NO322190B1 - Vaksinesammensetning som inneholder et antigen,en saponin og et sterol - Google Patents
Vaksinesammensetning som inneholder et antigen,en saponin og et sterol Download PDFInfo
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- NO322190B1 NO322190B1 NO19974859A NO974859A NO322190B1 NO 322190 B1 NO322190 B1 NO 322190B1 NO 19974859 A NO19974859 A NO 19974859A NO 974859 A NO974859 A NO 974859A NO 322190 B1 NO322190 B1 NO 322190B1
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- antigen
- composition according
- cholesterol
- vaccine composition
- vaccine
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Description
Oppfinnelsen angår nye vaksinesammensetninger, fremgangsmåter for deres fremstilling og anvendelse for fremstilling av vaksiner. Særlig angår foreliggende oppfinnelse vaksiner som inneholder et antigen, en immunologisk aktiv fraksjon som kommer fra barken av Quillaja Saponaria Molina slik som QS21, og et sterol.
Immunologisk aktive saponinrfaksjoner som har adj uvansaktivitet avledet fra barken i det søramerikanske treet Quillaja Saponaria Molina er kjent innenfor fagområdet. F.eks. QS21, også kjent som QA21, en Hplc renset fraksjon fra Quillaja Saponaria Molina tre og dens fremgangsmåte for produksjon er beskrevet (som QA21) i US-patent nr. S.0S7.S40. Quillaja saponin har også blitt beskrevet som en adjuvans av Scott et al., Int. Arens. Allergy Appl. Immun., 1985, 77,409. Anvendelse av QS21 som en adjuvans er imidlertid forbundet med visse ulemper. Når f.eks. QS21 blir injisert i et pattedyr som et fritt molekyl har det blitt observert at nekrose, dvs. lokalisert vevsdød, forekommer på injeksjonsstedet.
EP0415794Al beskriver at iscomer, fortrinnsvis dannet fra Quil A, kolesterol og et fosfolipid er nyttige som adjuvanser og kan kombineres med antigener etter iscom-dannelse.
WO92/06710 beskriver immunogene komplekser sammensatt av fortrinnsvis QA3 og et sterol. De kompleksene som er i form av iscomer omfatter i tillegg et fosfolipid.
WO90/03184 beskriver immunmodulerende midler i form av iscomer fortrinnsvis omfattende kolesterol og Quil A eller subkomponenter av disse.
W096/11711 beskriver tilberedninger omfattende Quil A-fraksjoner med god adjuvansaktivitet, lav hemolytisk aktivitet og god evne til å danne iscomer. Dette dokumentet ble publisert etter foreliggende søknads innleveringsdag, og kan således kun motholdes i forhold til nyhet.
WO94/00153 beskriver vaksinesammensetninger omfattende 3-de-O-acetylert monofosforyllipid A (3D-MPL) og QS21.
W094/27636 beskriver vaksinesammensetninger omfattende QS21,3D-MPL eller en kombinasjon av disse.
Det har nå overraskende blitt funnet at nekrose ved injeksjonsstedet kan unngås ved å anvende formuleringer som inneholder en kombinasjon av QS21 og et sterol.
Foreliggende oppfinnelse angår således en vaksinesammensetning omfattende et antigen, QS21 og et sterol, kjennetegnet ved at forholdet mellom QS21 og sterol er fra 1:1 til 1:100 (v/v) og QS21 er minst 90% rent. Sammensetningen ifølge oppfinnelsen inneholder fortrinnsvis den immunologisk aktive saponinfraksjonen i hovedsakelig ren form. Sammensetningene ifølge oppfinnelsen inneholder fortrinnsvis QS21 i vesentlig ren form, dvs. QS21 er minst 90% ren, fortrinnsvis minst 95% ren og mest å foretrekke minst 98% ren. Andre immunologisk aktive saponinfraksjoner som er nyttig i sammensetningen i oppfinnelsen innbefatter QA17/QS17. Sammensetningen i oppfinnelsen som omfatter QS21 og kolesterol viser minsket reaktogenisitet sammenlignet med sammensetningene hvori kolesterol er fraværende, mens adjuvanseffekten blir opprettholdt. Det er i tillegg kjent at QS21 degraderer under basiske betingelser der pH er ca. 7 eller høyere. En ytterligere fordel ved foreliggende sammensetning er at stabiliteten av QS21 ved basemediert hydrolyse er forbedret i formuleringer som inneholder kolesterol.
Forholdet mellom QS21 : sterol vil typisk være i størrelsesorden 1:100 til 1 :1 vekt/vekt. Fortrinnsvis er overskudd av sterol til stede, og forholdet mellom QS21 : sterol er minst 1 : 2 v/v. Typisk vil human administrering av QS21 og sterol være tilstede i en vaksine i et område på ca. 1 ug til ca. 100 ug, fortrinnsvis ca. 10 ug til ca. 50 ug pr. dose.
Foretrukkede steroler innbefatter B-sitosterol, stigmasterol, ergosterol, ergokalsiferol og kolesterol. Disse sterolene er velkjente innenfor fagområdet, f.eks. er kolesterol beskrevet i Merck Index, 11. utgave, side 341, som et naturlig forekommende sterol som finnes i animalsk fett.
Foretrukkede sammensetninger ifølge oppfinnelsen er de som danner liposomstrukturen. Sammensetninger der sterol/immunologisk aktive saponinfraksjoner danner en ISCOM struktur er også et trekk ved oppfinnelsen. Liposomene inneholder fortrinnsvis et nøytralt lipid, feks. fosfatidylcholin, som fortrinnsvis er ikke-krystallinsk ved romtemerpatur, f.eks. eggehvite fosfatidylcholin, dioleoylfosfatidylcholin og dilaurylfosfatidylcholin. Liposomene kan også inneholde et ladet lipid som øker stabilitet av liposom-QS21 strukturen hos liposomene som består av mettede lipider. I disse tilfellene er mengden av ladet lipid fortrinnsvis 1-20% v/v, mest å foretrekke 5-10%. Forholdet mellom sterol og fosfolipid er 1-50% (mol/mol), mest å foretrekke 20-25%.
Sammensetningene ifølge oppfinnelsen inneholder fortrinnsvis MPL (3-deacylert monofosforyllipid A, også kjent som 3D-MPL). 3D-MPL er kjent fira GB 2 220 211 (Ribi) som en blanding av 3 typer av De-O-acylert monofosforyllipid A med 4,5 eller 6 acylerte kjeder og blir fremstilt av Ribi Immunochem, Montana. En foretrukket form er beskrevet i internasjonal patentsøknad 92/116556.
Velegnede sammensetninger ifølge oppfinnelsen er de der liposomene til å begynne med blir fremstilt uten MPL, og MPL blir tilsatt fortrinnsvis som 100 nm partikler. MPL er derfor ikke inneholdt i vesikkelmembranen (kjent som MPL ute). Sammensetninger der MPL er inneholdt i vesikkelmembranen (kjent som MPL inne) danner også et trekk ved oppfinnelsen. Antigenet kan bli inneholdt i vesikkelmembranen eller inneholdt på utsiden av vesikkelmembranen. Oppløselige antigener er fortrinnsvis på utsiden og de hydrofobe eller lipiderte antigenene er enten inneholdt på innsiden eller utsiden av membranen.
Ofte vil vaksinen i oppfinnelsen ikke kreve noen spesifikk bærer og kan bli formulert i en vandig eller annen farmasøytisk akseptabelt buffer. I noen tilfeller kan det være fordelaktig at vaksinen i foreliggende oppfinnelse ytterligere vil inneholde alun eller være til stede i en olje i vannemulsjon, eller annen egnet bærer slik som f.eks. liposomer, mikrosfærer eller innkapslede antigenpartikler.
Vaksinesammensetningene vil fortrinnsvis inneholde et antigen eller antigensammensetning som har evne til å utløse en immunrespons mot et humant eller animalsk patogen. Antigen eller antigene sammensetninger som er kjent innenfor fagområdet kan bli anvendt i sammensetningene ifølge oppfinnelsen, inkludert polysakkaridantigener, antigen eller antigene sammensetninger avledet fra HIV-1, (slik som gp 120 eller gp 160), en hvilken som helst av katteimmunsviktvirus, human eller animalsk herpesvirus, slik som gD eller derivater av disse eller umiddelbart tidlig protein slik som ICP27 fra HSVI eller HSV2, cytomegalovirus (særlig human) (slik som gB eller derivater derav), Varicella Zoster virus (slik som gpl, II eller III), eller fra en hepatittvirus slik som hepatitt virus slik som hepatitt B virus f.eks. hepatitt B overflateantigen eller et derivat derav, hepatitt A virus, hepatitt C virus og hepatitt E virus, eller fra andre virale patogener, slik som Respiratory Syncytial virus (f.eks. HSRV F og G proteiner eller immunogene fragmenter derav beskrevet i US-patent 5.149.650 eller kimære polypeptider inneholdende immunogene fragmenter fra HSRV-proteiner F og G, f.eks. FG-glykoprotein beskrevet i US-patent 5.194.595), antigener avledet fra meningitt stammer slik som meningitt A, B og C, Streptoccoccus Pneumonia, human papilloma virus, influensavirus, Haemophilus Influenza B (Hib), Epstein Barr Virus (EBV) eller avledet fra andre bakterielle patogener slik som Salmonella, Neisseria, Borrelia (f.eks. OspA eller OspB eller derivater derav), eller Chlamydia eller Bordetella f.eks. P.69, PT og FHA, eller avledet fra parasitter slik som plasmodium eller toksoplasma.
HSV glykoprotein D (gD) eller derivater derav er et foretrukket vaksineantigen. Det er lokalisert på den virale membran, og ble også funnet i cytoplasma hos infiserte celler (Eisenberg RJ. et al; J of Virol 1980 35 428-435). Det omfatter 393 aminosyrer inkludert et signalpeptid og har en molekylvekt på tilnærmet 60 kD. Av alle HSV kappeglykolproteiner er dette sannsynligvis det best karakteriserte (Cohen et al J. Virology 60 157-166). In vivo er det kjent å spille en sentral rolle i viral tilknytning til cellemembraner. Glykoprotein D har videre vist seg å ha evnen til å utløse nøytraliserende antistoffer in vivo og beskytte dyr mot letal utfordring. En avkuttet form av gD molekylet mangler C-terminal ankerregionen og kan"bli produsert i pattedyrceller som et oppløselig protein som eksporteres ut i celledyrkningssupernatanten. Slike oppløselige former av gD er foretrukket. Produksjon av de avkortede formene av gD er beskrevet i EP 0 139 417. gD er fortrinnsvis avledet fra HSV-2. En utførelsesform av oppfinnelsen er et avkuttet HSV-2 glykoprotein D med 308 aminosyrer som omfatter aminosyrene 1 til 306 i naturlig forekommende glykoprotein med tilsetning av asparagin og glutamin i C-terminal ende av det avkuttede proteinet som mangler membranankerregionen. Denne form av protein innbefatter signalpeptidet som blir kløyvt for å tillate at det modne oppløselige 283 aminosyreproteinet blir sekretert fra en vertscelle.
I et annet trekk ved oppfinnelsen er hepatitt B overflateantigen et foretrukket vaksineantigen.
Slik det her ble anvendt innbefatter uttrykket "hepatitt B overflateantigen" eller "HBsAg" et hvilket som helst HBsAg antigen eller fragment derav som utviser antigenisitet av HBV overflateantigen. Det er underforstått at i tillegg til 226 aminosyresekvens av HBsAg antigen (se Tiollais et al, Nature, 317,489 (1985) og referansene der) kan HBsAg som her er beskrevet, om ønskelig inneholde alt eller deler av en pre-S sekvens som beskrevet i ovenfornevnte referanser og i EP-A 0 278 940. Særlig kan HBsAg omfatte et polypeptid som omfatter en aminosyresekvens som omfatter residiene 12-52 fulgt av residiene 133-145 fulgt av residiene 175-400 av L-proteinet av HBsAg relativt til den åpne leserammen på en hepatitt B virus av ad-serotype (dette polypeptid blir referert til som L<*>, se EP 0 414 374). HBsAg innenfor rekkevidden av oppfinnelsen kan også innbefatte pre-Sl-preS2-S polypeptid som beskrevet i EP 0 198 474 (Endotronics) eller nære analoger derav slik de som er beskrevet i EP 0 304 578 (Mc Cormick and Jones). HBsAg som her er beskrevet kan også referere til mutanter, f.eks. "escape mutant" som er beskrevet i WO 91/14703 eller europeisk patentsøknad nr. 0 511 855Al, særlig HBsAg der aminosyresubstitusjonen i posisjon 145 er til arginin fra glysin.
Normalt vil HBsAg være i partikkelform. Partiklene kan omfatte f.eks. S-protein alene eller kan være sammensatte partikler, f.eks. (L<*>,S) der L<*> er som definert over og S betegner S-proteinet av HBsAg. Denne partikkelen er fordelaktig i form hvori den ble uttrykt i gjær.
Fremstilling av hepatitt B overflateantigen S-protein er veldokumentert. Se f.eks. Harford et al. (1983) i Develop. Biol. Standard 54, side 125, Gregg et al (1987) i Biotechnology, 5, side 479, EP 0 226 846, EP 0 299 108 og referansene der.
Formuleringene innenfor rekkevidden av oppfinnelsen kan også inneholde et anti-tumorantigen og være nyttig for immunterapeutisk behandling av cancer.
Vaksinesammensetningen er generelt beskrevet i New Trends and Development in
Vaccines, forfattet av Voller et al., University Park Press, Baltimore, Maryland, U.S.A., 1978. Innkapsling i liposomer er beskrevet f.eks. av Fullerton, US-patent nr. 4.235.877. Konjugering av proteiner til makromolekyler er f.eks. beskrevet av Likhite, US-patent 4.372.945 og av Armor et al., US-patent 4.474.757.
Mengde protein i hver vaksinedose blir valgt som en mengde som induserer en immunbeskyttende respons uten signifikante, negative sideeffekter i typiske vaksiner. Slike mengder vil variere avhengig av det spesifikke immunogenet som blir benyttet og hvordan det blir presentert. Det blir generelt forventet at hver dose vil omfatte en 1-1000 jig protein, fortrinnsvis 2-100 ug, mest å foretrekke 4-40 ug. En optimal mengde av en spesiell vaksine kan bestemmes ved standard studier som involverer observasjon av passende immunresponser hos subjekter. Etter en initiell vaksinering, kan individene motta en eller flere forsterkede immuniseringer som er atskilt på tilstrekkelig måte. Sammensetningene ifølge foreliggende oppfinnelse kan f.eks. bli anvendt både profylaktisk og for terapeutiske formål. Foreliggende oppfinnelse angår således anvendelse av en sammensetning ifølge oppfinnelsen for fremstilling av en vaksine for profylaktisk behandling av virale, bakterielle eller parasittiske infeksjoner. Oppfinnelsen angår også anvendelse av en sammensetning ifølge oppfinnelsen for fremstilling av en vaksine for immunterapeutisk behandling av virale, bakterielle, parasittiske infeksjoner eller cancer.
Foreliggende oppfinnelse angår videre en fremgangsmåte for å lage en vaksinesammensetning ifølge oppfinnelsen, kjennetegnet ved at den omfatter blanding av QS21 og kolesterol med et antigen eller antigensammensetning.
De følgende eksemplene og data illustrer oppfinnelsen.
Eksempler
1.1 Fremgangsmåte for fremstilling av liposomer:
En blanding av lipid (slik som fosfatidylcholin enten fra eggeplomme eller syntetisk) og kolesterol og organiske oppløsningsmidler, blir tørket ned under vakuum (eller alternativt) under en strøm av inertgass). En vandig oppløsning (slik som fosfatbufret saltvann) blir deretter tilsatt, og beholder ristet inntil all lipid er i suspensjon. Denne suspensjonen blir deretter mikrofluidisert inntil liposomstørrelsen er redusert til 100 nm, og deretter sterilfiltrert gjennom 0,2 um filter. Ekstrusjon eller sonikering kan erstatte dette trinnet. Typisk kolesterol :fosfatidylcholinforhold er 1:4 (v/v), og den vandige oppløsningen ble tilsatt for å gi en endelig kolesterolkonsentrasjon på 5 til 50 mg/ml. Dersom MPL i organisk oppløsning blir tilsatt lipid i organisk oppløsning inneholder de endelige liposomene MPL i membranen (referert til som MPL inne).
Liposomene har en definert størrelse på 100 nm og ble referert til som SUV (for små unilamilære vesikler). Dersom denne oppløsningen blir gjentagende ganger frosset og tint, smelter vesiklene sammen og danner store multilamilære strukturer (MLV) med størrelse i området fra 500 nm til 15 um. Liposomene selv er stabile over tid og har ingen fusogen kapasitet.
1.2 Formuleringsfremgangsmåte:
QS21 i vandig oppløsning ble tilsatt til liposomer. Blandingen ble deretter tilsatt antigenoppløsningen som kan om ønskelig inneholde MPL i form av 100 nm partikler.
1.3 Lyrisk aktivitet av QS21 blir hemmet av liposomer som inneholder
kolesterol.
Når QS21 blir tilsatt erytrocytter, lyserer de dem og frigjør hemoglobin. Denne lytiske aktiviteten kan også bli målt ved å anvende liposomer som inneholder kolesterol i deres membran og en innelukket fluoriserende farge, karboksyfluoressein - når liposomene blir lysert blir fargen frigjort og dette kan bli overvåket ved fluoressensspektroskopi. Dersom fluoresserende lipposomer ikke inneholder kolesterol i membranen blir det ikke observert noe lysering av liposomene.
Dersom QS21 blir inkubert med liposomene som inneholder kolesterol forut for tilsetning av dette til erytrocytter, avtar lysering av erytrocyttene avhengig av forhold av kolesterol til QS21. Dersom et 1:1 forhold blir anvendt, blir det ikke påvist noe lytisk aktivitet. Dersom liposomene ikke inneholder kolesterol, krever hemming av lysering et tusen gangers overskudd av fosfolipid over QS21.
Det samme stemmer ved anvendelse av fluorescerende liposomer for å måle lytisk aktivitet. I grafen under ble den lytiske aktiviteten av 4 ug QS21 behandlet med liposomer som mangler kolesterol (1 mg eggeplomme lecitin pr. ml) eller som inneholder kolesterol (1 mg lecitin, 500 ug kolesterol pr. ml) målt ved fluorescens. Data viser at QS21 assosierer på en spesifikk måte med kolesterol i en membran, og forårsaker lysering (av celler eller fluorescerende liposomer). Dersom QS21 først assosierer med kolesterol i liposomer, er den ikke lenger lytisk mot celler eller andre liposomer. Dette krever et minimumsforhold på 0,5:1 chol:QS21 (v/v).
Kolesterol er uoppløselig i vandige oppløsninger og danner ikke en stabil suspensjon. In nærvær av fosfolipider hviler kolesterol i fosfolipid dobbeltlaget som kan danne en stabil suspensjon av vesikler kalt liposomer. For å unngå kravet om å tilsette fosfolipider ble et oppløselig derivat forsøkt. Polyoksyetanylkolesterol sebacat er oppløselig i vann ved 60 mg/ml selv ved et 2000 gangers overskudd ( v/ v) over QS21 ble det ikke påvist noe reduksjon i lytisk aktivitet av QS21.
1.4 Øket stabilitet av QS21 med liposomer inneholdende kolesterol.
QS21 er meget utsatt for hydrolyse ved en pH over 7. Denne hydrolyse kan bli overvåket ved å måle nedgang i toppen som tilsvarer QS21 på reversfase HPLC. Grafen under viser f.eks. at ved pH 9 og en temperatur på 37°C, blir 90% QS21 hydrolysert i løpet av 16 timer. Dersom liposomer som inneholder kolesterol blir tilsatt QS21 ved et forhold på 2:1 (cho):QS21 v/v), ble det ikke påvist noe hydrolyse av QS21 under samme betingelser. Dersom forholdet er 1:1 blir 10% av QS21 degradert.
Inkubering av 20 ug QS21 i nærvær av SUV som inneholder kolesterol ved pH 9 i 16tved37°C
Det kan konkluderes med at når QS21 assosierer med liposomer som inneholder kolesterol blir den mye mindre utsatt for baseformidlet hydrolyse. Hydrolyseproduktet blir beskrevet ved å ikke ha noe adjuvansaktivitet når den blir gitt parenteralt, således må vaksiner som inneholder QS21 bli formulert ved sure pH verdier og holdt ved 4°C for å opprettholde adjuvanssammensetning. Anvendelse av liposomer kan overvinne dette krav.
1.5 Reaktogenitetsstudier:
Mus injisert i tibialis muskelen med 5 ug QS21 (eller digitonin) tilsatt til økende mengder av liposomer (uttrykt på bakgrunn av ug kolesterol). Lytisk aktivitet blir uttrykt som ug QS21 ekvivalent, som menes at mengden av QS21 er nødvendig for å oppnå samme hydrolyse i prøven.
Rødhet, nekrose og toksisitet i muskelen på injeksjonsstedet ble vurdert visuelt etter at musen ble tatt livet av.
Data viser at når den lytiske aktiviteten blir opphevet ved tilsetning av liposomer som inneholder kolesterol blir toksisiteten på grunn av QS21 også opphevet.
1.6 Reaktogenisitet intra-muskulært i kaniner Verdier i U.I./L
Data viser at tilsetning av kolesterol-inneholdende liposomer til formuleringen reduserer betydelig heving i CPK (kreatin fosfokinase) forårsaket av QS21. Siden CPK økning er et mål på muskelskade viser dette nedgang i muskelskade og blir bekreftet av histopatologi.
1.7 Binding av liposom-QS21 kompleks til alun.
QS21 blir inkubert med nøytrale liposomer inneholdende overskudd kolesterol så vel som radioaktiv kolesterol og deretter inkubert med alun (AlfOHtø) i PBS. Hverken nøytrale liposomer eller QS alene binder til alun i PBS, men negativt ladde liposomer gjør det Sammen binder imidlertid QS21 og nøytrale liposomer til alun. Supernatanten inneholdt verken QS21 (analysert av orcinoltest) eller radioaktiv kolesterol.
Dette viser at QS21 har bundet til liposomene og muliggjør liposom-QS21 kombinasjon å binde til alun. Dette kan komme fra en negativ ladning som blir påført på liposomet av QS21, eller til en eksponering av hydrofobe regioner på liposomene. Resultatene innebærer også at QS21 ikke ekstraherer kolesterol fra membranen.
Dette viser at sammensetningene ifølge oppfinnelsen kan bli anvendt i alunbaserte vaksiner.
1.8 Sammenligning av liposomal QS21/MPL og fri QS21+MPL for antistoff
og CMI induksjon
SUV ble fremstilt ved ekstrusjon (EYPC:chol:MPL 20:5:1).
For MPL ut, ble liposomer fremstilt uten MPL og MPL ble tilsatt som 100 nm partikler.
QS21 ble tilsatt før antigen. Chol:Qs21 =5:1 (v/v)
MLV ble laget ved fryse-tørking av SUV 3x forut for antigentilsetning.
For å ha antigenet innelukket ble antigenet tilsatt SUV forut for fryse-tining og QS21 tilsatt etter fryse-tining. Antigeninnkapsling = 5% inne, 95% ute.
-mus (balb/c for gD, B 10BR for RTSs) ble injisert to ganger i fotputen.
gD er glykoprotein D fra Herpes Simplex virus. RTSs i Hepatitt B overflateantigen (HBsAg) genetisk modifisert for å inneholde eptiop fra Plasmodiium falciparum sporozoit.
Data viser at SUV/QS + MPL(ut) induserer høye antistofmter som minst så gode som QS21+MPL, såvel som indusering av en IL2 markør av cellebundet immunitet, mens den bråstanser QS21 reaktogenisitet.
Ytterligere resultater fra et annet eksperiment som sammenligner QS21 og QS21 i nærvær av kolesterol (SUV) i balb/c mus med HSV gD som antigen er vist under:
1.9 Sammenligning av gpl20 pluss liposomal MPL/QS21 med fri MPL/QS21
Liposomer = SUV inneholdende MPL i membran
Cfaol:QS21 = 6:1
Respons ble testet to uker etter en immunisering
Etter andre immunisering:
Data viser at QS21 assosiert med kolesterolinneholdende liposomer og MPL induserer Th/ThO respons lik MPL + QS21.
Ved dette formål av kolesterol til QS21, er QS21 ikke-toksisk i kaniner (ved CPK).
I et andre eksperiment ble balb/c mus immunisert intra-fotpute med gpl20 i nærvær av QS21 eller QS21 + SUV inneholdende kolesterol. Cytotoksisk T-lymfocyttaktivitet i miltceller ble målt
Dette viser at QS21 alene induserer CTL aktivitet, og at QS21 i nærvær av liposomer som inneholder kolesterol induserer CTL aktivitet minst så god som, eller bedre enn, QS21 alene.
2. Vaksiner
2.1 Formulering av HBsAg L<*>,S partikler.
HBsAg L<*>,S partikler kan bli formulert som følger:
10 ug HBsAg L<*>,S partikler/dose blir inkubert i 1 time ved romtemperatur under risting. Volumet blir justert ved å anvende vann for injeksjon og en PBS-oppløsning og fullført til et sluttvolum på 70 ul/dose med en vandig oppløsning av QS21 (10 ug/dose). pH ble holdt ved 7 ±0,5.
Tilsvarende formulering kan bli fremstilt ved å anvende 1 og 50 ug HBsAg L<*>,S også ved å anvende HBsAg S antigen.
Disse formuleringene kan bli testet i Woodchuck surrogatterapeutisk modell ved å anvende Woodchuck HB V antigener som en modell.
Woodchuck modell
DQ QS21 (dvs. QS21/kolesterol eller bråstanset QS21) kan bli testet i woodchuck terapeutisk modell der dyrene ble kronisk infisert med virus. Spesifikke woodchuck hepatitt virusvaksine kan bli tilsatt blandet med QS21 slik det er eller DQ og med eller uten MPL og administrert til dyrene hver måned i 6 måneder. Effektivitet av vaksinen kan bestemmes ved viral DNA klaring.
2.2 Marsvinmodell (HSV)
2.2.1 Profylaktisk modell
Grupper av 12 hunn Harley-marsvin ble enten injisert intramuskulært på dag 0 og dag 28 med følgende formuleringer:
1. eksperiment:
gD 5 ug + QS21 50 jig + SUV inneholdende 50 ug kolesterol
gD 5 ug + QS21 10ug + SUV inneholdende 10ug kolesterol
gD 5 ug + QS21 50 ug + SUV inneholdende 250 ug kolesterol
gD5 ug + QS21 50 ug
2. eksperiment:
gD 5 ug + MPL 12,5 ug +QS21 12,5 ug + SUV inneholdende 62,5 ug kolesterol, eller beholdt ubehandlet.
Dyrene ble tatt blodprøver av ved 14 og 28 dager etter andre immunisering, og sera testet for deres gD-spesifikke ELISA antistoff titere.
Dyrene ble deretter utfordret intravaginalt med 10^ pfu HSV-2 MS stamme. De ble vurdert daglig fra dag 4 til 12 for evaluering av primære herpes lesjoner. Vurderingen var som følger:
Vaginale lesjoner:
- blødning = 0,5
- rødhet i en eller 2 dager uten blødning = 0,5
- rødhet og blødning i en dag = 1
- rødhet uten blødning som varte minst 3 dager = 1
Ytre herpes vesikler:
- < 4 små vesikler = 2
- >= 4 små vesikler eller en stor vesikkel 4 >= 4 store lesjoner 8 sammensmeltende store lesjoner = 16
- sammensmelting av store lesjoner på alle ytre gemtalområder = 32.
Resultatene er vist i tabellen under:
Tabell og graf viser at i den profylaktiske modellen, ble et meget høyt nivå av beskyttelse mot primærsykdom indusert ved immunisering med gD / MPL / QS21 / SUV. Både forekomst av ytre lesjoner og lesjonsalvorlighet fremkom meget redusert i gruppen av dyr immunisert med gD / MPL / QS21 / SUV.
2.2.2 Terapeutisk modell
I den terapeutiske modellen ble hunn Harley-marsvin først behandlet med 10^ pfu HSV-2 MS stamme. Dyrene med herpes lesjoner ble deretter randomisert tilsatte grupper på 16.
På dag 21 og dag 42, ble de enten immunisert med en av følgende formuleringer:
- gD + MPL 50 ug + QS21 50 ug + SUV inneholdende 250 ug kolesterol,
- gD + Al(OH)3 . MPL 50 ug + QS21 50 ug + SUV inneholdende 250 ug kolesterol, eller ble holdt ubehandlet. De ble overvåket daglig fra dag 22 til 75 for evaluering av gjentagende sykdom. Vurderingen var som beskrevet for den profylaktiske modellen. Resultatene er vist i tabellen og grafen under:
Claims (12)
1.
Vaksinesammensetning omfattende et antigen, QS21 og et sterol,
karakterisert ved at forholdet mellom QS21 og sterol er fra 1:1 til 1:100 (v/v) og QS21 er minst 90% rent.
2.
Vaksinesammensetning ifølge krav 1,karakterisert ved at forholdet saponimsterolen er 1:2 (v/v).
3.
Vaksinesammensetning ifølge et hvilket som helst av kravene 1 til 2, karakterisert ved at sterolet er kolesterol.
4.
Vaksinesammensetning ifølge et hvilket som helst av kravene 1 til 3, karakterisert ved at den ytterligere inneholder 3D-MPL.
5.
Vaksinesammensetning ifølge et hvilket som helst av kravene 1 til 4, karakterisert ved at den ytterligere omfatter en bærer.
6.
Vaksinesammensetning ifølge krav 5,karakterisert ved at bæreren blir valgt fra gruppen som omfatter: olje-i-vannemulsjonen, alun, mikrosfærer og innkapslede antigenpartikler.
7.
Vaksinesammensetning ifølge et hvilket som helst av kravene 1 til 6, karakterisert ved at den videre omfatter et antigen eller en antigen sammensetning avledet fra et hvilket som helst av human immunsviktvirus, katteimmunsviktvinis, varicella zostervirus, herpes simplex virus type 1, herpes simplex virus type 2, human cytomegalovirus, hepatitt A, B, C eller E, respiratorisk syncytialvirus, human papillomavirus, influensavirus, Hib, meningittvirus, salmonella, neisseria, borrelia, clamydia, bordetella, palsmodium eller toksoplasma.
8.
Vaksinesammensetning ifølge et hvilket som helst av kravene 1 til 6, karakterisert ved at den videre omfatter et antigen avledet fra en tumor.
9.
Sammensetning ifølge et hvilket som helst av de foregående krav for anvendelse som et medikament.
10.
Anvendelse av en sammensetning ifølge et hvilket som helst av kravene 1 til 7, for fremstilling av en vaksine for profylaktisk behandling av virale, bakterielle eller parasittiske infeksjoner.
11.
Anvendelse av en sammensetning ifølge et hvilket som helst av kravene 1 til 8, for fremstilling av en vaksine for immunterapeutisk behandling av virale, bakterielle, parasittiske infeksjoner eller cancer.
12.
Fremgangsmåte for å lage en vaksinesammensetning ifølge et hvilket som helst av kravene 3 til 8, karakterisert ved at den omfatter blanding av QS21 og kolesterol med et antigen eller antigensammensetning.
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| PCT/EP1996/001464 WO1996033739A1 (en) | 1995-04-25 | 1996-04-01 | Vaccines containing a saponin and a sterol |
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| US6692752B1 (en) | 1999-09-08 | 2004-02-17 | Smithkline Beecham Biologicals S.A. | Methods of treating human females susceptible to HSV infection |
| US20030235557A1 (en) | 1998-09-30 | 2003-12-25 | Corixa Corporation | Compositions and methods for WT1 specific immunotherapy |
| KR100629028B1 (ko) | 1998-10-16 | 2006-09-26 | 글락소스미스클라인 바이오로지칼즈 에스.에이. | 애쥬번트 시스템 및 백신 |
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| NL9002314A (nl) * | 1990-10-23 | 1992-05-18 | Nederlanden Staat | Immunogene complexen, in het bijzonder iscoms. |
| CA2138997C (en) * | 1992-06-25 | 2003-06-03 | Jean-Paul Prieels | Vaccine composition containing adjuvants |
| CA2156525A1 (en) * | 1993-02-19 | 1994-09-01 | Susan Dillon | Influenza vaccine compositions containing 3-o-deacylated monophosphoryl lipid a |
| US5776468A (en) * | 1993-03-23 | 1998-07-07 | Smithkline Beecham Biologicals (S.A.) | Vaccine compositions containing 3-0 deacylated monophosphoryl lipid A |
| DE69426077T3 (de) * | 1993-05-25 | 2004-09-02 | Wyeth Holdings Corp. | Adjuvantien für impfstoffe gegen das respiratorische synzitialvirus |
| AUPM873294A0 (en) * | 1994-10-12 | 1994-11-03 | Csl Limited | Saponin preparations and use thereof in iscoms |
| GB9718901D0 (en) † | 1997-09-05 | 1997-11-12 | Smithkline Beecham Biolog | Vaccine |
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1996
- 1996-01-04 UA UA97105147A patent/UA56132C2/uk unknown
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1997
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1998
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1999
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2008
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| MK1K | Patent expired |