AÍOOH that needs to be present so ihs ymdm cotnpOMtioa; (ti) or· -otó ·«,parisa)s8ss«n«8|·.-:s«^^|»!»»If-: tóid ίο M rtmh $m tónl. amottni, hifensasstely. tik- additional astslgvs» may he adsorbed separately, mit onto a parttal atntnsnt ed AiOÜH jnsl d-.v she BBs.Ag. A mixed adsorption- grocer may also be provides! ibr sosoe aofigens belssg advorbesj •anmrateK other.-' being #sosffecd xe^atóilly. V>v v k mi wt ukt votaodutan m *»<e o^etltró^mdlinidoibe-'áavtóto,. .-Sifted a dor site addition of vacis ssisitge)».

According so one advantageosfe etoifeénntó* gsyenoniy by w&amp;y of exssnglih the fiiisAg ss adsorfesd sepsnstdiy onto a partial amount of ASOOÍi pra^ai ;n the final composition. fit panidof fho li> astd:l' assfi^iis as« septófelíy adsssfi^ noio she gdtfAlosta! pass of dse AiOOH. The HVl arid TMA -whiacplag aoagfs snfipos ars ttes a^fed to she;:;pr«|^mUors-t^dMmhi||: she AKX>H-lvr vo»npfex. eaeh of ifiessi two ndtospistg eistfgfs ondgsos fbefstsoive'i having been iadsvakiaisy pfeadsoíhéd sthfo AiT^T ^msdty. ®d· f^f^snrafiott·» fAtOO» ' HBvAg cosnpfex and AK'tOH - D-T-Pfxd-f1)A «orstpfey) die: conthsodd ikSíASdoiorsri a psspsmdiöo eoshprisapt she Ak κ.>11 tIBvAg-l1‘^tvd HiA so tyftfeh thd asrsosgsts ot eaefsidf the ofeotestts have:: beets oktsmsolo ohdsjn mmm. ehgvesgiosgdlT' irons 5 to 17 μκ ol HBsAg .·' dose; pseferahh i ft μ.> s dossh dons 20 to 40 Lf of D / doses preferably sVoos. 2? so 55 fSr slose; esgfroty pofesssfdy 30 Lf / dose (Lf- ifndS:ofiisteegferidn) (esgross^f5¾asvjfser t^as. «he sosooso «t ft »v ^catcr doto)> ihnn 3 to '25 Lí ot T ί ptxfershív note Rs k< K- Π dicse, ensiseSy pretetnhfy Rl k-f >' dose ieo-o'-sseO n ux'thóí oat, fsv ,s'TK'»u' .ν' Γ !.;·ί.ν.'ϊ úi -.i; ο' cOvoP *o 4ó U,' dosts), írom 20 ki Rs >rg oH'HA í ek>.x\ ps'to'es'ehh 25 ng / dose, *ÍO K'< 5 <\li \5 i\M ' C t. >>5> X ' '< » V ÍV; $lfi>t<li.ng to »oe particular embodiment of fh« invossisss, folio artiigeng, Which conveotteaMy #b:$lsí 01' s«,s''tsv'tmg v!í\! too -A„: addeo k t<o e-oooon>\l ϊο aed ρ-dnoüUí.>'\ o; ths t tspes mooíh, ps\?ou5 ** pdsasrit: vaccistess, i.e, types i, 2 ot 2,«? «lse, its the iísi ^sat ti would oof he accessary to vaednaie sg&amp;htvt Ée-3 type». io introduce only she types agoinst which protection ts sought. The anwuefe ot pohovsms per dose ?ósy iu particular be betwee ^.u -»ΉΙ »V**'>t ' m' sp -o > 4b t' rcr\ \ ste..! ^ í'>i o Ot *s wtKi <' s miw between I? 85id 36 ídi, in particular >2, tor type >.

These antigens sf« not »?ce»»rity preadsorhed onto- an ahansnssm s&amp;ii hetibe being addesl to she νρρϋ&amp;$ prepát atKss. Λí. eosdissg so esn- punieutsr eosbsxlimesu. she nuohod aeeosding so the invention isti method wherein: (0 its) the TsUsÁg tssid ít*e AlOOH are brought into contact in ti)* ui veres of nssy other antigen* and:the JIBsÁg Is allowed to adssnth onto she AIOOH Tor »t ted 4 huurv, preferably «I least 12 boats, estfirofy nates e< \ eg" ^ n atyK house e-eh* nr spej station cwttsnn s»g <m Mi KB! HR Agv usrpSux; (;) ;b} .·, preparation comprising she 1. Pi'xs! and RiA antsgesis. prendsorhed onio AIOOH, soul optknusSK mkhsionol fieic&amp;ioiVn p-.-nut^s antigens. such tss periadm surd aggSHttegans, is added-to rise pa \usd ό obkooed » vndps'h 0*> phosphate ioos a»v added 6> the jnepsfasion obtained in point {ss ib) in .order to. 1 :.Í.<^Í cesíoöskrassoss is>. the vaccine <0 4Í) tnMoM; (in) polio isoUgene ore oprioeshy added to the reeperetiois obtained sss point (ii): (iv) a pteparaiiott eotitaiithit: tiie Hth onitgen is added t» the preparsdion obsained inippmt (hr or |ssi|; (vj She pH e .uipi\5ed So ?.S ,:,4.1. as:d (vi) i<5! os least ooe caiiome amino »e*d is added so as ie eompiete she prepismtloo «Mated :id ssotnt i is 5 or {vss ixddo.' she adást I»» of the ΗΑ antigen, os' 'J>i at lea>s ten- iOSecec ososou as'sd :s added So sS.o shh áassi.en J vthoie at os k ^ leoe '4 s os st aü > u t ‘ »v ttn -. \ >o htdhe'vsssote os as less! 100 osg's.

Arcerdistg so -esc psrtkoior esvhodnsseist, hie sssOisisn· esiistposhson aceordsng h> the mventsitji x a ooisgsositiois cosnpsktnp ilissAg. dsphsheria torn· I), sessssms tócsa I', the Pl>.d end HIA ohooping ennejs ,οΟί.οί.Ο5 h&amp;tsng SvCn pi .adsciS'Kd Oijso AiV'St it I 0"' t Sd' .-ns i' aO>\ OpO ssso S'- she pnhe -. ,ds :o,, O: v,' i,}, ikast''s a f ,<m>ohk <! , ' s to d >·ικ'.κν\ \ i-UV \g piwm s" h xosrp'\5t\ ' \ kv'ps noaostted on the AiOUH tor st 'east 3 «moths storing ttom tto' dote of snamtfacture <*f «he cítrajxrviissm stored nt &amp; tempst'ottne of > * ,3 \.; ttod <n) iu least h$%, 70% <HAji*fcmMy 7500 of Jits loti! smtottni of t^:^:|^ípá pSÉtht' thltti:' «urapositioo is oos adsmisiioolfist AfOOH, ifps ^öüntf^amfftg isíkiivgp sísmoveí time. 5;s addhims by vntue of'ska method necordsssg h> iho mvmiiion, «ho antigens other «hart HBsAg tvhieh shooed that it was mivimmyeos^ for thorn to be adsorbed onto aiummasn oxide hydroxide in order to be aomiomgeoia, mm tiKo kept adsorbed. lbtiss ft jg indicated, by veny of exitmpfd ihnx &amp; «ο«^Ι|Ι$η ftbdiÉ®g.fF'®^ fn^hiónhAfty sospprtsl::

IdiA f 0 to .30 pg of HBsAg /mi: preferably 20 pgdhtf;

Stom 00 to tiO fdot D'tnl, pretetithiy- from 50 u> 70 U o»iv tlhsn IBM SO Lf οΠ'/ms, preferably from 10 to 30 If óvd; from 00 to 00 na ut FHA ost; pmsersbo SO pp nth - finnt 00 u< 00 pp at f* fvd'mL mermaids 5tt pg mi, nmn 3 ut«ti ogof t'RPnti, psetesafdy 20-34 ugml; from i to .7 síig s> AR)í HHm pnAerahK I d mg of AiOOH nd. phospisao ;> '! s ,o o .oneustiudm* at 3? to o? snMoi * psetesabH from OS u> 07 nvMol 3 of phosphate sons; frosn 1 00 to i {300 pg'mi of cationic amh«> adds. prsAerabfy from 40# to 800 pgétni; and optional^ p,d {t>v!fo·; types i, 3 and 3 in hnsetlvated Aims, in n ivmxmtive amount of SO, 30 snd 04 DU/nd

As psevsoosiy üsdsaaíed, a oontpcenoon aecotding to the invention smsy also <.ompme adsition&amp;i Bonh'fdk) l erfusih' aistsgeos, such S'- pertae.ms t<d 09 kDa) o« isgghnifiogcus. tkseripssoo of the tlporv ! igm, 5.- a vchen-a at s pssm mi u-eb-mi nm.ua; ,a, \n«e U earned smt aO-a -v addition of each component 3Ak01BlS tmiovts mhn'aie pteparstihm sd n hoik t2$d 5) <« * Ikpft 3.3s 3? AiOm« pdto Hill hexnvetesst xasoCihe 5 toe pteporation is ossned not undet .-tetiie emelmon - atsd v^ith «mOimams 'Sitrae:.

A Frppsratios of líBsAg sdsnrbísd onto AiOOH :A Mn'ii>g<s55e3At5t $«st%tsiofi of &amp;iut»mom nxsde hydroode {AlOOHi gel -sold by .Bresnstag A03. «3 S g of niumissíümdi is introduced asoptscsUy mh>« SO I tanh.

A3fet ^stnejtion tfnotsgh a..o 32 rot' idtm she volume o3 RBsAg teotoreti m e'btnsn a wkentity#* of 30 ne *ot m the tbe;d viter ate ss eontsoaoissfv ndvkvstothr tajvh aiready eofitasmíjp she ARtOH t t'r ms'tort'm A it to its to* 30 m 7 3 iu««s ,0 ,,)s,hsent r, nt|V\4oso ;.o a< toobt,oa a homos mu o; s NOH-mneien B - )be§wsstftra οί 13 * 1' » IM'vO * Fi i Λ sdsörís^l »«U* »!««»»«*« gel h'i $vsr,:Ok-l, δ m; Ahfe os' aisimiíiisss* gel, diphtheria iwxokl (öt, tetsssas tossral * >). isordairihi portássá; Sftxoid ίΡΆΟΆ v v ι«» \! t*Mi' Ιϊ> ΪΧ ίϊ li S.J It! ' i í \) \ P V l'd» V ' ÜXs ''' Is A homogeneous· s«s^m!öo fjf AI0O? I gél. söi|i% brpddi #0, ht f g sr>so &amp; 3501 tank d u > '0 ini h * Be* vj η>νΊ o e* V'Kv ss< < ' m^j'Kuí 0ts\ 1 t t v *hs »gx * i)' m,t >vi ! tin k Iíü1 v ! v »' Us Sk h X H'ü » u<k 1θ!>Ιΐ! ν*\ϋ\' j 1' >;<.'íh enUftüou» !« she ttraft xs»\'»no ut hO I f (hmsí ot ntKenkfton) mi .smi 00 I *-'mi O-kc *hc hóm*. &amp;e neons >»'\λ v has Kva eb-a u*t Λ vustn'ivuon .ot ^UO |>»-«:«»L»Mtíeo.ont«,Ak>*2t* :«»«1 ife&amp;v Őse suspension οΠ'ΗΛ preadsmbed <*m> AiOOH ere siseeíssivdv .iddi*£a«9tfoú&amp; «ttferfti ksÉ* k »o)er:?o :í?hkk. PTM süni FliA .eoüppitatiohs in Ősé tip) vhpsftg:ef2f Bgmsl· $1#%, Οι* vohísfö dí :M ;s|M óípikptae hifiik· repfftM ίθί:01>0θί0δ Irtfó imlMgi/i i$ Aided sOin* (iiísdfko thtoggh s 0.32 piti ipftBx i! , í!v í \ , Π \ * kd, ". i'vosw'ri ss tód s<:>sls·' fos- at lead 14 hours at a ísm^xsíííU$re oí5 t :);>C.

Γ - Prepanstmu oí the rass-tiire ot HBsAg t 0 ♦ T * f FBA lie ^νί,Μ a so* v«s δ 0 apes»' % a a hk\ »< ptm t s ‘ > he vSASsft.><.ns>KaiKd >>s s.s>sm b 1 h s \t te is k0 to -sí! a ' χ{ δ ΐ} a eg- \ v s m spension, !he volume of $<K> mM phosphate bs;!T»t seipilreii ΐ·.> obtahs a phftspj'i;sie; sfts> eoiU^!!stebi5h :0f 4fl :S3klO:l3l in the Oha! ftomptsitson ;s Slsets adtlftti after ftjfrftiiosx shsoiish a 0.0.2 ura fsbes·. 13 - S&amp;tso'fttiöu ot the eleetrostelk sites ut she attsmssutsis gel ItOsAg * l> * ? -s FIs si e I it Λ .eemjrée* wttfe a solution ofoutino acids A solution stfissTSisso adds eontasmng i 2 essesstisS sussisxo aeOSs. having she tollowing cftss^ieslit^hx^F^ft^®^·· - Argmsrse hyvIroehios'sOe .,.0 1 g/i, i.ft; ).75 g?iftíhígkifte • C>SSÍtK: ......);2 g/i - Hbikke ..,,s,,Mm, 0A g;i

·>:. |:|ti|ftíip|áft' , - < : ν::ϊΐ:':>Χ'ΐί:: 2 6 gO

- j.endue..................... 2,6ψ I - bysise .hydrochlwkie.. 3.65 go, he. 25) I. g,d of lyske - Methionine............ 0.75 p/l - I'heuMvikonne . .. 1..65 g-i -%-mötsiöe.,;·..;.............. 2.4 g/i - Trypínfskan ·.< ·,:, vV.,.,. y.,,,.,. 0.4 gd ·· lyraxine ! Jgd :-- ¥fc,,.....,,,lip

Thai k k< ss»\ 3 5 v* g.d d^atnlno·a«"y&amp; toe.U«dWfc 5,44 g··i os'utionk amino *ckh <H«v Arg - Lyx}.

-On* ' S v *t x H> i ^ *» S ,!<» ^n>< Kiih 0 , ‘ ft'K with stimog iw Id be 11¾ amino MÜÜ sAifenvilBi^^iiKrosJgk a 8.22 pm filler w cotusmtousty tokkal k> the mixture obhihsed hffe m m··k?: PbfA 3:gooeegkatkoyof -|f|-pgtitI of estlnpip amino aeida In the 8M;t^mpsíjkm, K -- pH Adjissfsrtent S x rU or ms suspenxtenropimtted *« posm » J "U'i I ' -Ogu' u\iiv * * ‘sodium hvdroskSeni2.5 N. k -- Addition of the pofin atifigopi -&amp;:.preparation eopigpuog ppltovitm xerotypes i. - and > ut inactivated form «.Mahoney* I and Saohett xti-gpis, rssspeetsveiyl iMiered through a 0-24 pm filter. is shea introduced into th« Sank comamutg the suspension obtained in E.

C - Addition of PRF T

An smermads&amp;te «.ohmon -d' ERE- Γ is tirsi of ad prepared in ibe foHrwmg wav; Trlx-mcro-sc bush-.-:. fdtervd ^forehand through :s <U2 pm filter. is added to a preparaiku? ofPRJM' filtered through a 0.22 pn? fdlsr. so as :iseorumsitse an mte« mediate mi More. S'fds i* infiod'iMNi weptsoaUv m«o ski. 'mentre otmm-'\i in S', H - hinat adjwMtmmtpteie \lt! VI I «<, < (. d |ac i J\|V is OS WO vl i «< « <>' fOnlpt. iifp e. ui OSiM.A Ά * i< Vida, ι <i in seuee dii' t&amp;tuet vySame ni i'd s s«. added. I he». » sexessan, Use pli «r «ρν m-xiure is adjusted ín pH 7.1 j. is.: hy adding a nreíikered 2.5 id sodium hydroxide or kt% acetu: amd solution. T he mixtme A stored id ? ;- ;V <; inén d'xt< ibn'ed smo i»yr>oges or honk;. m a p»op<>i Oon nf Ú 5 od do -'

Ode: d.5 nd dose dnn. eogiaisk kOd ggof A= :ih i 0 ug of Η'ϋχΛκ, no ipsa than Μ Η i of D, m k*s* than 40 M.f of Ti lS gg of fs, 25 gg of i-HA, between >8 mtd 43 Dii {D anttgeo o«hs) of poito type I, between 5 anri 0 i >s s of poiks tyf-e 2, between i? and id DU of polio type 3, VI ug of VfiP (in the fortn of i'RF- f). phosphate ions a- a ekhkenSraiKni of 40 MMnkl Tris-iaetoi.e hnSor at a uoneemnssion of 2.5 roMol/l of fris anef or 2 t :?.55W-of· sucrose, arid nko aao ug oi i.atn>nie ..orbno η-,'χΐχ sd us -- Arg -· 1 .y-.,,-. klithkaldridl;:

Ilte vaccine contpnssthm ptapami oceenitog: i&amp;ihvmm%$k above w^tósá^-a^llateaí *rlah eompreddfea hexctvaient vnccin© aiteady pteaent oo Ahashttckeí, vttddrett against the same diseases as tbc y atomé ptepoted aeeotsJmg ío &amp;»st»ve«t3ao. whooping sxmgix politx Hih ntfeetkmc a«d hepotttw B^ bsx wblebíbssib líssífeölar the drawbackthst o pstst sí $ is iyophiiized and therefore nxtsxstes on operáltat) to take sgs Ahes Ippbsbsibs |5s’i<'!' to the sdsnAAtsStsa sproeedtae. tSoHhgdfr t't««Kv' «rxn. tk ' vu e* ofv^* « x - ^npoeotottv were· ottoWibrdííf^.tfi s wssethesohosos; cwsipSfsthg lidíWhs ddtöhitsisíed 0É3!$ attá b sooaths. Thei .lápod. vaobioe prepared s8«<^éis§.-M-:iií8:5s»attioá,:ot· ihe· invention proves* fo be vers welt federated. ami as o«t»»»ö|ostfeas the vsaésbs prsssbtíssss thomorkeo

hXi^RlMENI Ab DATA

Fereeotage astsssrptiOS of íJB* Ag/amoxoxt of oosmhxorbod FÜí^T

Thíps hawhosóf ihat bxdk product (Pb V3$*4l~12> ^tWfe:S^^oh^áiS^iÍJ«teáint#tófe::|I:11^34I)···”' alf the hsabhes haváig 'bge».:ebtaxsed sasordbxgm d)s easn»|ile provided - were stored at : 5*C and «?«%·:·>*;! at wsricssx* sím®s sverw psíMfMFF -and 22 motets*, the^stseo^tMia^ioh· of HBsÁ;gaís#:f:hs ooxsoíh^

The percentage adsotptkm of the VIBvAg *as dstomdaedpas- was pstídbasly Mieat<?át ttom the tótat liBsAg; extent ana the noxxadsorhed BBsAg mwmi tbs mtb-»s%g:s:sas^feh Π IS A method no-cording to tlx· shies defined by the laioipto-ifiraeia^sta^itvb Bt#%* tho f !B«% was captured h> an asht-MBsAg prim s v tao ><. s o * dthex, of h>M t> f> > sw b of « *»h west pitxe t ne UBc \>>. this hwiiii was Mated: Aftthüáa anti-HStóg 'sm^k^monoeiöt^a^ii^yj o^ip:'ií^· whísh wtor hsssh' detected hy means of-tsg^őaidasss«ö^fed atü||P :p^eS*rt8Í: :a»Ülitoáy< Á: lahwapphte. :s8hs?tste tor tpsroxkhisib í«,U:o»»<".rt>1benaiöine tTMÖ), sx-t veá-as· «-dewloplog agmt>: Pheo It was aháetb s ooIöe· dé¥etope4 tho intensity of wttteh was p^Htríional to the amotim of HBsA| oaptoraslia ithe wolh 1:'he: sesoka: wore; 5 !ÍW( >d> the M! twuu W Vfi\'S XX ÍO^í ü!KO \ ^ to order ίο dcteíiflioe the percentage ad-ioqdiotí oí hie Uíb;Ag. she vnacíse was eohncleh to <í-'n-;rifngst>oa ,^gpO g; 5 mf\; 20VCX which made il pocink ;<ϊ íoceoer the supernatant contain mg ttse nooads-wbed HBsAg. S be saovgias oisopemahmts to he tested were mhaed so t i tS.A hotter eosoprssosg a dea^rpttoo hssOer, in 2-sbld sedal oiithion» in a «attge incHtdext. for «sample, Ixdweest Β40ΰ οίκ1 tíb> ht>d, jt O SX SXi V ΐ Ú f * iti h ¥> * >1 s I ^ \ Ί ^ e't onv'gft ts s'i 1 ! ! t i dí#lá;sátM IbliÉsat»^ hetwoeis l/ü.gnd

;A ih-wels sdsie coated whh the pitmttsry nscote-'toosti tssitshn-.ty was mcotsated hw \2 h as AC and then washed svith is PBVTween ah cotsososx Use ctihshcasa >s' she syp^nafasxts, <>t stse total varessw and oftlte sssassdssoj range wese dsso'sdmed inio the weha The sr-xasthwy asohx?dy woe then added anditte developing oos estrried oos with :t!?- xu s t ^ i ο,! v ϊ |x d >s,v< 1 tresnsO c 1 eoesAw) «V v sv x·- t>s xsd* < S H€t itefte was 3Ö wíh ?lí« #!§*

Iwee» 2ö sobdoo. A IMró '(áieített baí&amp;f} .3» .mtó«á. te·: Λ» ρΛΛ: weUi. «hkI oí^ws^t. ito is&amp;me PÉmaxav The pkse wasMáaí 00 4li «S $M 88¾..

The sammoR of ííiosadsoAed RRIM' wss svalosssefe fey HPÁBC-TAD (high pmfmmm®· mim spfesop «shmsnaíöifsphiyio:pdskíl delsefeoo} I» iho;Édlö»lo| ^sp á siásdassl raep :öfím&amp;rsa«e i BE.P*T of ISA fe> ÍZS.^míwmfmt of#U fnspnsá 1¾ snipes to Be fessed· sssi sise lhe-stasiiaoiiraoge ssmpip smo eeooifeípd as SOfKí g for Λ min as smfe-em :iap^ÉBsl: Tho soprossMix :wer&amp; eolhssfed ásd diós hy&amp;tiágz®$:, wdSi:3: ,h$ N NaO h»1uUo« conMining ghjeosasíios'· S->phosphaSe as mlsnsd ss&amp;odarö. A felsők p<R% M8C| tM ki -M&amp;Qlí -r intvrml α&amp;βώαά) λκν Silded.

The eferomaiogt&amp;phy sv&amp;s csnied mt wdh a moldle phsss composed oí 3 5 mM NnOI I and I i4 öíM öl sodmm acs-ate, i'ojéxaed inio the eofesmn as a nde cd I 2 sol/oss. í^iMasÉlph# WM»rii£iq0H${ (Boriké ««.* of the PRP peak * sütik* »tm f f: |PIP cookíksiRidl i-hw· wfeki !ía;í ís she slope and "b" i% the hpjpgf bps llhs. fesi»«í.

Üss<%sörfstk?osteef btsbíhthe ^iBáAgeös'síamöílp hitéé hlfehéTőfuhat bhtbpaehaef (FÖhiS-tfccse bMéis^-BiÉBbyíéggntíí hohley ζβ 44-45-4¾¾ ef u;ik|U|4 0bp4ibtiös eeippibeh4441)4: s$$M miigm&amp;fak ofammém^ráfag fa a jihélit heSöathtá 4 pptri áip| BSsfgftip BíBImít !Ms that destahheá itt the esaiepie Φί>$% «&amp;$ abohesiesi This pte|5afh|lás eMbihéiT ifi 0.5: tál: iÖ:kj| öflIlsAg, 3Ö Lf öttHi SÜ Lf öf 44, 31 μρ öf Bt, 2Sp|eof FÍ4A, 4h DO fif fgtttávihfis typé l, |: t)Ü et poiiiJVii'uS Cvgá 2, 32 011 ní'pohövtnss type 3, 15 pg »C;PBh0o the ibris sí FhfF-T), Ö..fi sfig öf A!, fihöáfiháíe Ihat át a eöséesttfMsás öíbá ntMoMitsafitonafe ions et a sííataetítítóeo of 30 iskfót/i, Tab-suetese bhfíht át a éefiefeéfiMkíh éf TSpMoi/l with tespeet to Tab: and 2454% with respeot to etweese, ásít 14 fig. ítf eatíösb gfiühfi sekis (hEs: --- Ábp - Bys) oHghsaítog trónt the Mi 44 m«4iam.^íio"val808«)» gB 4.4 - 4,4 , lltstessiB obtained were the íiEkswsng:

The aíráemss ot noondborbed EÉF-4' íseasateá over the saste peaksg showed that: ihere wfis khíe: vá$áik>fi eosspared wish Esne tg ;sk! were therefore saEstaeiery,:. jHówéyers these re&amp;uifö, show :ti?$h is ihb eáhe, Mfish

Claims (2)

1. does ns>t corfVstptvid te a ínefnühniOü sA'ismed hy vessz rd a maisod zs ixnvhng to the snveníjsHo tns- uepsishg B SzSidttev KitdgCSX did Oot r'ertuiiü iidssüsod Ott thst .Steossem OXsie OS sls'Ostsie. Experimental tinta relating to the c;ma«h: amino tieids Λ cs'-n-posilion according to the invention resokitig directly írom die expó'. intendő ptotocol cacti esi oat in ate ex ample provided arid a composition obtained by vn'toe. of a ptorovsn tnodiited in thai a composition csmtalnisg only the three eaitotbe amino acids (Arg · t.ys ·- HH) bad been *Bbtfi!t*f<l for the composition of the id essen! tat atom» as ids vvete esnopartrei o itb teg&amp;td to she nomtdvortsco amoom sit t hi - s at the cad, oio ctols-re m e h* the amount of oonadsorhed PkP-i oso observed, thereby soroséig that only the eltörne amirv acids are important. i. i.djhm folyékony oUbanysigdtomfeírűelö eiMiitusáta, amely tartalmaz legalább ,d»mhmmi td-hkii'O'sidse kAiOOft';. vs heistOftsz fl Svl\, ss etCigCist $He,4p\ cv >! s » < » . s* χίίι'Ί aiders, at s v hotdnmk * pd-v hot ,η-h κ<ρ ndst-s pofesaeksBttiiiS till, alsói a..:h«|pfe« Bi fels^at aiiigdh AfCXdlbh adsmdioafva yah, rotg a Msb antigén net» asizeieva VaOt:: ahol - a hepbife B iisgihi tat igára AKX>Brs suBzxirbeáijuK, Hy módon AiOOSbHBsA|ykompiexet kapunk, a AtiXdnilUAg'B-'iorb'v legalább tt»t> no; : ksma'aou >0m Uinmos •m-ms-as s-s l'' mMott koncemskiciójó idsztitkm jelenlétében ósszsásívs-sji.ik a Hit! antigénnel. 3, Á® li igénypont szerinti eijaraa ah»! a HBsAg antigén AiOOkhiznszpenzió ás BBs.-Up'sUi.szpsmzio ispiMhb 4 drln kcreszitii történd kövemével s;g» teaekeverésévd vsa as tdundmomra sdszorbcátvs. .5, A?, i ias-isspotii szérián eljárta, shot a HBsAg antigén AiOOB-'-eosepeneso ás lIBsAg^wisrpeozio : e i i ·.!>" | '· , g g,^s s'»te· o's t I' <do sWsrae t issna* diám mii d » hs\tB h. Az i igénypont szérián epriig ahol a IIBsAg antigen AiGOJi-s/nsspenrid ás 11 Λ-srersí:p*íieit> 'lögáiúhh 30· 34 Órást keresztül tdrtenh ke veresd ve·! vald ósszeketetésávei van u *mmt«H?rora ad»zorbeálvü. n ,\f igénypontok. bármelyike szert ri ή eijarás, s23.nl jeliemmé, hogy a kát ionos enenosav a Mib ghtigennel t«tUNU> íkvvs-ks venB ehm van ne AlOöH/HBsAg· komplexhez adva. n az i vágj a 3. igénypont szerinti eij.tr.B, azstüt loilemezveg .bstgy a katiöstos aatimsjav az. AiO= >H ; n. \ -\*>" 'kwJ '0 i\s- SüvStvis t ΐ b stg^nk' A4 7. \s eie/<' u'án'Penis'v sarí!>...'hike ízért Ό en-ees, gzzat jelhatozve, mgv <* k^zlht-uo e Bt"· üntigébhel történd ó^zaktrwrás elsMt van »z AIÖÖH/HBsAg-komplexhez asivst. 8·. A;í döA> igénypontok bármely ik« ta»«nti djára*·, »tml jribmetM* hegy az AiOOH/DBsAg-kunmlexeí tótóltoéöy ι»Η-> * Hife tmmb asvtkovews dbu \1*0,I énekre san beáiigYÖ. %s i „e ' o\ ήϊ i c· v* **«0! MUme*'·*· »> o ios>. \ ' I <. < \ 'As - tegdább égy* dBMns-, mmUM-t pdtkfc· &amp; si^máfköiH^ésAMA»#» kftcBi vátesaiotf aseiseml és Ms!tv&amp;|AnK>Kkkhkk<;xkk>5 tartalmazó kéaxítmány előállítása, &amp;> az AIO0H/HBsAg-*ompl«s bssaekeMíféss· a kí*xttmén»yek a ΠΒ> aitilgéonel történd összekeverés dóti. Λ U* ! ,íhrΆ --,¾ί ίϋ ,Sí - ,η üü'fisl idUste^e leg' * kníe\ \mv! > j kevrtoa'ro doAs''kíní !' HÍ. π V π<. ,'kOgn! . iV-Art kín Cvó by <Ti<.hvOy: UbUViÍíiU0V^N^'h«1nkV.vkx.tUa.;^)\'SÍ>l«E:,í és keveréssnl mindegyiksoJigémlKi:í,z.á3eés közbe. U. Ac I. igénypont sjwrinti-eljfcfe, asual.j«limi'*ve, hogy tartalmazza a következőket: - 3 BlksAgmik az AÍÜOlt «senny igenek egy sészére történő aősaorfeeáiási*· ««ely a γέρο ké-Aoodíyben sdemévö ísíísí, AKKbli egyb&amp;nnsdn. dKB oráe ketesztök Ily niődon ΛΚΧ.Η0Ή B.;Ag'komplex • pAtim/amo**» a következők egymást kővető adtoArbeáláaa egy további AkXSR'mtsmyiaégre:' difebheovm (Dk Eídonisnobo i'Ti, Bi'-rJstetiü í'wrtif&amp;'ii*· tisztított tözinja íPT-Híi); amely R5aga.:p?eads;sörbeáiv&amp;: AiÜOB-m, és B&amp;-<lcttiiie fiUna'nitwus hemagglutinin (FHA), amely maga pt^tóasbifeálva vm AvV1! i iO i .. O be '. < J Ά^! iiií .V XkMjB. IP Ά, XO V Λ w epéx A - tbíszfStionok ho/z&amp;aláui olyan e»«fty>*égb<m, amely tehetővé teui a végső késM$»48fl^8'"4ö. ffiMiiM koncemrtk;«dérévé;, - tvgaiabb eg) k«t Ionos amesosav höz.?áatteaa olyan mennyiségben; amely lehetővé issd a· végső késíiliíH s'sben legalább JÖÖ mgö koncemraciö «térését*. - a el í bed leess d Idi,1 ertbkn, - ^olkesfíligének hozzáadása maktsváfi íimtáptan, * ailisb .set igén hozzáadása, - a pH bed ihass 7,1 dl,; értékre. < ss v>rtk>srtO·' lí. -(crtos lás' b^suaiom. \ s «. ain^kbi ti! A?, eiöso igéoypoorek bénoebAp szirtijei eljátáj.. a.sral jsliesa'sve. Ia>gy legalább .7>0 I isbónovog-ks-'s'inen> ke··.Ad rgen mertékoen B, OH»km).ag-késziiméjsy, «πκΊ> az eíbrti igenyponOik !>ám*rty»ke szermb dekami vas» eiőáiHÜW^.'is. u>iJMi/.rt b'gsBrtb s begs,íi.sz J5 ebem: sebvéni v}ütsAe) λ a sbb aert^ot aossiyej Jesanjjvriehéijébez 'köJsjegáis poilrlbo/énbeoe fon/rás alkot. bl Az vlo/b igessypo’d sreroiti olKaevag készeotóex azzal p-ikesezvé, bpgy: tsrlsiéísa:: tlíftemn. ítemM.Sk>5 pobe- 4§ skMekkdhbgns-sfitjgéol h. 15. A 13. vsg> bi igiíeypooí <®amu oitóanyag-kásalsmény. aszol jellemmé bogy mrf&amp;imam· bpláldk - a heoatisisz. Is ieiszml síglgéek HbsAg-t. - a diíiériaaebgdi} tiiftéíusíosle (i.í.s femeekhaiy a íekeoisz.oaigéíst Ka&amp;oussloxle (Ti :l>te4jábaeS; ,s ti>OP 0**8*1> fíksSXU'aíAítíS Μ軣*Σ*«»»ν pN$) ÍÖSTRÍp' l»5Si .:f»jrm#N«k ~ si polk>&amp;f5(sg£oek«( 1, 2 <5« 5 íipusl»H3 vá i;ms ok in ski ;vál( v i su-s RsrmpisHi. ' o \ U W5 n\ ^ho«r>v((gU't,'!i(5Ci"s «*osl itfkmxxs* 8*>*(v kiosdrs VisS^h - 10--3(5 Mg H.BsAg-t KiilHHfcrrasakeak - 40-8(51. f B?i piOf teöí&amp;áOk - ;0-:K>i.r r-í!«jliülí«et5ké(ik - 40-60 og FHA-t mimiltereokííO, - 40-"í*FI ví~t •lüSOOx-ftnkí'ni, -:--60 y« OROo tmihh&amp;renfccnk PRO-r-kkftjagsUBR - *ng Λ MOH - msOsfsMa ski's - .53-45 reMökml fos&amp;Oiou!. - H)0-:0UO sr>g,0 kaík-ixo aHo«öS3v<j(. - s--s:s. .?-«>. «s. ,5-uá Opusa poSiovOast is',<fkssv;\U k>wuáb&amp;!k S’Skáro ffi). .16 és 04 DEúnf íMOSfíSsé^^- 3 7. A 18. igén) ps.>nl ssermlt olídmy»^·ke><0««én>, ra*»I hogy l&amp;ípmuMopIPte - 0(5 Mgknl BfesAg-k - -(5-70 1 1 i(0 D-í, MMOU/m; r-k - SO MgOssi ΓΉΑ-4 - 40 Mg/íík 0 lAO-f 0 >' j ís s5f M > ingák? > t sPtkiik í ' - 5.5 >s;g/s'íi5 AK.K 01-5. - '13.4;: mMoik íbszfáliosk - 400-808 msy'l kutlmsos &amp;iyeks>say.4, - j-si..
2. 2-es és 3-55.S lípusú poHovImt 5rsí^kliváli R(rmá4>«í>? gstsdte:1 lS ésE>333ssΪ