WO2021165312A1 - Adjuvant de vaccin comprenant un microlatex inverse - Google Patents
Adjuvant de vaccin comprenant un microlatex inverse Download PDFInfo
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- WO2021165312A1 WO2021165312A1 PCT/EP2021/053873 EP2021053873W WO2021165312A1 WO 2021165312 A1 WO2021165312 A1 WO 2021165312A1 EP 2021053873 W EP2021053873 W EP 2021053873W WO 2021165312 A1 WO2021165312 A1 WO 2021165312A1
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- oil
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- water
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- 239000003813 safflower oil Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229940057910 shea butter Drugs 0.000 description 1
- 230000004905 short-term response Effects 0.000 description 1
- NGSRGPMIUOKCKY-UHFFFAOYSA-M sodium;2,2-bis(prop-2-enoxy)acetate Chemical compound [Na+].C=CCOC(C(=O)[O-])OCC=C NGSRGPMIUOKCKY-UHFFFAOYSA-M 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- JNYAEWCLZODPBN-CTQIIAAMSA-N sorbitan Polymers OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 1
- 229940057429 sorbitan isostearate Drugs 0.000 description 1
- 229950003429 sorbitan palmitate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- VPYJNCGUESNPMV-UHFFFAOYSA-N triallylamine Chemical compound C=CCN(CC=C)CC=C VPYJNCGUESNPMV-UHFFFAOYSA-N 0.000 description 1
- PJHKBYALYHRYSK-UHFFFAOYSA-N triheptanoin Chemical compound CCCCCCC(=O)OCC(OC(=O)CCCCCC)COC(=O)CCCCCC PJHKBYALYHRYSK-UHFFFAOYSA-N 0.000 description 1
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- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
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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
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- 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
-
- 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
- A61K39/102—Pasteurellales, e.g. Actinobacillus, Pasteurella; Haemophilus
-
- 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
- A61K39/12—Viral antigens
- A61K39/155—Paramyxoviridae, e.g. parainfluenza virus
- A61K39/17—Newcastle disease virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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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
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
- A61K2039/552—Veterinary vaccine
-
- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
-
- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
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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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55588—Adjuvants of undefined constitution
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/16011—Herpesviridae
- C12N2710/16111—Cytomegalovirus, e.g. human herpesvirus 5
Definitions
- the present invention relates to a particular vaccine adjuvant, its preparation and the vaccine comprising it.
- a vaccine composition generally consists of an antigen, an immunogenic compound which induces protection against a disease of interest, and a vaccine adjuvant, which allows the amplification of the immune response of the vaccinated animal against the. antigen.
- adjuvants in the vaccine compositions makes it possible in particular to increase the intensity of the humoral or cellular immune response conferred by a dose of vaccine, making it possible to ensure a better level of protection; to prolong the duration of protection conferred by a dose of vaccine; to obtain, with a lower antigenic dose, an efficacy equivalent to that conferred by a full dose used without adjuvant; reduce the number of immunizations required to ensure vaccine protection.
- emulsions comprising at least one oily phase and at least one aqueous phase (such as for example the so-called Freund's adjuvants), liposomes, synthetic polymers.
- immunostimulants adjuvants of biological origin (saponin, chitosan, cytokines, oligonucleotides ...) or mineral salts insoluble in water (for example aluminum hydroxide, which is very commonly used).
- Oily vaccine adjuvants are composed of oil and surfactants and allow vaccines to be formulated in the form of emulsions, the aqueous phase of which contains the vaccine antigen.
- oils used mention may be made of oils of vegetable origin, mineral oils, synthetic oils and oils of animal origin.
- the surfactants present in the oily adjuvants are emulsifying surfactants, exhibiting a hydrophilic character characterized by a value of the Hydrophilic-Lipophilic Balance (HLB) of between 8 and 19, more particularly between 8 and 15.
- HLB Hydrophilic-Lipophilic Balance
- Such a hydrophilic surfactant may consist of example of an alkylpolyglycoside or a mixture of alkylpolyglycosides; to saponins; in lecithins; polyoxyethylated alkanols; into polymers comprising polyoxyethylene and polyoxypropylene blocks; in esters obtained by condensation of a fatty acid, advantageously a fatty acid which is liquid at 20 ° C. with a polyol-sugar, such as, for example, sorbitol, mannitol or glycerol; in esters obtained by condensation of a fatty acid, advantageously a liquid fatty acid at 20 ° C with an ethoxylated sugar.
- a polyol-sugar such as, for example, sorbitol, mannitol or glycerol
- esters obtained by condensation of a fatty acid advantageously a liquid fatty acid at 20 ° C with an ethoxylated sugar.
- the surfactants present in the oily adjuvants can also be emulsifying surfactants of the “water-in-oil” type, denoting surfactants having a sufficiently low HLB value, preferably greater than or equal to 1 and less than 8.0 allowing d 'obtain water-in-oil emulsions, for which the aqueous phase is dispersed in the lipophilic fatty phase.
- surfactants of the water-in-oil type mention may be made of the esters of anhydrohexitol and of a linear or branched, saturated or unsaturated aliphatic carboxylic acid, comprising from 12 to 22 carbon atoms optionally substituted with one or more groups. hydroxyls, or a mixture of these esters.
- the vaccine emulsions obtained can be of the water-in-oil, oil-in-water or water-in-oil-in-water type, depending in particular on the nature of the surfactant system used.
- the adjuvants of the water-in-oil emulsion type make it possible to significantly increase the humoral and cellular response against the vaccine antigen over a prolonged period compared to the non-adjuvanted vaccine or compared to the vaccine adjuvanted with an aqueous adjuvant such as aluminum hydroxide. Such a long-term response can make it possible to reduce the number of vaccine injections.
- the adjuvants of the water-in-oil emulsion type are used in particular for the preparation of vaccine compositions intended for the vaccination of cattle, sheep, goats, fish and avian species against viral, bacterial or parasitic pathogens.
- Some synthetic polymers also have immunostimulatory properties and have been used as adjuvants in vaccines.
- immunostimulating polymers used as adjuvants in veterinary vaccines there may be mentioned in particular block copolymers of polyoxyethylene and polyoxypropylene (POE-POP), polyethyleneimines, homopolymers of acrylic acid in their sodium forms, copolymers of acrylic acid and acrylic acid esters (also called carbomers).
- POE-POP polyoxyethylene and polyoxypropylene
- polyethyleneimines polyethyleneimines
- homopolymers of acrylic acid in their sodium forms copolymers of acrylic acid and acrylic acid esters (also called carbomers).
- the polymers obtained from acrylic acid, methacrylic acid, esters of acrylic acid or esters of methacrylic acid can be synthesized by a precipitating polymerization process in a suitable solvent or by emulsion polymerization. reverse, as described in the patent application published under the number FR2922767A1.
- the carbomers are used at mass contents of the order of one percent for applications as a vaccine adjuvant, and their dilution is in the form of a fluid and translucent easily injectable vaccine.
- polymeric adjuvants have very good safety and induce a strong short-term response against the associated antigen, and are used in particular for the vaccination of pigs, as described for example in the patent application published under the number WO2007094893).
- ready-to-use polymeric oily immunity adjuvant means a mixture consisting of an oily phase containing at least one surfactant and a polymer, already sterilized and which can be immediately put into use. works by mixing with the aqueous antigenic medium in an emulsification step.
- polymeric oily adjuvant is used with the aim of obtaining vaccine, prophylactic or therapeutic emulsions which are stable over time.
- the first way of proceeding consists in adding in an oily phase at least one polyacrylic acid, a polymer whose carboxylic groups are not salified, and which is in the form of a powder.
- the powder remains difficult to stabilize in the oil in the form of a suspension and may present sedimentation problems over time.
- the adjuvant obtained in such a way leads to the production of emulsions of an acidic nature, since the polymer is not neutralized and more particularly not neutralizable during the emulsification process. All these parameters make this technical solution unsatisfactory.
- the second way of proceeding consists in adding an aqueous gel, previously formed by the addition of at least one polyacrylic acid in water, in an oily adjuvant.
- the dispersion of an aqueous gel in an oily phase presents the first constraint of not guaranteeing the homogeneity of the mixture obtained at the end of this process.
- this route involves the major risk of leading to a phase shift of the dispersed phase thus leading to the non-homogeneity of the desired product.
- the third way of proceeding is to disperse a polymeric adjuvant such as a polyacrylate, in the form of an inverse latex (or W / O type emulsion, the dispersed aqueous phase of which comprises a polyacrylate whose carboxylic functions have been previously neutralized in the form of an alkali metal salt or an ammonium salt) in the oily adjuvant.
- a phase shift is observed over time, leading to heterogeneity of the oily adjuvant.
- the vaccine compositions are in the form of an emulsion that cannot be sterilized, it is therefore necessary to sterilize the oily adjuvants, by filtration or by heat by passage in an autoclave, before the step of emulsification with the antigenic medium. It should also be noted that the surfactants contained in oily adjuvants are generally not compatible with sterilization by irradiation.
- the oily adjuvant is sterilized by passing the heat of an autoclave or by sterilizing filtration on the one hand, and
- the polymeric adjuvant is hydrated, diluted and sterilized in solution by passing through the heat of an autoclave, on the other hand, and
- the polymeric adjuvant is mixed aseptically with the aqueous antigenic medium, and
- the aqueous mixture of the polymeric adjuvant and the antigenic medium is emulsified aseptically with the sterile oily phase.
- stable means the absence of phase shift, of solidification of the polymer during storage), easily sterilizable and which makes it possible to achieve stable emulsions over time at + 4 ° C for 1 year and for at at least 1 month at + 37 ° C (in other words showing no sedimentation or phase shift).
- the oily polymeric adjuvant according to the invention should make it possible to obtain vaccine compositions which are effective from an immunological point of view.
- a solution of the present invention is a vaccine adjuvant comprising at least one inverse microlatex.
- inverse micro-latex denotes an inverse microemulsion comprising at least one polymer of polyelectrolyte type.
- microemulsion denotes a mixture of two immiscible liquids, thermodynamically stable, stabilized by the presence of a surfactant system comprising at least one emulsifying surfactant.
- a microemulsion is generally transparent because the droplet size of the dispersed phase is characterized by an average particle diameter less than or equal to 200 nanometers, and preferably less than or equal to 100 nanometers.
- inverse microemulsion denotes a microemulsion as defined above, for which the dispersed phase is an aqueous phase and the continuous phase is an oily phase.
- polymer of polyelectrolyte type denotes a polymer in which all or part of the monomeric units present in the polymer carries an ionized chemical function.
- a polymer of anionic polyelectrolyte type predominantly comprises monomer units having an anionic function
- a polymer of cationic polyelectrolyte type predominantly comprises monomer units having a cationic function.
- polymer of anionic and crosslinked polyelectrolyte type denotes a polymer of anionic polyelectrolyte type as defined above and which comprises, through its constituent monomer units, at least one monomer unit having at least two reactive functions which can be involved during the polymerization reaction and thus allowing at least two polymer chains to be linked together.
- the reverse micro-latexes are prepared by carrying out a process which comprises the following steps: A step a) of preparing an aqueous solution containing the monomers and the possible different additives (such as for example a crosslinking monomer)
- step c) of adding an initiator of radical type to initiate a radical polymerization reaction in adiabatic medium and
- the vaccine adjuvant according to the invention may exhibit one or more of the following characteristics: the reverse microlatex comprises an oily phase, an aqueous phase, at least one surfactant of the water-in-oil type (W / O ), at least one surfactant of oil-in-water (O / W) type and an anionic and crosslinked polyelectrolyte; with said anionic and crosslinked polyelectrolyte comprising at least one crosslinking monomer and at least one hydrophilic monomer unit.
- the hydrophilic monomer unit comes from acrylic acid totally or partially salified with an alkali or alkaline earth metal salt or an ammonium salt. acrylic acid is totally or partially salified with a sodium salt or an ammonium salt, preferably with a sodium salt.
- the anionic and crosslinked polyelectrolyte comprises a monomeric unit of formula
- said adjuvant further comprises an oil (H 1 ), at least one surfactant of the water-in-oil type (Ei) and at least one surfactant of the oil-in-water type (E 2 ).
- the adjuvant comprises between 1% and 10% by mass of surfactant of the water-in-oil type (Ei), preferably from 3% to 8% by mass.
- the adjuvant comprises between 1% and 10% by mass of surfactant of the water-in-oil type
- the adjuvant comprises, for 100% of its mass: a) from 50% to 97.5% by mass of said oil (H 1 ), preferably from 60% to 90% b) from% to 10% by mass of said surfactant of the type water-in-oil (Ei), preferably from 3% to 8% c) from 1% to 10% by mass of said surfactant of the oil-in-water type (E 2 ), preferably from 3% to 8%; and d) from 0.5% to 30% by mass of at least one inverse microlatex, preferably from 1 to 10%, more preferably between 1% and 10%, it being understood that the sum of the mass contents a) + b) + c) + d) is equal to 100%.
- the oil (H 1 ) is a white mineral oil.
- the oil (H1) could also be a mineral oil, such as for example paraffin oil, petrolatum oil, an isoparaffin.
- the inverse microlatex included in the vaccine adjuvant according to the invention will comprise, for 100% of its mass:
- the oil (H 1 ) included in the vaccine adjuvant which is the subject of the present invention is identical or different from the oil (H2) included in the reverse micro-latex. According to one particular aspect, the oil (H 1 ) included in the vaccine adjuvant which is the subject of the present invention is identical to the oil (H 2 ) included in the reverse microlatex.
- oils (H 2 ) and the oils (H 1 ) are chosen in particular from: oils of vegetable origin, such as sweet almond oil, coconut oil, monoi oil, oil castor oil, jojoba oil, olive oil, rapeseed oil, peanut oil, sunflower oil, wheat germ oil, corn germ oil , soybean oil, cottonseed oil, alfalfa oil, poppy oil, pumpkin oil, evening primrose oil, millet oil, barley oil , rye oil, safflower oil,nadooulier oil, passionflower oil, hazelnut oil, palm oil, shea butter, apricot kernel oil , calophyllum oil, sysybrium oil, avocado oil, calendula oil; vegetable oils and their ethoxylated methyl esters; oils of animal origin, such as squalene, squalane; synthetic oils, especially esters of fatty acids such as butyl myristate, propyl myristate, cetyl myristate, isopropyl palmitate
- dimethylpolysiloxanes methylphenylpolysiloxanes
- silicones modified with amines silicones modified with fatty acids
- silicones modified with alcohols silicones modified with alcohols and fatty acids
- silicones. modified with polyether groups epoxy modified silicones
- silicones modified with fluorinated groups silicones modified with cyclic silicones and silicones modified with alkyl groups.
- the fatty phase may not include silicone oil; mineral oils, hydrocarbons, such as paraffin oil, petrolatum oil, white mineral oils and isoparaffins, obtained by distillation of petroleum and by the implementation of subsequent treatment steps such as for example steps desulfurization, deasphalting, extraction of aromatic compounds, extraction of waxes and other finishing treatment steps.
- white oil mineral oils in accordance with FDA regulations 21 CFR 172.878 and CFR 178.3620 (a), listed in the United States Pharmacopoeia, US XXIII (1995) and in accordance with the purity requirements of the European Pharmacopoeia (2008).
- the term “light oil” means an oil (H2), of low boiling point (from 100 ° C to 250 ° C at atmospheric pressure), included in the fatty phase of the reverse micro-latex, also consisting of at least one oil of higher boiling point; said light oil being intended to be evaporated during a step of concentration by distillation of the inverse micro-latex formed in order to obtain a concentrated inverse micro-latex.
- isoparaffins comprising from 7 to 14 carbon atoms sold under the brand names lsopar TM C, lsopar TM E, lsopar TM G, lsopar TM H, lsopar TM L and lsopar TM M. .
- the surfactant of the water-in-oil type (Ei) included in the vaccine adjuvant object of the present invention is identical or different from the surfactant of the water-in-oil type (E'i) included in the reverse micro-latex.
- the surfactant of the water-in-oil type (Ei) included in the vaccine adjuvant which is the subject of the present invention is identical to the surfactant of the water-in-oil type (E'i). included in the reverse micro-latex.
- surfactant denotes a compound which modifies the surface tension between two surfaces and which is an amphiphilic molecule, that is to say that it has in its structure a lipophilic part and a lipophilic part. another hydrophilic part
- a surfactant makes it possible to solubilize and / or disperse a phase of a certain polarity in another phase of different polarity.
- surfactant of the water-in-oil type denotes surfactants having a sufficiently low HLB value, preferably greater than or equal to 1 and less than 8.0, making it possible to obtain water-in-oil emulsions, for in which the aqueous phase is dispersed in the lipophilic fatty phase.
- esters of anhydrohexitol and of linear or branched, saturated or unsaturated aliphatic carboxylic acid comprising from 12 to 22 atoms. carbon optionally substituted with one or more hydroxyl groups, or a mixture of these esters.
- hexitol is meant hexols derived from hexoses such as sorbitol, mannitol, dulcitol (also called galactitol) or iditol.
- anhydrohexitol denotes the products resulting from the dehydration of hexitols.
- anhydrohexitols there are for example anhydro sorbitols, anhydro mannitols, anhydro dulcitols or anhydro iditols.
- anhydrohexitols is meant mono anhydrohexitols (such as for example sorbitan, mannitan, dulcitan, iditan), optionally in admixture with dianhydrohexitols (such as for example isosorbide, isomannide, isodulcide , isoidide) obtained as side products during the same dehydration reaction.
- mixture of esters denotes the esters obtained either from a single acid and a single hexitol, or from a single acid and a mixture of several hexitols, or from a mixture of several acids of a single hexitol, or from a mixture of several acids with several hexitols.
- ester of anhydrohexitol and of linear or branched, saturated or unsaturated aliphatic carboxylic acid comprising from 12 to 22 carbon atoms optionally substituted with one more hydroxyl group
- esters of acids chosen from dodecanoic acids , dodécèno ⁇ ques, tétradécano ⁇ ques, tétra35cèno ⁇ ques, hexadécano ⁇ ques, hexadécèno ⁇ ques, octadecanoic, octadecenoic, octadecadienoic, octadécatrièno ⁇ ques, octadécatétraènoiques, eicosano ⁇ ques, eicoséno ⁇ ques, eicosadièno ⁇ ques, docosano ⁇ ques, docosenoic, hydroxy hexadécano ⁇ ques, hydroxyoctadécano ⁇ ques
- ester of anhydrohexitol and of linear or branched, saturated or unsaturated aliphatic carboxylic acid comprising from 12 to 22 carbon atoms optionally substituted with a several hydroxyl groups
- esters of acids chosen from lauric acid, isolauric acid, 4-dodecenoic acid, 5-dodecenoic acid, myristic acid, palmitic acid, hypogeic acid, stearic acid, isostearic acid, oleic acid, iso-oleic acid, linoleic acid, isogeranic acid, linolenic acid, arachidic acid, acid 10, 13-ecosadienoic acid, behenic acid, erucidic acid, cetoleic acid, brassic acid, 3-hydroxy hexadecanoic acid, 4-hydroxy hexadecanoic acid, 11-hydroxy hexadecanoic acid, 16-hydroxy hexadecanoic acid, 12-hydroxy stea
- esters are obtained by esterification of the corresponding acids and anhydrohexitols.
- the esterification reaction is known to those skilled in the art; it is described in numerous patents and reference books.
- esters of anhydrohexitol, and of linear or branched, saturated or unsaturated aliphatic carboxylic acid, comprising from 12 to 22 carbon atoms optionally substituted with one or more hydroxyl groups mention may be made of sorbitan laurate (marketed under the brand name Montane TM 20), mannitan laurate, dulcitan laurate, sorbitan isolaurate, mannitan isolaurate, ducitan isolaurate, sorbitan palmitate, mannitan palmitate, dulcitan palmitate , sorbitan stearate (marketed under the brand name Montane TM 60), mannitan stearate, dulcitan stearate, sorbitan isostearate (marketed under the brand name Montane TM 70), mannitan isostearate , dulcitan isostearate, sorbitan oleate (marketed under the trade name Montane TM 80), mannitan laur
- surfactants of the water-in-oil type (Ei) and (E'i) mention may also be made of sorbitan oleate ethoxylated with 5 moles of ethylene oxide (5 EO) marketed by the applicant under the Montanox TM 81 name, the diethoxylated oleoketyl alcohol (2 EO) sold by the applicant under the name Simulsol TM OC72.
- 5 EO ethylene oxide
- Simulsol TM OC72 the diethoxylated oleoketyl alcohol
- surfactant of the oil-in-water type denotes surfactants having a sufficiently high HLB value, preferably greater than or equal to 8.0 and less than or equal to 20, preferably greater than or equal to 8.0 and less than or equal to 15.0, making it possible to obtain oil-in-water emulsions for which the lipophilic fatty phase is dispersed in the aqueous phase.
- esters of anhydrohexitol and of linear or branched, saturated or unsaturated aliphatic carboxylic acid comprising from 12 to 22 carbon atoms optionally substituted with one or more hydroxyl groups, or a mixture of these esters, which subsequently undergo a step of addition of ethylene oxide to a varying degree between 2 and 30 molar equivalents of oxide of ethylene.
- esters of anhydrohexitol and of linear or branched, saturated or unsaturated aliphatic carboxylic acid comprising from 12 to 22 carbon atoms optionally substituted with one or more hydroxyl groups, and ethoxylated
- surfactants of the oil-in-water type (E 2 ) and (E'2) mention may be made of ethoxylated vegetable oils such as, for example, castor oil ethoxylated at 25 EO marketed by the applicant under the name Simulsol TM.
- alkylpolyglycosides More particularly alkylpolyglucosides and polyalkylxylosides, or a mixture of alkylglycosides, lecithins, saponins, alkanols.
- polyoxyethylated, polymers comprising polyoxyethylene and polyoxypropylene blocks lauryl alcohol ethoxylated with 7 moles of ethylene oxide (7 EO) marketed by the applicant under the name of Silmulsol TM P7, pentaethoxylated oleoketyl alcohol (5 EO) ), octaethoxylated oleoketyl alcohol (8 EO), decaethoxylated oleoketyl alcohol (10 EO) marketed by the applicant under the name Simulsol TM OC 710, or polyethoxylated sorbitan hexaoleates marketed under the names G-1086 TM and G -1096 TM.
- a monomeric crosslinking unit denotes a unit derived from a monomer having at least two reactive functions by which covalent bonds can be established between the polymeric chains in extension and said crosslinking monomer.
- a monomeric crosslinking unit can be derived from a monomer which can include at least two ethylenic functions in its structure and, when engaged in a radical polymerization reaction with acrylic monomers, said crosslinking monomer can bind from covalently with two acrylic polymer chains during the propagation step, to obtain a crosslinked polymer.
- crosslinked polymer denotes a nonlinear polymer in the form of a three-dimensional network which is insoluble in water, but swellable in water and therefore leading to the production of a chemical gel.
- crosslinked polymer denotes a polymer composed of at least one monomeric crosslinking unit and at least one other monomeric unit, and more particularly of a hydrophilic monomeric unit.
- hydrophilic monomer unit means a monomer unit derived from a monomer soluble in water and more particularly soluble in water at a temperature greater than or equal to 5 ° C., more particularly at a temperature. temperature greater than or equal to 10 ° C, more particularly at a temperature greater than or equal to 20 ° C.
- the crosslinked polymer may comprise hydrophilic monomeric units derived from: 2-methy 2 - [(1-oxo 2-propenyl) amino] 1-propanesulfonic acid in free acid form or partially or totally salified; acrylic acid in free acid form or partially or totally salified, methacrylic acid in free acid form or partially or totally salified, itaconic acid in free acid form or partially or totally salified, 2-carboxyethyl acrylic acid in free acid form or partially or totally salified, maleic acid in free acid form or partially or totally salified, acrylamide, N, N-dimethyl acrylamide, methacrylamide, N-isopropyl acrylamide, acrylate (2 -hydroxy ethyl), (2,3-dihydroxy propyl) acrylate, (2-hydroxy ethyl) methacrylate, (2,3-dihydroxypropyl) methacrylate, vinyl pyrrolidone.
- monomeric crosslinking unit denotes a monomeric unit resulting from a diethylene or polyethylene monomer, in particular chosen from dimethacrylate ethylene glycol, diethylene glycol diacrylate, ethylene glycol diacrylate, diallyl urea, triallylamine, trimethylol propanetriacrylate, methylene-bis (acrylamide) or a mixture of these compounds, diallyoxyacetic acid or a salt thereof such as sodium diallyloxyacetate, or a mixture of these compounds.
- the surfactants present in the adjuvant according to the invention are surfactants of the water-in-oil type (E 1 ) or of the water-in-oil type (E ' 1 ), as defined and described above, exhibiting a characteristic lipophilic characterized by an HLB value greater than or equal to 1 and less than 8 and surfactants of the oil-in-water type (E 2 ) or of the oil-in-water type (E '2 ), as defined and described previously, exhibiting a hydrophilic character characterized by an HLB value greater than or equal to 8 and less than or equal to 20.
- a subject of the present invention is also the use of an inverse microlatex as defined above, for the preparation of a vaccine adjuvant.
- the process for preparing a vaccine adjuvant according to the invention comprises a step of sterilizing the vaccine adjuvant by sterilizing filtration or autoclaving.
- the filtration will preferably be carried out on a filter having pores with an average diameter less than or equal to 0.22 microns (see standard ISO 13408-2: 2018 (fr)).
- the adjuvant Before being filtered, the adjuvant can be pre-filtered.
- the adjuvant can be pre-filtered using hydrophobic filters having pores with an average diameter of 0.45 ⁇ m.
- the pre-filtration and filtration steps can be carried out in a single step which involves the use of hydrophobic filters with double membranes, of which a first membrane has pores of average diameter of 0.45 ⁇ m and the second membrane has pores of diameter mean 0.2 ⁇ m or the combination of a first hydrophobic filter having pores of average diameter of 0.45 ⁇ m and a second hydrophobic filter having pores of average diameter of 0.2 ⁇ m. This means that the first membrane or the first filter has larger pores than the second membrane or the second filter.
- the first membrane or the first filter have pores with a diameter greater than or equal to 0.3 ⁇ m, preferably pores with a diameter less than or equal to 0.6 ⁇ m and more particularly equal to 0.45 ⁇ m.
- the second membrane has pores of diameter less than or equal to 0.22 ⁇ m in order to obtain a sterilizing action.
- the filters and membranes used for the filtration and / or pre-filtration of the adjuvant can consist of polymeric supports of the PTFE (Poly-Tetra-Fluoro-Ethylene), PP (Polypropylene) type.
- said process for preparing an adjuvant according to the invention comprises the following steps: a) Preparation with mechanical stirring and at room temperature of an oily phase comprising at least one oil and an emulsifying system comprising at least one surfactant of the water-in-oil type (Ei) and / or of the oil-in-water type (E 2 ); b) Addition of at least one inverse microlatex with mechanical stirring at room temperature; c) Maintaining mechanical stirring at room temperature until a homogeneous mixture is obtained.
- ambient temperature means a temperature greater than or equal to 15 ° C and less than or equal to 30 ° C.
- a subject of the present invention is also a vaccine comprising the adjuvant according to the invention as well as at least one aqueous solution (S) of at least one antigen or of at least one in vivo generator of a compound comprising a sequence of amino acids.
- S aqueous solution
- the vaccine will comprise:
- said vaccine is in the form of an emulsion of water-in-oil type or of oil-in-water type.
- antigen or at least one in vivo generator of a compound comprising an amino acid sequence is meant either killed microorganisms, such as viruses, bacteria or parasites, or purified fractions of these microorganisms. , or living microorganisms whose pathogenicity has been attenuated.
- viruses which can constitute an antigen according to the present invention there are orthomyxoviruses such as influenza virus, paramyxoviruses such as Newcastle disease virus, coronaviruses such as bronchitis virus. infectious, herpes viruses such as Aujeszky's disease virus or Marek's disease virus. Mention may be made, as microorganism of the bacterial type which may constitute an antigen according to the present invention, of E.
- coli and those of genera Pasteurella, Avibacterium, Staphylococcus and Streptococcus.
- parasites there are those of the genera Eimeria, Trypanosoma, and Leishmania.
- Mention may also be made of recombinant viruses, in particular non-enveloped viruses, such as adenoviruses, vaccinia virus, Canarypox virus, herpes viruses or baculoviruses.
- a living non-enveloped viral recombinant vector is also designated, the genome of which contains, preferably inserted into a part which is not essential for the replication of the corresponding enveloped virus, a sequence encoding an antigenic subunit inducing antibody synthesis and / or a protective effect against the aforesaid enveloped virus or pathogenic microorganism; these antigenic subunits can be, for example, a protein, a glycoprotein, a peptide or a peptide fraction and / or protective against an infection by a living microorganism such as an enveloped virus, a bacterium or a parasite.
- the exogenous gene inserted into the microorganism may be, for example, derived from an Aujeszky virus.
- the purpose of this latter nucleotide sequence is to allow the expression of a compound comprising an amino acid sequence, this compound itself having the aim of triggering an immune reaction in a host organism.
- the vaccine as defined above comprises an antigen concentration which depends on the nature of this antigen and on the nature of the subject treated. It is however particularly remarkable that an adjuvant according to the invention makes it possible to significantly reduce the usual dose of antigen required.
- the adequate concentration of antigen can be determined in a conventional manner by those skilled in the art. Generally, this dose is of the order of 0.1 pg / cm 3 to 1 g / cm 3, more generally between 1 pg / cm 3 and 100 mg / cm 3 .
- the concentration of said generator in vivo in the composition according to the invention depends, here again, in particular on the nature of said generator and on the host in which it is administered. This concentration can be readily determined by one skilled in the art, on the basis of routine experience.
- the in vivo generator when the in vivo generator is a recombinant microorganism, its concentration in the composition according to the invention generally between 10 2 and 10 15 microorganisms / cm 3 and preferably between 10 5 and 10 12 microorganisms / cm 3 .
- its concentration in the composition obtained according to the process which is the subject of the invention can be between 0.01 g / dm 3 and 100 g / dm 3 .
- the vaccine as defined above, is prepared by mixing the adjuvant phase and the antigenic phase, optionally adding water or a pharmaceutically acceptable diluent medium.
- the method for preparing the vaccine according to the invention comprises the following steps: a) Preparation of the vaccine adjuvant according to the invention, b) Mixing of the vaccine adjuvant obtained in step a) with an antigenic medium.
- the antigenic medium is intended to form a vaccine, we will speak of vaccine antigenic medium.
- antigenic medium denotes an aqueous medium comprising at least one antigen or at least one in vivo generator of a compound comprising an amino acid sequence, as described above.
- the mixture will be such that the vaccine will comprise, for 100% of its mass, between 10% and 80% by mass of adjuvant and between 20% and 90% by mass of antigenic medium, preferably between 50% and 80% by mass of adjuvant and between 20% and 50% by weight of antigenic medium, and even more preferably between 50% and 70% by weight of adjuvant and between 30% and 50% by weight of antigenic medium.
- an immunostimulant chosen from among saponins, animal and / or vegetable and / or mineral and / or synthetic oils, surfactants, aluminum hydroxide, lecithins can optionally be added to the mixture. and lecithin derivatives.
- the antigenic medium will be added to the adjuvant gradually with high shear stirring to form an emulsion.
- a vaccine in the form of an emulsion preferably of water-in-oil type, stable and homogeneous, is obtained.
- the final vaccine can be administered from manufacture and can be stored for at least 1 year, at a temperature of + 4 ° C (depending on the nature of the antigen (s) present in the vaccine and their physicochemical stability over time).
- the vaccine is intended to be administered in human or veterinary therapy by injection, oral, parenteral, mucosal or in-ovo.
- Example 1 Preparation of inverse microlatexes based on sodium polyacrylate
- Inverse microlatexes comprising as polymer a crosslinked sodium polyacrylate are prepared according to the teachings of European Patent Publication No. 1,371,692 B1, which is incorporated herein by reference. More particularly the teachings of paragraph [0021], of paragraphs [0025] and [0026], of paragraphs [0033] to [0048], and even more particularly of paragraphs [0039] to [0041] (example 2) of the European patent published under the number 1371 692 B1, are used to prepare the reverse microlatexes. For each of the microlatex prepared, a fluid white mineral oil, Marcol TM 52, sold by the company Exxon Mobil, is used.
- reverse microlatex (A) when the mass quantity of surfactants is equal to 14%
- reverse microlatex (B ) when the mass amount of surfactants is equal to 18%
- the inverse microlatex (C) when the mass amount of surfactants is equal to 22%
- the inverse microlatex (D) when the mass amount of surfactants is equal to 25%.
- the reverse microlatexes (A), (B), (C) and (D), obtained after radical polymerization, are in the form of opalescent to translucent oily compositions. These reverse microlatexes contain 60% by mass of a mixture of oily phase and surfactants, 15% by mass of crosslinked sodium polyacrylate and 25% by mass of water.
- the process for preparing the reverse microlatex (A) is carried out using mannitan oleate as a water-in-oil type surfactant in place of sorbitan oleate, to obtain the reverse microlatex (E).
- the process for preparing the reverse microlatex (B) is carried out using mannitan oleate as the water-in-oil type surfactant in place of sorbitan oleate, to obtain the reverse microlatex (F).
- the process for preparing the reverse microlatex (C) is carried out using mannitan oleate as a water-in-oil type surfactant in place of sorbitan oleate, to obtain the reverse microlatex (G).
- the process for preparing the reverse microlatex (D) is carried out using mannitan oleate as a water-in-oil type surfactant in place of sorbitan oleate, to obtain the reverse microlatex (H).
- the inverse microlatexes (E), (F), (G) and (H) are in the form of an opalescent to translucent oily composition, containing 60% by mass of a mixture of oily phase and surfactants, 15% by mass of crosslinked sodium polyacrylate and 25% by mass of water.
- the process for preparing the reverse microlatexes (A), (B), (C), and (D), described in Example 1.1, is carried out in the presence of a mixture of acrylic acid and lauroyl methacrylate tetraethoxylated (2 mol%), to obtain the reverse microlatexes (A '), (B'), (C), and (D ') respectively.
- the inverse microlatexes (A '), (B'), (C), and (D ') are in the form of opalescent to translucent oily compositions, containing 60% by mass of a mixture of oily phase and surfactants, 15 % by mass of the crosslinked copolymer of acrylic acid and of tetraethoxylated lauroyl methacrylate and 25% by mass of water.
- the process for preparing the inverse microlatex (B) of Example 1 is carried out in the presence of a larger quantity of water, so as to obtain an inverse microlatex (B '') in the form of compositions opalescent to translucent oily, containing 49% by mass of a mixture of oily phase and surfactants, 15% by mass of crosslinked sodium polyacrylate and 36% by mass of water.
- Example 4 Preparation of adjuvants according to the invention
- the polymeric oily adjuvants are prepared according to the following process: a) Preparation with mechanical stirring and at room temperature of an oily phase comprising at least one oil and an emulsifying system comprising at least one surfactant of the water-in-oil type (Ei) and / or of the oil-in-water type (E 2 ); b) Addition of reverse microlatex or reverse latex, with moderate mechanical stirring (50 to 150 revolutions. min 1 ) at room temperature; c) Maintaining moderate mechanical stirring (50 to 150 revolutions. min 1 ), at room temperature, until a homogeneous mixture is obtained.
- the term “ambient temperature” means a temperature greater than or equal to 15 ° C and less than or equal to 30 ° C.
- the adjuvants ADJ1, ADJ2, ADJ3, ADJ'l are prepared and are characterized by the constitutions described in Table 1:
- Example 5 Evaluation of the adjuvants according to the invention and of the comparative adjuvants
- the stability of the adjuvants according to the invention ADJ1, ADJ2, ADJ3 and of the comparative adjuvant ADJ'l is evaluated according to the following protocol: i) A quantity of 90 mL of the mixture is introduced into a climatic chamber regulated at 20 ° C. composition to be tested and contained in a 100 ml bottle, for a period of one year. The visual appearance of the composition tested. ii) A quantity of 90 ml of the composition to be tested and contained in a 100 ml flask is introduced into a climatic chamber regulated at 37 ° C., for a period of one month (ml). Before stabilizing in the enclosure and after a period of one month, the visual appearance of the composition tested is evaluated. By stability is meant the absence of phase shift and / or sedimentation observed. The results of the observations are shown in Table 6 below. [Table 6]
- Table 6 stability results of the adjuvants ADJ1, AD J 2, ADJ3 according to the invention, and of the comparative adjuvant ADJ'l
- Heterogeneous heterogeneous, two or three phases observed, presence of deposit.
- the adjuvants ADJ1, ADJ2, ADJ3, ADJ'l according to the invention exhibit homogeneous aspects under the storage conditions described below, while heterogeneous aspects (phase shift and sedimentation) are observed for the comparative adjuvant ADJ'l. over time and at different temperatures. 5.3. Characterization of the stability properties of vaccine compositions containing adjuvants according to the invention
- the stability properties of the placebo vaccine emulsions containing the adjuvants according to the invention ADJ1, ADJ2, ADJ3, are evaluated on a quantity of 200 grams (prepared in a 250 mL beaker of low form) according to the following protocol, using a mixer Silverson type L4 or L5 rotor-stator equipped with its standard head fitted with a standard emulsion grid: i / 60 grams of aqueous phase are added in 140 grams of adjuvant with mechanical stirring using a stirrer Silverson type L4 or L5 at a rotational speed of 1000 revolutions / minute (during this step the stirring head must be placed 0.5 cm from the bottom of the beaker).
- ii / the emulsion is produced by subjecting the mixture obtained in step i / to high shear (with the Silverson L4 or L5 stirrer) for a period of 3 minutes at a speed of rotation of 4000 revolutions / minute (or 7 m / s).
- the emulsions obtained at the end of step ii / are fluid, homogeneous and injectable.
- the term “fluid” is understood to mean more particularly a liquid emulsion, the dynamic viscosity of which, measured using a Brookfield of the LVDV1 + type fitted with a mobile M62 at a speed of rotation of 60 revolutions / minute, at 20 ° C, is between 30 and 40 mPa.s.
- the stability of the emulsions obtained is characterized as follows: i) A quantity of 25 mL of the composition to be tested and contained in a 30 mL flask is introduced into a climatic chamber regulated at 4 ° C., for a period of one year. Before stabilizing in the enclosure and after a period of one month (M1), three months (M3), six months (M6) and one year (Al), the visual appearance of the composition tested. ii) A quantity of 25 ml of the composition to be tested and contained in a 30 ml flask is introduced into a climatic chamber regulated at 20 ° C., for a period of one year.
- the adjuvant properties of the polymeric oily adjuvants ADJ1, ADJ2 and ADJ3 according to the invention and as described in the preceding examples have been characterized on several vaccine models and several animal species.
- the adjuvant according to the invention ADJ3 was formulated with an ovalbumin solution to obtain a vaccine intended to be injected into mice.
- the adjuvant according to the invention ADJ2 was formulated with a bacterial antigenic medium consisting of inactivated bacteria of Pasteurella Multocida to obtain a vaccine intended to be administered to avian species.
- ADJ1 was used for the formulation of a viral vaccine intended for avian species against Newcastle disease and influenza of the H9N2 type.
- Test 1 Test in mice, using ovalbumin as antigen
- the test is carried out on OF1 mice in a 90-day vaccination protocol with ovalbumin (OVA) as the antigenic model.
- OVA ovalbumin
- the vaccines were prepared from an antigenic solution of OVA prepared in physiological serum at 10 mg / ml, and sterilized by filtration through a 0.22 ⁇ m filter.
- the formulation of the vaccine comprising the OVA antigen and the ADJ3 adjuvant according to the invention is carried out by emulsification through an i-connector in an adjuvant according to the invention ADJ3 / antigenic medium 70/30 (volume / volume). [Table 8]
- the safety of the vaccines is assessed by observing the local reactions at the injection sites.
- the vaccine efficacy is evaluated by the detection by ELISA method of antibodies of the IgG1 and IgG2a type in the blood. This detection is carried out on the day of vaccination (“Primary vaccination” at D0), then after 14 days (D14), at the time of the vaccination booster on the twenty-eighth day (D28), then on the forty-second day (D42), then on the fifty-sixth day ( D56), then on the ninetieth day (D90) at the time of euthanasia.
- FIG. 1 is a graph representing the response of the IgG1 antibody against the OVA antigen in mice for a vaccine comprising the adjuvant ADJ3 according to the invention.
- FIG. 2 is a graph representing the response of the IgG2a antibody against the OVA antigen in mice for a vaccine comprising the adjuvant ADJ3 according to the invention.
- the vaccine groups consist of 11 male and female chickens distributed randomly between the groups.
- the formulation containing the adjuvant ADJ2 according to the invention is carried out using an emulsifier of the Tube Drive type (sold by the company Ika) in sterile DT50 tubes in the ADJ2 adjuvant according to the invention / antigenic medium ratio of 70/30 (weight / weight): speed 3 for 2 minutes (1100 revolutions / minute) for the pre-emulsion then speed 9 for 6 minutes (4000 revolutions / minute).
- the animals are vaccinated on D0. Local reactions are observed on slaughter on D42. Blood samples will be taken on D0, D14, D42. Antigen-specific ELISA assays will be carried out for the detection of the level of antibodies in the sera using a commercial detection kit (ID Screen Pasteurella multocida chicken and turkey indirect kit marketed by ID-VEt).
- ID-VEt Antigen-specific ELISA assays will be carried out for the detection of the level of antibodies in the sera using a commercial detection kit (ID Screen Pasteurella multocida chicken and turkey indirect kit marketed by ID-VEt).
- ID-VEt commercial detection kit
- the vaccine comprising the adjuvant ADJ2 according to the invention is well tolerated in chickens, since no critical local reaction is observed at slaughter. Significantly higher antibody titers are also observed for the vaccine adjuvanted with the adjuvant ADJ2 compared to the non-adjuvanted vaccine in chickens, as shown in Table 10 below.
- Table 10 IgY antibody response against Pasteureila muftoçida . in chickens for a vaccine comprising the adjuvant ADJ2 according to the invention.
- Test 3 Vaccine test in chickens, Newcastle Disease / Avion Influenza viral antigen
- Table 11 constitution of the vaccine groups tested
- the test vaccine is formulated using the ADJ1 polymeric oily adjuvant according to the invention by emulsification in an ADJ1 adjuvant according to the invention / antigenic medium ratio of 70/30 (weight / weight) with the antigenic medium containing the two AIV and NDV inactivated viral valences.
- the control group is not vaccinated.
- the vaccines are injected intramuscularly on D0. Blood samples are taken on D0, D7, D14, D21 and D28 after vaccination and analyzed by haemagglutination inhibition test to determine the specific antibody titers against each valence (AIV and NDV).
- AIV and NDV haemagglutination inhibition test
- a protection test is carried out on D28 after vaccination to measure the viral load after test (2.10 6 EID50 in 0.2 ml intravenously of AIV H9N2 virus strain XZ).
- Oropharyngeal and cloaca swabs are collected 5 days after viral challenge and inoculated into SPF chick embryos to measure viral presence after two generations of transmission.
- FIG. 3 is a graph representing the evolution of the antibody titre against Newcastle disease strain LaSota (NDV) from D0 (or D0) to D28 (D28).
- NDV Newcastle disease strain LaSota
- FIG. 4 is a graph representing the evolution of the antibody titre against avian influenza type H9N2 (AIV) from D0 (or D0) to D28 (D28).
- FIG. 5 is a graph representing the rate of protection (number of animals protected / total number) provided by the test vaccine group in comparison with the control group.
- the adjuvants according to the invention are characterized by: filtration kinetics, in particular on filters of the hydrophobic type (in particular made of PolyTetraFluoro Ethylene or PTFE) with an average pore diameter of 0.2 micrometers, suitable for obtaining an adjuvant sterile stability over time at 20 ° C and 37 ° C, i.e. remaining homogeneous and clear in appearance, without showing phase shift and / or sedimentation phenomena obtaining stable vaccine emulsions, formed by emulsification of said adjuvants in the presence of aqueous vaccine phase.
- filters of the hydrophobic type in particular made of PolyTetraFluoro Ethylene or PTFE
- PTFE PolyTetraFluoro Ethylene
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Abstract
Description
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Priority Applications (7)
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US17/801,224 US20230052315A1 (en) | 2020-02-20 | 2021-02-17 | Vaccine adjuvant comprising an inverse microlatex |
BR112022016519A BR112022016519A2 (pt) | 2020-02-20 | 2021-02-17 | Adjuvante de vacina que compreende um microlátex inverso |
JP2022549574A JP2023515028A (ja) | 2020-02-20 | 2021-02-17 | 逆マイクロラテックスを含むワクチンアジュバント |
KR1020227031834A KR20220143706A (ko) | 2020-02-20 | 2021-02-17 | 인버스 마이크로라텍스를 포함하는 백신 애주번트 |
CN202180016008.5A CN115151246A (zh) | 2020-02-20 | 2021-02-17 | 包含反相微胶乳的疫苗佐剂 |
MX2022010233A MX2022010233A (es) | 2020-02-20 | 2021-02-17 | Adyuvante de vacuna que comprende un microlatex inverso. |
EP21705950.0A EP4106723A1 (fr) | 2020-02-20 | 2021-02-17 | Adjuvant de vaccin comprenant un microlatex inverse |
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FR2001698 | 2020-02-20 | ||
FR2001698A FR3107454B1 (fr) | 2020-02-20 | 2020-02-20 | Adjuvant de vaccin comprenant un microlatex inverse |
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US (1) | US20230052315A1 (fr) |
EP (1) | EP4106723A1 (fr) |
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KR (1) | KR20220143706A (fr) |
CN (1) | CN115151246A (fr) |
BR (1) | BR112022016519A2 (fr) |
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CN114316132A (zh) * | 2022-01-28 | 2022-04-12 | 赛纳生物科技(北京)有限公司 | 一种乳液聚合合成功能性聚合物微球的方法 |
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WO2011117506A2 (fr) * | 2010-03-24 | 2011-09-29 | Société d'Exploitation de Produits pour les Industries Chimiques SEPPIC | Diluants adjuvants de vaccins vivants pour maladies porcines |
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- 2020-02-20 FR FR2001698A patent/FR3107454B1/fr active Active
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- 2021-02-17 KR KR1020227031834A patent/KR20220143706A/ko active Search and Examination
- 2021-02-17 JP JP2022549574A patent/JP2023515028A/ja active Pending
- 2021-02-17 MX MX2022010233A patent/MX2022010233A/es unknown
- 2021-02-17 CN CN202180016008.5A patent/CN115151246A/zh active Pending
- 2021-02-17 EP EP21705950.0A patent/EP4106723A1/fr active Pending
- 2021-02-17 WO PCT/EP2021/053873 patent/WO2021165312A1/fr active Application Filing
- 2021-02-17 BR BR112022016519A patent/BR112022016519A2/pt unknown
- 2021-02-17 US US17/801,224 patent/US20230052315A1/en active Pending
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WO2007094893A2 (fr) | 2005-12-29 | 2007-08-23 | Boehringer Ingelheim Vetmedica, Inc. | Utilisation d'une composition immunogène de pcv2 pour la réduction de symptômes cliniques |
FR2922767A1 (fr) | 2007-10-24 | 2009-05-01 | Seppic Sa | Procede de preparation d'une composition vaccinale comprenant au moins un antigene et au moins un adjuvant. |
FR2922767B1 (fr) | 2007-10-24 | 2009-12-18 | Seppic Sa | Procede de preparation d'une composition vaccinale comprenant au moins un antigene et au moins un adjuvant. |
WO2011117506A2 (fr) * | 2010-03-24 | 2011-09-29 | Société d'Exploitation de Produits pour les Industries Chimiques SEPPIC | Diluants adjuvants de vaccins vivants pour maladies porcines |
FR3026012A1 (fr) * | 2014-09-23 | 2016-03-25 | Seppic Sa | Administration par voie orale d'au moins une substance active pharmaceutique et/ou antigenique |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114316132A (zh) * | 2022-01-28 | 2022-04-12 | 赛纳生物科技(北京)有限公司 | 一种乳液聚合合成功能性聚合物微球的方法 |
Also Published As
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FR3107454B1 (fr) | 2023-02-10 |
EP4106723A1 (fr) | 2022-12-28 |
FR3107454A1 (fr) | 2021-08-27 |
KR20220143706A (ko) | 2022-10-25 |
JP2023515028A (ja) | 2023-04-12 |
US20230052315A1 (en) | 2023-02-16 |
MX2022010233A (es) | 2023-01-18 |
CN115151246A (zh) | 2022-10-04 |
BR112022016519A2 (pt) | 2022-10-11 |
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