WO2011154119A1 - Fabrication d'un vaccin sec stabilisé à administration par voie orage à partir d'un virus vivant atténué - Google Patents

Fabrication d'un vaccin sec stabilisé à administration par voie orage à partir d'un virus vivant atténué Download PDF

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Publication number
WO2011154119A1
WO2011154119A1 PCT/EP2011/002760 EP2011002760W WO2011154119A1 WO 2011154119 A1 WO2011154119 A1 WO 2011154119A1 EP 2011002760 W EP2011002760 W EP 2011002760W WO 2011154119 A1 WO2011154119 A1 WO 2011154119A1
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Prior art keywords
drying
vaccine
aqueous composition
weight
vol
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PCT/EP2011/002760
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English (en)
Inventor
Pierre Chouvenc
Alain Françon
Catherine Noel
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Sanofi Pasteur Sa
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Publication of WO2011154119A1 publication Critical patent/WO2011154119A1/fr

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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
    • A61K39/12—Viral antigens
    • A61K39/125—Picornaviridae, e.g. calicivirus
    • A61K39/13—Poliovirus
    • 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
    • A61K39/12—Viral antigens
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5254—Virus avirulent or attenuated
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32611—Poliovirus
    • C12N2770/32634—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a method for preparing a dry oral vaccine, composed of a live attenuated virus of which the stability of the infectious titer over time is improved. According to one particular mode, a dry oral vaccine that can be used without prior rehydration is obtained.
  • Vaccines composed of live attenuated viruses are for the most part fragile and are generally provided in freeze-dried form, despite the drop in the infectious titer caused by the freeze-drying, which is particularly large in the case of the poliovirus. Various attempts to reduce this drop are reported in the prior art.
  • thermostable Oral Poliovaccine An initiative was launched by the WHO between 1990 and 1995 (Children's vaccine initiative product development group on thermostable Oral Poliovaccine), in order to encourage the development of a liquid or freeze-dried, thermostable oral polio vaccine (OPV). This action was carried out in the context of the poliomyelitis eradication program, the instability of the OPV vaccine limiting the success of vaccination with this vaccine.
  • patent DD-A-299 213 A7 relates to a method for stabilizing a dry vaccine composed of the live measles virus.
  • This method comprises a step of freezing this virus at -20° in a composition which must comprise arginine, dextran, trehalose or sorbitol and a phosphate buffer, followed by a step of desiccation for 48 hours at 22°C.
  • the loss of infectious titer of the virus is 0.81 log, but the method described in this document does not result in a dry vaccine in a form that can be administered orally and comprises a desiccation step, the relatively long duration of which has proved problematic for industrial exploitation.
  • stability during a long storage period.
  • US 2006/0127414 proposes a method of stabilizing poliovirus (IPV - inactivated polio vaccine) by drying, which makes it possible to obtain a highly viscous vaccine which requires rehydration. This method was not, however, applied to the oral vaccine (OPV).
  • the subject of the present invention is a method for preparing a dry oral vaccine, comprising a live attenuated virus, by drying (desiccating) an aqueous composition comprising:
  • ballast agent selected from the group made up of monosaccharides, oligosaccharides, polysaccharides and the sugar alcohols which are derived therefrom, and also mixtures thereof;
  • a thickener selected from the group made up of monosaccharides, oligosaccharides, polysaccharides and the sugar alcohols which are derived therefrom, and also mixtures thereof;
  • a stabilizer comprising a surfactant, amino acids and urea, in a buffered liquid medium.
  • the drying operation can be carried out according to conventional techniques. Freeze-drying and vacuum-drying are in particular mentioned.
  • the drying is not continued beyond the time required to obtain a product which has a residual moisture content of between 5% and 10% (weight/weight), limits included. It is indicated that this residual moisture content can be conveniently determined according to the Karl Fischer method.
  • the drying operation for example the freeze-drying, is carried out in a few hours, advantageously in less than 24 hours, preferably in less than 12 hours, particularly preferably in less than 8 hours, which, from the industrial point of view, is of great advantage.
  • the dry weight of the aqueous composition used in the method according to the invention and which is subjected to the drying operation is between 70% and 85% (weight/weight) limits included, of the total weight of the aqueous composition.
  • the four components (i) to (iv) contribute thereto in various proportions, the greatest contribution thereto coming from the ballast agent and the minute contribution thereto coming from the virus.
  • the ballast agent is present in the aqueous composition intended to be dried, at a concentration between 80% and 00% (limits included) of the maximum solubility of the ballast agent in an aqueous medium between 25 and 35°C.
  • the thickener is present in the aqueous composition intended to be dried, at a concentration of between 0.08 and 0.12 g/100 ml, limits included.
  • the stabilizer is present in the aqueous composition intended to be dried, at a concentration of between 40% and 80%, advantageously 50% and 70%, preferably 55% and 60% (vol./vol.), limits included.
  • the method according to the invention can be carried out in order to obtain any dry oral vaccine containing a live attenuated virus as antigen. It is perfectly suitable for the preparation of vaccines composed of heat-sensitive viruses.
  • dry vaccine is intended to mean a vaccine of solid, non-liquid consistency.
  • oral vaccine means a vaccine intended to be administered orally.
  • the virus may be any virus against which it is desirable to obtain a live attenuated vaccine intended to be administered orally.
  • the poliovirus and the rotavirus are viruses against which a dry oral vaccine is entirely suitable. These viruses each exhibit strain variations such that a sub-classification applies.
  • the poliovirus is at the current time divided up into three serotypes: 1 , 2 and 3; and the rotavirus is divided up into an even higher number of serotypes.
  • serotypes G1 , G2, G3, G4, G8 and G9 are, for example, mentioned.
  • the method according to the invention applies to all the serotypes of these viruses.
  • the ballast agent may, for example, be dextran, maltodextran, glucose, xylose, galactose, arabinose, fructose, D-mannose, sorbose, maltose, sucrose, sucrose, lactose or trehalose; the latter being preferred.
  • the trehalose can be used at a concentration of between 60 and 85 g/100 ml (limits included), advantageously of 0.7 g/ml (70% weight/vol).
  • the ballast agent may also be a sugar alcohol such as sorbitol, mannitol, xylitol, glycerol, erythritol or arabitol.
  • the ballast agent may also be a mixture of the compounds mentioned, for example a mannitol-sorbitol mixture.
  • the thickener may, for example, be xanthan, carob, guargel, alginate and mucigel; xanthan being preferred since this thickener also has stabilizing effects on viruses.
  • the xanthan can be used at a concentration of 0.1 % (weight/vol.).
  • the stabilizer is a mixture, in particular a liquid mixture, combining the following compounds: at least one surfactant, amino acids, urea and a buffer.
  • the active surfactant may be any surfactant. Mention is in particular made of sodium dodecyl sulfate (anionic surfactant) and also nonionic surfactants such as those of polyoxyethylenated sorbitan ester type. An example of the latter is the product known under the trade name TweenTM.
  • a mixture of amino acids may be a mixture of essential amino acids or a mixture of nonessential amino acids. Both types of mixture are advantageously used in the stabilizing composition that is of use for the purposes of the present invention.
  • the buffer can be any saline or non-saline buffer. Phosphate buffers and the HEPES buffer are in particular mentioned.
  • the stabilizer may also comprise (i) one or more polysaccharides such as dextran; and/or (ii) one or more sugar alcohols; in particular sorbitol and mannitol.
  • a mixture that is of use as a stabilizer can be made up:
  • a surfactant for example between 0.005% and 0.02% vol ./vol.
  • urea for example between 0.5% and 1.5% weight/vol.
  • a buffer for example between 15 and 40 mM
  • a sugar alcohol for example between 5% and 10% weight/vol.
  • a polysaccharide for example, between 1 and 2% weight/vol.
  • a liquid mixture having function of a stabilizer may, for example, be composed of the following products and mixtures (composition S1 ): Tween® 80 (Polysorbate 80, 0.01% weight/vol.), HEPES (20 mM), sorbitol (5% weight/vol.), mannitol (2.5% weight/vol.), arginine hydrochloride (Arg-HCI) (2.14% weight/vol.), cysteine-HCI (Cys-HCI, 0.00001% weight/vol.), BME essential amino acids mixture 100xc (20% vol./vol.), MEM nonessential amino acids mixture 100xc (20% vol./vol.), dextran 70 (1.5% weight/vol.), urea (0.9% weight/vol.).
  • the BME and MEM mixtures used are as follows:
  • An aqueous composition that is of use for the purposes of the present invention can be obtained by dissolving a ballast agent, e.g. trehalose and a thickener, e.g. xanthan, in a liquid stabilizer comprising, e.g. at least one surfactant, a buffer, amino acids and urea; then by adding an appropriate amount of virus.
  • a ballast agent e.g. trehalose and a thickener, e.g. xanthan
  • a liquid stabilizer comprising, e.g. at least one surfactant, a buffer, amino acids and urea
  • the drying is carried out using an aqueous composition divided up into samples such that, after drying, the dried samples are of a size suitable for oral administration, without prior rehydration.
  • the dividing up into samples can be carried out in several ways: the aqueous composition can, for example, be divided up in cells, (e.g., cupules thermoformed from a PVC sheet) or in large drops on a plate. Under these conditions, the size of the cells and of the drops can be adjusted so as to correspond, in the end, to a vaccine dose. It is sufficient for the individual to take this dose as it is, to place it on the tongue, where it will disintegrate of its own accord.
  • the composition is frozen in liquid or gaseous nitrogen, in the form of microbeads, in particular according to the technique described in WO 2010/003670.
  • the drying of the microbeads is subsequently finished off.
  • the dry microbeads are subsequently divided up into doses of identical weight, to be taken directly by the intended recipient.
  • Freeze-drying is a drying method which is conventionally carried out in two stages: freezing and sublimation.
  • freezing and sublimation it is indicated that the aqueous composition, once divided up in cells or on a plate, can be frozen at approximately -70°C.
  • the temperature is then brought back up to between -40 and -30°C, limits included, for example -35°C, at which temperature the sublimation is subsequently carried out at a pressure of 300 to 400 bar.
  • the sublimation stage ends with the temperature being brought back up to between +5 and +15°C, limits included, for example +10°C.
  • the cells are then sealed with aluminum foil. It is subsequently sufficient to pierce a cell, to take the vaccine dose that it contains and to apply it to the tongue.
  • the dry doses produced on plates are simply collected in bottles.
  • aqueous composition divided up into microbeads e.g. of 800 ⁇ to 1 mm in diameter
  • the sublimation stage as described above can be carried out directly.
  • the microbeads are divided up into a vaccine dose, for example in a single-dose hermetically sealed bottle.
  • the product obtained according to one particular embodiment of the method according to the invention does not need to be taken up extemporaneously with any solvent at the time of administration.
  • the method according to the invention makes it possible to preserve the infectious titer of the live attenuated virus and therefore the vaccinating power of the dry oral vaccine which contains it.
  • the virus contained in the product obtained by means of the method shows a loss of infectious titer compared with that determined before drying using the aqueous composition, which loss is, surprisingly, very small: less than one or two log. Furthermore, after accelerated aging by heating and freeze-drying for 7 days at 45°C, a drop in infectious titer of the same order of magnitude is observed, which is a sign that the dry live vaccine obtained by means of the method according to the invention has an outstanding stability over time.
  • the subject of the invention is also a dry oral vaccine comprising a live attenuated virus that can be obtained by means of a method according to the invention.
  • the infectious titer of which is at most 1 or 2 log (log base 10) lower compared with that determined using the aqueous composition that is used in the method of production before it is subjected to the drying.
  • the vaccine according to the invention is suitable for oral administration in its dry form (without prior rehydration).
  • the virus contained in the vaccine according to the invention may be any of those described as being able to be part of the aqueous composition for use in the method according to the invention.
  • a vaccine according to the invention can comprise (i) serotypes 1 , 2 and/or 3 of the poliovirus; or (ii) one or more serotypes of the rotavirus.
  • aqueous composition for use in the method according to the invention, comprising:
  • ballast agent selected from the group comprising monosaccharides, oligosaccharides, polysaccharides, the sugar alcohols which are derived therefrom, and also mixtures thereof;
  • a stabilizer comprising a surfactant, amino acids, urea and a buffer; and, optionally,
  • a - Preparation of a dry oral polio vaccine An aqueous composition is prepared by dissolving, in a stabilizing liquid preparation S1 , S2 or S3, xanthan of a final concentration of 0.7 g/ml (70%) and a filler, the final concentration of which is given in table I hereinafter.
  • a stabilizing liquid preparation S1 , S2 or S3 xanthan of a final concentration of 0.7 g/ml (70%) and a filler, the final concentration of which is given in table I hereinafter.
  • CCID 50/d Approximately 7 CCID 50/d of the poliovirus made up of serotypes 1 , 2 and 3 (CCID 50/d: viral dose which infects 50% of cell cultures) and prepared by propagation on cell cultures according to the recommendations given by the European Pharmacopoeia Ed.: 6.1 , are then incorporated.
  • the stabilizing preparations S1 to S3 are as follows:
  • S2 Sorbitol (5% weight/vol.), mannitol (2.5% weight/vol.), Arg-CI (2.14% weight/vol.), Cysteine-HCI (Cys-Cys-HCI, 0.00001 % weight/vol.), BME essential amino acids mixture 100xc (40% vol./vol.), MEM nonessential amino acids mixture 100xc (40% vol./vol.), Dextran 70 (1.5% weight/vol.) and urea (0.9% weight/vol.).
  • S3 BME essential amino acids mixture 100xc (10% vol./vol.) and MEM nonessential amino acids mixture 100xc (10% vol./vol.).
  • the aqueous composition is then divided up into the 0.3 ml cells of a PVC thermoformed sheet.
  • the sheet with the cells is frozen at -70°C.
  • Sublimation is carried out at - 35°C for 2 hours, and then at + 10°C for 6 hours, at a pressure of 350 pbar throughout.
  • the cells are then sealed with aluminum foil.
  • the dry product obtained is in the form of a pastille formed by the cells. To the eye, it has a homogeneous white color. Its percentage residual moisture is between 7% and 8%. Its resistance/ coherence is sufficient to perforate the aluminum foil which seals the cells. It disintegrates rapidly on contact with water or saliva.
  • infectious titer of the virus before and after freeze-drying and also after freeze- drying followed by storage at 37°C or 45°C for 7 days is determined by the CCID50 technique (determination of the titer infecting 50% of cell cultures) described in the European Pharmacopoeia Ed.: 6.1 , page 3588, and specified hereinafter.
  • the viral preparation to be titered is diluted from -1 to - 6 or -7 (in log) in 96-well plates in a proportion of 50 ⁇ per well with a 1xc MEM culture medium supplemented with 2% (vol./vol.) of fetal calf serum (not containing anti-polio antibodies), 4% (vol./vol.) of a 5.6% sodium bicarbonate solution and 0.2% (vol./vol.) of a 400xc solution of penicillin-didromycin antibiotics.
  • anti-anti-polio type 2 antiserum plus anti-polio type 3 antiserum diluted in MEM medium in order to neutralize the polioviruses type 2 and poliovirus type 3, contained in the viral preparation (measurement of type 1 titer);
  • anti-polio type 1 antiserum plus anti-polio type 3 antiserum diluted in MEM medium in order to neutralize the poliovirus type 1 and poliovirus type 3, contained in the viral preparation (measurement of type 2 titer);
  • anti-polio type 1 antiserum plus anti-polio type 2 antiserum diluted in MEM medium in order to neutralize the poliovirus type 1 and poliovirus type 2, contained in the viral preparation (measurement of type 3 titer).
  • a negative control column is formed with 100 ⁇ of MEM medium per well.
  • the plates are covered and agitated for 1 hour at 36°C.
  • Hep-2 (Cincinnati) cell suspension 100 ⁇ of Hep-2 (Cincinnati) cell suspension, at 50 000 cells/ml, are added to each well. The plates are then placed in an incubator at 36°C, for 9 days without agitation.
  • the cytopathogenic effects are read in each well after having verified the integrity of the cell controls.
  • the number of positive wells is determined.
  • the titer is calculated using a linear regression of the number of positive wells (transformed using the "arcsine square root” function) as a function of the dilutions (transformed by logarithm transformation).
  • the stability of the dry oral polio vaccine containing trehalose, xanthan and the S1 preparation as described above is compared to that observed with (i) a liquid oral polio vaccine obtained according to the D2O method (the method of R. Crainic) and (ii) a commonly used liquid oral polio vaccine based on MgCI 2 , 1 M (T vaccine).
  • the infectious titer of each of the three serotypes is determined during a storage period of 3 months at 25°C, for 3 weeks at 37°C or of 7 days at 45°C.

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Abstract

Cette invention concerne un procédé de fabrication d'un vaccin sec à administration orale composé d'un virus vivant atténué dont la stabilité a été améliorée par rapport aux résultats obtenus à ce jour sur ce point. Le procédé consiste pour l'essentiel à déshydrater une composition aqueuse contenant non seulement le virus, mais encore un agent de charge, un agent épaississant et un agent stabilisant offrant l'avantage d'être présents à une concentration telle que le poids à sec de la composition est élevé. Avantageusement, le séchage peut se poursuivre jusqu'à ce que la teneur en eau résiduelle se situe entre 5 et 10% environ. Le vaccin ainsi obtenu peut donc être administré par voie orale sans réhydratation préalable.
PCT/EP2011/002760 2010-06-07 2011-06-06 Fabrication d'un vaccin sec stabilisé à administration par voie orage à partir d'un virus vivant atténué WO2011154119A1 (fr)

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FR1054443A FR2960781B1 (fr) 2010-06-07 2010-06-07 Preparation d'un vaccin oral sec stabilise, compose d'un virus vivant attenue
FR1054443 2010-06-07

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Cited By (2)

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CN110585439A (zh) * 2019-09-30 2019-12-20 长春生物制品研究所有限责任公司 一种改良型的冻干甲型肝炎减毒活疫苗稳定剂、疫苗半成品、疫苗成品及其制备方法
CN116874555A (zh) * 2023-09-08 2023-10-13 成都华任康生物科技有限公司 一种置换液及其试剂盒和相关应用

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EP3581202A1 (fr) * 2018-06-14 2019-12-18 University College Cork-National University of Ireland, Cork Composition et procédé de stabilisation de vaccins dans un format de dosage solide

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110585439A (zh) * 2019-09-30 2019-12-20 长春生物制品研究所有限责任公司 一种改良型的冻干甲型肝炎减毒活疫苗稳定剂、疫苗半成品、疫苗成品及其制备方法
CN116874555A (zh) * 2023-09-08 2023-10-13 成都华任康生物科技有限公司 一种置换液及其试剂盒和相关应用
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