NL8803111A - Meningococcus class 1 outer-membrane protein vaccine - useful to immunise against meningococcal disease - Google Patents
Meningococcus class 1 outer-membrane protein vaccine - useful to immunise against meningococcal disease Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/095—Neisseria
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/22—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Neisseriaceae (F)
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- C07—ORGANIC CHEMISTRY
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
- C07K14/255—Salmonella (G)
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
- C07K16/1203—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria
- C07K16/1217—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria from Neisseriaceae (F)
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
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- A61K2039/6068—Other bacterial proteins, e.g. OMP
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
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- C07K2319/00—Fusion polypeptide
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Abstract
Description
Multivalent meningococcen klasse I buitenmembraaneiwit vaccin.Multivalent meningococcal class I outer membrane protein vaccine.
De uitvinding heeft betrekking op vaccins, welke gebaseerd zijn op meningococcen buitenmembraaneiwitten.The invention relates to vaccines based on meningococcal outer membrane proteins.
Meningococcen-ziekte wordt bijna uitsluitend veroorzaakt door sero-groep A,B,C,W,Y meningococcen. Ter bestrijding van deze ziekte kan een tetravalent A,C,W,Y-polysaccharide-vaccin worden toegepast. Dit vaccin bezit de aan polysacchariden inherente immunologische eigenschappen, zoals een slechte immunogeniteit bij jonge kinderen en geen inductie van het immunologische geheugen bij individuè'n, die niet eerder met de desbetreffende bacterie in aanraking zijn geweest. Dientengevolge worden de polysaccharide-vaccins slechts bij risicogroepen zoals militairen en reizigers naar gebieden met een hoge incidentie aan de meningococcen-ziekte alsook tijdens verheffingen van de ziekte toegepast.Meningococcal disease is caused almost exclusively by sero group A, B, C, W, Y meningococci. A tetravalent A, C, W, Y polysaccharide vaccine can be used to combat this disease. This vaccine has the immunological properties inherent in polysaccharides, such as poor immunogenicity in young children and no induction of the immunological memory in individuals who have not previously had contact with the bacterium in question. As a result, the polysaccharide vaccines are only used in at-risk groups such as the military and travelers to areas with a high incidence of meningococcal disease and during elevations of the disease.
Een groot probleem ten aanzien van de ontwikkeling van een geschikt polysaccharide-vaccin tegen meningococcen-ziekte is gelegen in de zeer geringe immunogeniteit van het zogenaamde B-polysaccharide. Een mogelijke verklaring hiervoor is zeer waarschijnlijk gelegen in de grote overeenkomst in structuur tussen het B-polysaccharide en humane glycolipi-den. Daar groep B-meningococcen in vele landen meer dan 50% van de gevallen van meningococcen-ziekte veroorzaken (Poolman J.T. et al., Meningococcal Serotypes and Serogroup B Disease in North-West Europe, The Lancet, September 1986, blz. 555-558) biedt de toepassing van het bovengenoemd tetravalent A,C,W,Y-polysaccharide-vaccin geen soelaas, het is nog wel mogelijk de immunogeniteit van het B-polysaccharide sterk te verhogen door een chemische modificatie, maar hierbij rijst de vraag in hoeverre een dergelijk gemodificeerd B-polysaccharide na vaccinatie aanleiding zal geven tot ongewenste nevenreacties ten gevolge van een auto-immuunrespons·A major problem with regard to the development of a suitable polysaccharide vaccine against meningococcal disease lies in the very low immunogenicity of the so-called B polysaccharide. A possible explanation for this is most likely due to the great similarity in structure between the B polysaccharide and human glycolipids. Since group B meningococci cause more than 50% of cases of meningococcal disease in many countries (Poolman JT et al., Meningococcal Serotypes and Serogroup B Disease in North-West Europe, The Lancet, September 1986, pp. 555-558 ) the application of the above-mentioned tetravalent A, C, W, Y-polysaccharide vaccine does not offer any relief, it is still possible to strongly increase the immunogenicity of the B-polysaccharide by chemical modification, but the question arises to what extent a such modified B polysaccharide after vaccination will give rise to undesired side reactions due to an autoimmune response
Getracht is derhalve buitenmembraaneiwitten van meningococcen als alternatief voor de kapsel-polysacchariden als vaccin toe te passen aangezien antistoffen tegen deze eiwitten een bactericide activiteit bezitten. Meningococcen bezitten echter vele buitenmembraaneiwitten, waarbij een tweetal typen eiwit door Aanvraagster zijn geselecteerd voor vaccin-ontwikkeling: klasse 1 en klasse 2/3 buitenmembraaneiwitten (Frasch, C.E. et al., Serotype Antigens of Neisseria meningitidis and a Proposed Scheme for Designation of Serotypes, Reviews of Infectious Diseases, Vol. 7, No. 4, July-August 1985, blz. 504-510). Hiervan afgeleide buitenmembraaneiwit-vaccins tegen de meningococcen-ziekte "bevatten gezuiverde klasse 1 en 2/3 buitenmembraaneiwitten van één stam, waarbij het endotoxine-gehalte tot een zo laag mogelijke waarde is teruggebracht. Het bezwaar van een dergelijk type vaccin is echter gelegen in de stam-afhankelijke immuniteit, welke hiermede wordt gei'nduceerd. Er komen namelijk binnen het species Keisseria meningitidis (meningococcen) meerdere klasse 1 en 2/3 buitenmembraaneiwitten voor. Getracht is derhalve een multivalent vaccin met buitenmembraaneiwitten van meerdere stammen te bereiden om zodoende een mogelijkheid voor het opwekken van een brede bescherming te verkrijgen. Tijdens in dit verband uitgevoerde onderzoek naar de bactericide werking van antistoffen (o.a. monoclonaal) en bescherming in proefdieren is naar voren gekomen, dat antistoffen vooral tegen klasse 1 buitenmembraaneiwitten werkzaam zijn. Het epidemiologisch onderzoek laat echter zien, dat er ongeveer tien verschillende klasse 1 buitenmembraaneiwitten bij meningococcen voorkomen· Het kombi-neren van vijf of meer klasse 1 buitenmembraaneiwitten met de tot dusverre bekende zuiveringstechnieken is echter niet mogelijk vanwege het meezuiveren van endotoxine, een lipopolysaccharide, dat toxisch is.Therefore, attempts have been made to use meningococcal outer membrane proteins as an alternative to capsular polysaccharides as a vaccine since antibodies against these proteins have a bactericidal activity. Meningococci, however, possess many outer membrane proteins, with two types of proteins selected by the Applicant for vaccine development: class 1 and class 2/3 outer membrane proteins (Frasch, CE et al., Serotype Antigens or Neisseria meningitidis and a Proposed Scheme for Designation of Serotypes, Reviews of Infectious Diseases, Vol. 7, No. 4, July-August 1985, pp. 504-510). Outer membrane protein vaccines against meningococcal disease "derived therefrom" contain purified class 1 and 2/3 single-membrane outer membrane proteins, the endotoxin content of which has been reduced to the lowest possible value. However, the drawback of such a type of vaccine lies in the strain-dependent immunity, which is hereby induced, as multiple class 1 and 2/3 outer membrane proteins occur within the Keisseria meningitidis (meningococcal) species, therefore an attempt has been made to prepare a multivalent vaccine with outer membrane proteins of multiple strains in order to provide a possibility to generate a broad range of protection During studies in this context into the bactericidal action of antibodies (including monoclonal) and protection in laboratory animals, it has been found that antibodies are mainly active against class 1 outer membrane proteins. see that there are about ten different Preventing Class 1 Outer Membrane Proteins in Meningococci · Combining five or more Class 1 Outer Membrane proteins with hitherto known purification techniques is not possible due to co-purification of endotoxin, a lipopolysaccharide, which is toxic.
Gevonden werd, dat de bovengenoemde nadelen kunnen worden opgeheven met behulp van een vaccin, dat gekenmerkt wordt door een of meer fragmenten van meningococcen klasse 1 buitenmembraaneiwitten. Deze fragmenten zijn geselecteerd op reactiviteit met bactericide antistoffen en bevatten een aanvaardbaar laag gehalte aan endotoxine. Meer in het bijzonder bevat het vaccin volgens de uitvinding oppervlakkig gelocaliseerde fragmenten van klasse 1 eiwitten, welke van een gekombineerd klasse 1 en 2/3 buitenmembraaneiwit-preparaat zijn afgeleid.It has been found that the above drawbacks can be overcome with the aid of a vaccine characterized by one or more fragments of meningococcal class 1 outer membrane proteins. These fragments have been selected for reactivity with bactericidal antibodies and contain an acceptably low endotoxin content. More particularly, the vaccine of the invention contains superficially located fragments of class 1 proteins derived from a combined class 1 and 2/3 outer membrane protein preparation.
Kaast het bovenvermelde voordeel van een laag endotoxine-gehalte levert de uitvinding het voordeel op van redelijk goed in waterig milieu oplosbare produkten; dit in tegenstelling tot de ongefragmenteerde hydrofobe buitenmembraaneiwitten, welke met behulp van aanzienlijke hoeveelheden detergentia en dergelijke in oplossing moeten worden gehouden.In addition to the above-mentioned advantage of a low endotoxin content, the invention provides the advantage of products which are reasonably well soluble in an aqueous medium; this in contrast to the unfragmented hydrophobic outer membrane proteins, which must be kept in solution with the aid of considerable amounts of detergents and the like.
Meer in het bijzonder heeft de uitvinding betrekking op vaccins, welke door de aanwezigheid van een of meer fragmenten van groep A,B,C,W en/of Y-meningococcen klasse 1 buitenmembraaneiwitten worden gekenmerkt .More particularly, the invention relates to vaccines, which are characterized by the presence of one or more fragments of group A, B, C, W and / or Y-meningococcal class 1 outer membrane proteins.
Daar gebleken is, dat de hierboven beschreven klasse 1 buitenmembraaneiwitten bij A,B,C,W,Y-meningococcen voorkomen wekt een multivalent klasse 1 buitenmembraaneiwit-fragmenten-vaccin volgens de uitvinding eer» bactericide immuunrespons op tegen al deze serogroepen. Dit impliceert, dat het A,C,W,Y-polysacchariden-vaccin vervangen kan worden door een vaccin volgens de uitvinding als breedwerkend vaccin tegen de meningo- coccen-ziekte.Since it has been found that the class 1 outer membrane proteins described above occur in A, B, C, W, Y meningococci, a multivalent class 1 outer membrane protein fragment vaccine of the invention elicits a bactericidal immune response against all these serogroups. This implies that the A, C, W, Y polysaccharides vaccine can be replaced by a vaccine according to the invention as a broad-acting vaccine against meningococcal disease.
Gezien het gegeven, dat de meningococcen-ziekte tegenwoordig hoofdzakelijk door groep B meningococcen wordt veroorzaakt alsook het feit dat de bij groep B-meningococcen klasse 1 buitenmembraaneiwitten ook bij groep A,C,W,Y-meningococcen voorkomen, heeft de uitvinding met voordeel betrekking op een vaccin, dat door een of meer fragmenten van groep B meningococcen klasse 1 buitenmembraaneiwitten is gekenmerkt. Bij voorkeur wordt bij de bereiding van een dergelijk vaccin van ten minste tien stammen van groep B meningococcen uitgegaan, welke stammen op de tien verschillende klasse 1 buitenmembraaneiwitten zijn geselecteerd.The invention advantageously relates to the fact that the meningococcal disease is currently mainly caused by group B meningococci and that the outer membrane proteins in group B meningococci class 1 also occur in group A, C, W, Y meningococci. to a vaccine which is characterized by one or more fragments of group B meningococcal class 1 outer membrane proteins. Preferably, in the preparation of such a vaccine, at least ten strains of group B meningococci are started from, which strains are selected on the ten different class 1 outer membrane proteins.
De vaccins volgens de uitvinding bevatten bijvoorbeeld 5-10 buiten-membraaneiwitfragmenten, welke door een cyanogeenbromide-behandeling van klasse 1 buitenmembraaneiwitten worden verkregen.For example, the vaccines of the invention contain 5-10 outer membrane protein fragments, which are obtained by class 1 outer membrane protein cyanogen bromide treatment.
Voorts kunnen de vaccins volgens de uitvinding met voordeel meningococcen C polysaccharide en/of detergentia bevatten. In dit verband wordt opgemerkt, dat zowel zwitterionogene, kationogene, anionogene en niet-ionogene detergentia kunnen worden toegepast. Voorbeelden van dergelijke detergentia zijn Zwittergent 3-10, Zwittergent 3-14 (N-tetra-decyl-N, N-dimethyl-3-ammonia-l-propaansulfonaat), Tween-20 en natrium-desoxycholaat.Furthermore, the vaccines according to the invention can advantageously contain meningococcal C polysaccharide and / or detergents. In this connection it is noted that zwitterionic, cationic, anionic and nonionic detergents can be used. Examples of such detergents are Zwittergent 3-10, Zwittergent 3-14 (N-tetra-decyl-N, N-dimethyl-3-ammonia-1-propanesulfonate), Tween-20 and sodium deoxycholate.
Tevens kan het vaccin volgens de uitvinding een adsorbent zoals aluminiumhydroxide, calciumfosfaat of met voordeel aluminiumfosfaat bevatten.The vaccine according to the invention can also contain an adsorbent such as aluminum hydroxide, calcium phosphate or advantageously aluminum phosphate.
De bereiding van multivalent meningococcen eiwitfragment-vaccins wordt onderstaand nader toegelicht; deze toelichting dient niet beperkend te worden uitgelegd.The preparation of multivalent meningococcal protein fragment vaccines is further explained below; this explanation should not be interpreted restrictively.
A) Stammen/kweekprocedureA) Strains / culture procedure
De stammen 44/76 (B:15:P1.16), 187 (B:4:P1.1), Swiss4 (B:4:P1.15), B2106 (B:4:P1.2), 395^ (B;KT:P1.9), M990 (B:6:P1.6), M1080 (B:1:P1.1), 2996 (B:2b:P1.2), M982 (B:9:P1.9), S3446 (B:14:P1.14), H355 (B:15:P1.15) en 6557 (B:17:P1.17) werden vanuit voorkultures van -70°C in schudkolven geê’nt en van daaruit in fermentorkultures van 40, 140 of 350 liter overgebracht. Het semi-synthetische medium bezat de onderstaande samenstelling: L-glutaminezuur 1,3 g/1, L-cysteine. HC1 0,02 g/1, Na2HPÖ4 .21^0 10 g/1, KC1 0,09 g/1, NaCl 6 g/1, NfyCl 1,25 g/1, MgSO4.7h20 0,6 g/1, glucose 5 g/1, Fe(K03)3 100/um, gistdialysaat.Tribes 44/76 (B: 15: P1.16), 187 (B: 4: P1.1), Swiss4 (B: 4: P1.15), B2106 (B: 4: P1.2), 395 ^ (B; KT: P1.9), M990 (B: 6: P1.6), M1080 (B: 1: P1.1), 2996 (B: 2b: P1.2), M982 (B: 9: P1 .9), S3446 (B: 14: P1.14), H355 (B: 15: P1.15) and 6557 (B: 17: P1.17) were seeded into shake flasks from pre-cultures of -70 ° C and from there transferred into fermenter cultures of 40, 140 or 350 liters. The semi-synthetic medium had the following composition: L-glutamic acid 1.3 g / l, L-cysteine. HCl 0.02 g / 1, Na2HPÖ4 .21 ^ 0 10 g / 1, KC1 0.09 g / 1, NaCl 6 g / 1, NfyCl 1.25 g / 1, MgSO4.7h20 0.6 g / 1, glucose 5 g / l, Fe (K03) 3 100 µm, yeast dialysate.
Gedurende de kweek in de fermentor werden de pH en PO2 gekontro- leerd en automatisch op een pH van 7,0-7,2 en een luchtverzadiging van 102 geregeld. De cellen werden met behulp van centrifugeren en wassen met steriel 0,14M NaCl geoogst en bij -20°C opgeslagen of gevriesdroogd.During the culture in the fermentor, the pH and PO2 were checked and automatically adjusted to a pH of 7.0-7.2 and an air saturation of 102. The cells were harvested by centrifugation and washing with sterile 0.14M NaCl and stored or lyophilized at -20 ° C.
B) Zuivering van de door middel van cyanogeenbromide-behandeling verkregen fragmenten van klasse 1 buitenmembraaneiwitten.B) Purification of the fragments of class 1 outer membrane proteins obtained by cyanogen bromide treatment.
De onder trap A) verkregen bacteriemassa werd in 0,5M CaCl2, 12 (w/v) Zwittergent 3-14 (Zw 3-14) en 0,14M NaCl, een pH van 4,0 en 100 ml per gram droog gewicht geëxtraheerd. Ka resuspendering werd de pH op 6,0 gebracht. De suspensie werd gedurende 1 uur bij kamertemperatuur geroerd en vervolgens gecentrifugeerd (1 uur, 3000xg) waarna het supernatant steriel werd verzameld. Aan het supernatant werd 202 ethanol (v/v) toegevoegd en na 30 min. roeren werd het produkt gecentrifugeerd (30 min., lO.OOOxg) waarna het supernatant aseptisch werd verzameld. Het supernatant werd vervolgens door middel van diafiltratie in een Amicon Hollow Fiber System (KID x 50, cut off 50.000) geconcentreerd en ontdaan van CaCl2 en ethanol· Het concentraat werd met 0,1K natriumacetaat, 25 mM EDTA, 0,052 Zw 3-14 en een pH van 6,0 tot het oorspronkelijke volume verdund en daarna opnieuw geconcentreerd door middel van een diafiltratie. Deze procedure werd vijf maal herhaald. De pH van het laatste concentraat werd op een waarde van 4,0 gebracht. Aan het concentraat werd 202 (v/v) ethanol toegevoegd en na 30 min. roeren werd het produkt gecentrifugeerd (30 min., lO.OOOxg), waarna de verkregen pellet in 702 mierezuur (v/v) werd opgenomen en met een 10-voudige overmaat cyanogeen-bromide (CKEr) gedurende 16 uren bij kamertemperatuur behandeld. Het CKBr en het mierezuur werden via indamping verwijderd en opgenomen in 0,2M Iris, 6M ureumoplossing; pH = 7,2. Het supernatant, dat de fragmenten van de klasse 1 buitenmembraaneiwitten met een molecuulgewicht van ongeveer 20.000-25.000 dalton bevatte, werd tenslotte door middel van gelfiltratie met behulp van Sephacryl S-200 of TSK-2000 met 0,2K Iris en 6M ureumoplossing als loopmiddel gezuiverd. De gewenste fracties werden verzameld en geconcentreerd. Als kriteria golden hierbij zuiverheid van de fragmenten van het klasse 1-buitenmembraaneiwit en een laag endo-toxine-gehalte.The bacterial mass obtained under step A) was extracted into 0.5M CaCl 2, 12 (w / v) Zwittergent 3-14 (Zw 3-14) and 0.14M NaCl, pH 4.0 and 100 ml per gram dry weight . Resuspension was adjusted to pH 6.0. The suspension was stirred at room temperature for 1 hour and then centrifuged (1 hour, 3000xg) after which the supernatant was collected sterile. 202 ethanol (v / v) was added to the supernatant, and after stirring for 30 min, the product was centrifuged (30 min, 100,000xg) and the supernatant collected aseptically. The supernatant was then concentrated by diafiltration in an Amicon Hollow Fiber System (KID x 50, cut off 50,000) and stripped of CaCl 2 and ethanol. The concentrate was washed with 0.1K sodium acetate, 25mM EDTA, 0.052 Zw 3-14 and diluted a pH of 6.0 to the original volume and then concentrated again by diafiltration. This procedure was repeated five times. The pH of the last concentrate was adjusted to a value of 4.0. 202 (v / v) ethanol was added to the concentrate, and after stirring for 30 min, the product was centrifuged (30 min, 100,000xg) and the resulting pellet was taken up in 702 formic acid (v / v) and with a 10 -fold excess cyanogen bromide (CKEr) treated at room temperature for 16 hours. The CKBr and formic acid were removed by evaporation and taken up in 0.2M Iris, 6M urea solution; pH = 7.2. The supernatant, containing the fragments of the class 1 outer membrane proteins with a molecular weight of about 20,000-25,000 daltons, was finally purified by gel filtration using Sephacryl S-200 or TSK-2000 with 0.2K Iris and 6M urea solution as the eluent. . The desired fractions were collected and concentrated. The criteria for this were purity of the fragments of the class 1 outer membrane protein and a low endotoxin content.
Voor het bereiden van vaccins werden een aantal van dergelijke fragmenten van verschillende klasse 1 buitenmembraaneiwitten (vijf tot tien) gemengd tot een eindconcentratie van 1 mg/ml eiwit, gemengd met meningococcen C polysaccharide (w/w = 1:1) en gedialyseerd.For vaccine preparation, a number of such fragments of different class 1 outer membrane proteins (five to ten) were mixed to a final concentration of 1 mg / ml protein, mixed with meningococcal C polysaccharide (w / w = 1: 1) and dialyzed.
Een andere mogelijkheid voor het bereiden van vaccins volgens de uitvinding bestaat uit het gebruik van Tween-20 en natriumdesoxocholaat als detergent. Bij deze methode is het gebruik van meningococcen C poly-saccharide overbodig.Another possibility for preparing vaccines according to the invention consists in the use of Tween-20 and sodium deoxocholate as a detergent. In this method, the use of meningococcal C polysaccharide is unnecessary.
De aldus verkregen multivalente klasse 1 buitenmembraaneiwit-vaccins werden gemengd met aluminiumfosfaat tot een eindconcentratie van 20-50 /ug/ml/individueel klasse 1 buitenmembraaneiwit en 2 mg/ml Al2(P04)3· Een humane dosis van dit vaccin is 0,5 ml, zodat maximaal 100-250 /ug eiwit per vaccinatie zal worden toegediend in geval van een decavalent vaccin.The multivalent class 1 outer membrane protein vaccines thus obtained were mixed with aluminum phosphate to a final concentration of 20-50 µg / ml / individual class 1 outer membrane protein and 2 mg / ml Al2 (PO4) 3. A human dose of this vaccine is 0.5. ml, so that a maximum of 100-250 µg protein per vaccination will be administered in the case of a decavalent vaccine.
L: De samenstelling van de bereide vaccins werd gecontroleerd door middel van een kwantitatieve antigeen-bepalingstest met behulp van mono-clonale antilichamen, op molecuulgrootte door middel van HPLC (hoge-druk-vloeistof-chromatografie) en op de immunogeniteit van alle aanwezige klasse 1 eiwit-fragmenten en met behulp van de gebruikelijke onscha-delijkheidstests.L: The composition of the prepared vaccines was checked by quantitative antigen assay using monoclonal antibodies, molecular size by HPLC (high pressure liquid chromatography) and immunogenicity of all Class 1 present protein fragments and using the usual harmlessness tests.
Claims (11)
Priority Applications (15)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8803111A NL8803111A (en) | 1988-12-19 | 1988-12-19 | Meningococcus class 1 outer-membrane protein vaccine - useful to immunise against meningococcal disease |
| NL8900036A NL8900036A (en) | 1988-12-19 | 1989-01-06 | Meningococcus class 1 outer-membrane protein vaccine - useful to immunise against meningococcal disease |
| NL8901612A NL8901612A (en) | 1988-12-19 | 1989-06-26 | Vaccines against meningococcal infections - contg. outer membrane proteins or fragments |
| EP90901397A EP0449958B9 (en) | 1988-12-19 | 1989-12-19 | Meningococcal class 1 outer-membrane protein vaccine |
| JP50166290A JP3436756B2 (en) | 1988-12-19 | 1989-12-19 | Vaccine based on class I outer membrane protein of Neisseria meningitidis |
| DE68921895T DE68921895T3 (en) | 1988-12-19 | 1989-12-19 | MENINGOCOCCALES CLASS I EXTERNAL MEMBRANE PROTEIN VACCINE. |
| PCT/US1989/005678 WO1990006696A2 (en) | 1988-12-19 | 1989-12-19 | Meningococcal class 1 outer-membrane protein vaccine |
| AU48219/90A AU640118B2 (en) | 1988-12-19 | 1989-12-19 | Meningococcal class 1 outer-membrane protein vaccine |
| ES90901397T ES2070312T5 (en) | 1988-12-19 | 1989-12-19 | CLASS 1 MENINGOCOCIC EXTERNAL MEMBRANE PROTEIN VACCINE. |
| AT90901397T ATE120093T1 (en) | 1988-12-19 | 1989-12-19 | MENINGOCOCCALES CLASS I OUTER MEMBRANE PROTEIN VACCINE. |
| NO912369A NO305463B1 (en) | 1988-12-19 | 1991-06-18 | Method of Preparing a Vaccine against Neisseria meningitidis, class 2/3 minus mutant of Neisseria Neisseria meningitidis strain, as well as microorganism expressing a fusion protein |
| DK199101174A DK175788B1 (en) | 1988-12-19 | 1991-06-18 | Vaccine against meningococcal diseases, including components thereof, their use and recombinants expressing them |
| FI912965A FI113009B (en) | 1988-12-19 | 1991-06-18 | Procedure for Preparing a Vaccine against the Neisseria meningitidis Bacteria and Neisseria meningitidis Strain |
| US08/204,808 US7118757B1 (en) | 1988-12-19 | 1994-02-15 | Meningococcal class 1 outer-membrane protein vaccine |
| US08/461,651 US7238345B1 (en) | 1988-12-19 | 1995-06-05 | Recombinant microorganism expressing meningococcal class 1 outer membrane protein |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8803111 | 1988-12-19 | ||
| NL8803111A NL8803111A (en) | 1988-12-19 | 1988-12-19 | Meningococcus class 1 outer-membrane protein vaccine - useful to immunise against meningococcal disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NL8803111A true NL8803111A (en) | 1990-07-16 |
Family
ID=19853404
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8803111A NL8803111A (en) | 1988-12-19 | 1988-12-19 | Meningococcus class 1 outer-membrane protein vaccine - useful to immunise against meningococcal disease |
| NL8900036A NL8900036A (en) | 1988-12-19 | 1989-01-06 | Meningococcus class 1 outer-membrane protein vaccine - useful to immunise against meningococcal disease |
| NL8901612A NL8901612A (en) | 1988-12-19 | 1989-06-26 | Vaccines against meningococcal infections - contg. outer membrane proteins or fragments |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8900036A NL8900036A (en) | 1988-12-19 | 1989-01-06 | Meningococcus class 1 outer-membrane protein vaccine - useful to immunise against meningococcal disease |
| NL8901612A NL8901612A (en) | 1988-12-19 | 1989-06-26 | Vaccines against meningococcal infections - contg. outer membrane proteins or fragments |
Country Status (1)
| Country | Link |
|---|---|
| NL (3) | NL8803111A (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1944371E (en) | 1998-05-01 | 2015-07-13 | Novartis Ag | Neisseria meningitidis antigens and compositions |
| EP2290083B1 (en) | 1999-04-30 | 2014-08-20 | Novartis Vaccines and Diagnostics S.r.l. | Conserved neisserial antigens |
| GB9911692D0 (en) * | 1999-05-19 | 1999-07-21 | Chiron Spa | Antigenic combinations |
| EP1860191A3 (en) * | 1999-05-19 | 2008-02-13 | Novartis Vaccines and Diagnostics S.r.l. | Combination neisserial compositions |
| EP1790660B1 (en) | 2000-02-28 | 2012-06-20 | Novartis Vaccines and Diagnostics S.r.l. | Heterologous expression of neisserial proteins |
| GB0121591D0 (en) | 2001-09-06 | 2001-10-24 | Chiron Spa | Hybrid and tandem expression of neisserial proteins |
| EP2351579B1 (en) | 2002-10-11 | 2016-09-21 | Novartis Vaccines and Diagnostics S.r.l. | Polypeptide vaccines for broad protection against hypervirulent meningococcal lineages |
| GB0408977D0 (en) | 2004-04-22 | 2004-05-26 | Chiron Srl | Immunising against meningococcal serogroup Y using proteins |
| US9259462B2 (en) | 2010-09-10 | 2016-02-16 | Glaxosmithkline Biologicals Sa | Developments in meningococcal outer membrane vesicles |
| JP2015521595A (en) | 2012-06-14 | 2015-07-30 | ノバルティス アーゲー | Vaccine for serogroup X meningococcus |
-
1988
- 1988-12-19 NL NL8803111A patent/NL8803111A/en not_active Application Discontinuation
-
1989
- 1989-01-06 NL NL8900036A patent/NL8900036A/en not_active Application Discontinuation
- 1989-06-26 NL NL8901612A patent/NL8901612A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NL8900036A (en) | 1990-07-16 |
| NL8901612A (en) | 1990-07-16 |
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