EP0776362A1 - Procede de preparation du virus grippal, antigens obtenus et leurs applications - Google Patents

Procede de preparation du virus grippal, antigens obtenus et leurs applications

Info

Publication number
EP0776362A1
EP0776362A1 EP95922563A EP95922563A EP0776362A1 EP 0776362 A1 EP0776362 A1 EP 0776362A1 EP 95922563 A EP95922563 A EP 95922563A EP 95922563 A EP95922563 A EP 95922563A EP 0776362 A1 EP0776362 A1 EP 0776362A1
Authority
EP
European Patent Office
Prior art keywords
viral
purified
virus
carried out
fragmentation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95922563A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jean-Michel Violay
Guy Court
Catherine Gerdil
Hervé CHALUMEAU
Patrick Mc Verry
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AVENTIS PASTEUR
Original Assignee
Pasteur Merieux Serum et Vaccines SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pasteur Merieux Serum et Vaccines SA filed Critical Pasteur Merieux Serum et Vaccines SA
Publication of EP0776362A1 publication Critical patent/EP0776362A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • 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
    • A61K39/145—Orthomyxoviridae, e.g. influenza virus
    • 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
    • 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
    • A61K2039/5252—Virus inactivated (killed)
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16161—Methods of inactivation or attenuation
    • C12N2760/16163—Methods of inactivation or attenuation by chemical treatment

Definitions

  • the invention relates to a method of fragmentation of the live influenza virus, of simple implementation, leading to a destruction of the infectious power, usable in particular in the production of an inactive influenza vaccine, or in obtaining viral antigens for purposes diagnostic
  • influenza virus or influenza virus is a single stranded, helical symmetrical RNA virus belonging to the orthomyxovindae family.
  • the known antigens are essentially represented by the following structural proteins.
  • HA protein hemagglutinin located on the surface of the envelope
  • Nucieoprotein and protein M are the internal antigens specific for viral types A and B, hemagglutirune and neuraminidase determining the subtypes of virus A.
  • Hemagglutirune is the most immunogenic glycoprotein of the viral constituents The hemagglutirune content is used to express the load of viral antigens in influenza vaccines, however it is now established that all of the viral antigens intervene in the stimulation of immune response and that internal antigens play a major role in the cell-mediated response
  • Nucieoprotein is the main target antigen of Cytotoxic T Lymphocytes (CTL), no CTL specific for hemagglutinin having been demonstrated in humans
  • the viral fragmentation makes it possible to rupture the envelope and to release all the viral anugeni ⁇ ues sites NP, M, RNA viral Polymerases, HA and NA
  • the vaccines obtained by this process are therefore extremely immunogenic and give seroconversions superior to those obtained with vaccines containing only surface antigens (which represent only 36% of the viral constituents) Fragmented virion vaccines are also better tolerated than more reactogenic whole virion vaccines
  • the fragmentation processes used combine solvent-detergent treatments such as polysorbate / anesthetic ether or polysorbate / chloroform [Institut Pasteur (Adamowic ⁇ -Muller) US Patent N ° 4522809]
  • Our simple implementation process allows fragmentation of the purified live influenza virus without solvent at room temperature. This process involves the removal of detergent and unwanted substances to obtain the viral fragmentation product in a perfectly defined buffered, isoionic ionic environment.
  • This process results in a very significant reduction in the infectious area of the purified g ⁇ ppal virus suspension, up to total inactivanon depending on the operating conditions selected such as the concentration and duration of contact between detergent and g ⁇ ppai virus.
  • the present invenuon has for its object a process for the preparation of purified influenza antigens, from a liquid containing the influenza virus, comprising the stages of concentration, purification, fragmentation and possibly inactivation, characterized in that
  • the pu ⁇ fication step comprises several ultra cent ⁇ fugauon steps separated by a filtration step.
  • the fragmentation step is carried out on the living virus in the presence of an amphiphilic nonionic detergent followed by removal of the undesirable substances by filtration retaining all of the viral constituents.
  • influenza virus used is obtained by culture on sensitive host cells, such as marnrriifer cells: monkey, hamster, pig kidney cells, ferret, mouse cells or the cells from embryos, human lung tissue, or chicken embryo fibroblasts.
  • sensitive host cells such as marnrriifer cells: monkey, hamster, pig kidney cells, ferret, mouse cells or the cells from embryos, human lung tissue, or chicken embryo fibroblasts.
  • the most common system for industrial vaccine production is the embryonated chicken egg, this is the preferred system.
  • the present invention therefore also relates to the method as described above, characterized in that the influenza virus is obtained by culture on an embryonated egg.
  • the fertilized eggs must be carefully selected and come from healthy farms, reserved for this production.
  • the eggs are then incubated for 2 to 3 days in culture ovens regulated in temperature and humidity so as to ensure viral infection under optimal conditions. These conditions vary depending on the influenza strains and the viral seeds used. The incubation is completed by rapid refrigeration at 5 ⁇ 3 ° C. The allantoic fluid, very rich in viral particles, is then taken from the infected eggs.
  • the pu ⁇ fication technique proposed in the present process is based on the zonal uitracent ⁇ fugauon
  • This uitracentnfugation is preferably carried out in gradient of ⁇ ensite, preferably in gradient of sucrose but one can also operate on gradient of cesium chloride.
  • the cent ⁇ fugation is carried out at an acceleration which is preferably around 90,000 G, said centrifugation can be carried out continuously or by successive loads.
  • the viral pa ⁇ icuies are separated according to their size, density and shape. Only gradient fractions containing the virus are taken
  • the process object of the present application comprises a sequence of several ultracentrifugation stages, preferably two successive stages separated by a filtration stage.
  • filtration step is meant either a single filter or a sequence of several filtrations, the last of which can be of the order of 0.3 ⁇ m and preferably of approximately 0.5 ⁇ m, for example of 0.45 ⁇ m.
  • This sequence applied to the live influenza virus, ensures reproducible in ⁇ ust ⁇ elle pu ⁇ fication of strains of influenza virus cultivated on embryonic eggs.
  • the suspension of concentrated punished virus is optionally standardized by dilution to constant values of opaque densities (OD) of the viral protein content of the sample to be treated.
  • the final concentration can, for example preferably be between 200 and 1000 ⁇ g of protein per ml.
  • the dilution is preferably carried out using a ste ⁇ le buffer, for example PB S (Phosphate Buffered Saline)
  • PB S Phosphate Buffered Saline
  • the viral fragmentation is carried out at room temperature (20-25 ° C) by addition to the suspension of purified live virus and possibly standardized with an amphiph ⁇ e nonionic detergent.
  • This detergent is preferably a product having the general formula
  • R represents an octyie or nonyie radical and n represents an integer equal to or greater than 3.
  • Triton X-100 ® Triton X-165 ®
  • Triton X-205 ® Triton X-305 ®
  • Triton X-405 ® Triton X-405 ®
  • nonionic amphiphilic detergent which is preferably used is Triton X-100 or octoxynol-9.
  • the fragmentation reaction is carried out with stirring, for example for at least one hour of contact, but it can be carried out for a much longer time, for example up to 24 hours. Fragmentation is normally carried out in an atmosphere zone controlled at room temperature.
  • the viral structure is dissociated.
  • the viral envelope is ruptured, releasing, in the medium, the internal constituents, in particular the NP and M antigens, the only known antigens involved in the cell-mediated immune response. Part of the surface antigens (HA, NA) is also released.
  • HA, NA surface antigens
  • Fragmentation is stopped by removing the detergent.
  • the technique for removing unwanted substances uses a filtration membrane whose porosity allows the passage of detergent molecules and other non-viral solutes and retains the viral fragmentation product.
  • the operation is carried out by tangential filtration on a membrane with a porosity less than or equal to 100 Kilos Daltons, preferably around 50 Kilos Daltons, the sample is diafiltered during this ultrafiltration by 10 to 30 volumes of sterile isotonic buffer, preferably PB S.
  • the subject of the invention is therefore a process as described above, characterized in that the step of eliminating undesirable substances is carried out according to a diafiltration method allowing the suspension of the fragmented virus suspension with a buffer solution using a filtration membrane retaining the major part of the viral constituents.
  • the suspension of fragmented virus is concentrated in a desired volume which can be adapted to a standard viral concentration by measurement of OD.
  • the viral inactivation tests carried out at the end of this treatment show that the fragmentation process causes a very significant drop in the infectious titre of the suspension of purified virus, which can go as far as total inactivation of the influenza virus whatever the viral type (A or B).
  • the invention therefore also relates to a method as described above, characterized in that the fragmentation step is carried out under conditions allowing total inactivation of the purified influenza virus.
  • Viral inactivation can optionally be supplemented by the addition, if necessary, of an inactivating agent (formalin, ⁇ propiolactone) according to techniques known to those skilled in the art.
  • an inactivating agent formalin, ⁇ propiolactone
  • a preservative and any other additive may possibly be added to the vaccine obtained. - /
  • the invention also relates to a process as dec ⁇ t above caracte ⁇ se in that one operates either according to step A or according to the two steps A and B
  • a subject of the invention is also a process for the preparation of punctate genital anugens from a concentrated allantoic liquid containing the living g ⁇ ppai virus, characterized in that
  • the viral concentrate is purified by ultracent ⁇ fugation zonaie, preferably on a sucrose gradient, filtering the harvest obtained preferably up to a pore size of 0.3 ⁇ m minimum then repeating the ultracentrifugation operation,
  • pu ⁇ fiee viral suspension is standardized by dilution in aqueous buffer
  • the standardized product is fragmented by adding ⁇ 'octoxvnol 9 and then proceeds to remove the unwanted substances by diafiltration using ultrafiltration using a buffer solution,
  • the present invention also has for its object to be medicaments, the viral fragments as obtained according to the process described in one of the claims 1 to 9 above, as well as the application of the purified local antigens as obtained according to the process described above for the preparation of a general vaccine for humam or veterinary use and finally the application of purified local antigens as obtained according to the process above, for the preparation of products usable for diagnostic purposes
  • the allantoic liquid which is formed is then concentrated by ultrafiltration and stabilized in citrate buffer.
  • the viral concentrate is purified by zonal ultracent ⁇ fugation in saccnarose gradient (10 to 55%) at 35,000 revolutions per minute The operation is carried out in continuous flow
  • the harvest of the viral fractions of the seed represents approximately 800 ml
  • the sucrose concentration is close to 40% This harvest is filtered up to 0.45 ⁇ m, the final volume of suspension, after filtering, is equal to 15 liters
  • the suspension of purified virus (1010 ml) is standardized by dilution in PB S stenie buffer, so as to obtain a protein concentration como ⁇ se between 200 and 1000 ⁇ g / mi
  • the volume of the virus suspension is 2000 ml.
  • the infectious titre is greater than 10 10 ID50 / mi.
  • the viral fragmentation is carried out by the aseptic addition of 10 ml (0.5% vol / vol) of octoxynoi 9 (T ⁇ ton X 100) under magnetic stirring, at laboratory temperature
  • the viral suspension which has a flocculauon
  • the diafiltrauon is carried out asequently at constant sample volume by ultrafiltration on memorane 50 Kd, using a volume of Phosphate Buffer (PBS) ) isotonic equalizes to 20 liters.
  • PBS Phosphate Buffer
  • the sample is freed from detergent and sucrose (reduction of 100 times).
  • the infectious titer, after fragmentation, is reduced to 10 1 - 2 ID50 / mi, which represents a reduction greater than a factor of 10 9 , this for one hour of treatment.
  • the vaccine obtained was filtered through 0.2 ⁇ m and added with me ⁇ hiolate (0.01% weight / vol.). This test made it possible to produce 13,000 ml of monovalent A / Beijing 32/92 X 117 vaccine titrating 137 ⁇ g of HA / ml.
  • the vaccinating properties of the preparations verified by administration to humans and animals (mice), have made it possible to obtain seroconversions inducing immunological protection, according to the criteria for clinical evaluation of influenza vaccines.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Mycology (AREA)
  • Pulmonology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Peptides Or Proteins (AREA)
EP95922563A 1994-08-16 1995-06-06 Procede de preparation du virus grippal, antigens obtenus et leurs applications Withdrawn EP0776362A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9410039 1994-08-16
FR9410039A FR2723740B1 (fr) 1994-08-16 1994-08-16 Procede de preparation d'antigenes du virus grippal, antigenes obtenus et leurs applications
PCT/FR1995/000727 WO1996005294A1 (fr) 1994-08-16 1995-06-06 Procede de preparation du virus grippal, antigens obtenus et leurs applications

Publications (1)

Publication Number Publication Date
EP0776362A1 true EP0776362A1 (fr) 1997-06-04

Family

ID=9466323

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95922563A Withdrawn EP0776362A1 (fr) 1994-08-16 1995-06-06 Procede de preparation du virus grippal, antigens obtenus et leurs applications

Country Status (10)

Country Link
US (1) US6048537A (ja)
EP (1) EP0776362A1 (ja)
JP (1) JPH10504033A (ja)
AU (1) AU701024B2 (ja)
CA (1) CA2197683C (ja)
FR (1) FR2723740B1 (ja)
MX (1) MX9701183A (ja)
NZ (1) NZ288254A (ja)
WO (1) WO1996005294A1 (ja)
ZA (1) ZA956797B (ja)

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DE19938767C2 (de) * 1999-08-16 2002-10-24 Tad Pharma Gmbh Spaltimpfstoffe
GB9924351D0 (en) 1999-10-14 1999-12-15 Brennan Frank Immunomodulation methods and compositions
EP1103610A1 (en) * 1999-11-26 2001-05-30 Introgene B.V. Production of vaccines from immortalised mammalian cell lines
US6951752B2 (en) 2001-12-10 2005-10-04 Bexter Healthcare S.A. Method for large scale production of virus antigen
KR100473070B1 (ko) * 2002-08-31 2005-03-10 박승국 시각적 유도장치를 이용한 외국어 학습 및 교습 시스템
EP1636352B1 (en) * 2003-06-20 2010-08-18 Microbix Biosystems Inc. Improvements in virus production
BRPI0511152A (pt) * 2004-05-20 2007-12-04 Id Biomedical Corp processo para a produção de uma vacina de influenza
US7691368B2 (en) 2005-04-15 2010-04-06 Merial Limited Vaccine formulations
AR054822A1 (es) 2005-07-07 2007-07-18 Sanofi Pasteur Emulsion inmuno adyuvante
US20080241184A1 (en) 2005-08-25 2008-10-02 Jules Maarten Minke Canine influenza vaccines
EA014028B1 (ru) * 2005-11-04 2010-08-30 Новартис Вэксинс Энд Диагностикс Срл Эмульсии, содержащие свободное поверхностно-активное вещество в водной фазе в качестве адъюванта сплит вакцин против гриппа
CA2642485A1 (en) * 2006-02-23 2007-08-30 Leonard Moran Improved methods of producing avian eggs and birds of specified germ-free status
CA2685308A1 (en) * 2007-04-27 2009-01-29 Dow Global Technologies Inc. Improved production and in vivo assembly of soluble recombinant icosahedral virus-like particles
CA2687122C (en) * 2007-05-04 2017-06-13 Baxter International Inc. Two-step temperature profile for the propagation of viruses
RU2496519C2 (ru) * 2007-08-28 2013-10-27 Бакстер Интернэшнл Инк. Способ получения препарата, содержащего вирусные антигены, и применение препарата
TW200936758A (en) * 2007-11-02 2009-09-01 Intervet Int Bv Orthomyxoviridae propagation
TWI444384B (zh) * 2008-02-20 2014-07-11 Gilead Sciences Inc 核苷酸類似物及其在治療惡性腫瘤上的用途
MX2010008799A (es) 2008-03-05 2010-09-07 Sanofi Pasteur Proceso para estabilizar una composicion de vacuna que contiene adyuvante.
AU2009227674C1 (en) 2008-03-18 2015-01-29 Seqirus UK Limited Improvements in preparation of influenza virus vaccine antigens
JP5843615B2 (ja) 2009-02-06 2016-01-13 グラクソスミスクライン バイオロジカルズ ソシエテ アノニム 密度勾配超遠心分離によるウイルスまたはウイルス抗原の精製
AU2010252661B2 (en) * 2009-05-29 2013-08-22 Novartis Ag Assays for influenza virus hemagglutinins
SG179037A1 (en) 2009-09-10 2012-04-27 Merial Ltd New vaccine formulations comprising saponin-containing adjuvants
US9644187B2 (en) 2010-04-14 2017-05-09 Emd Millipore Corporation Methods of producing high titer, high purity virus stocks and methods of use thereof
DK2741740T3 (en) 2011-08-12 2017-06-06 Merial Inc VACUUM-SUPPORTED CONSERVATION OF BIOLOGICAL PRODUCTS, IN PARTICULAR OF VACCINES
FR3025107B1 (fr) 2014-08-29 2018-10-05 Calixar Procede de preparation d'un antigene vaccinal, antigene vaccinal obtenu et utilisations
TWI745278B (zh) 2014-10-10 2021-11-11 以色列商艾畢克生物實驗有限公司 發泡性降低之疫苗組合物
CN109475615B (zh) 2016-06-17 2023-04-07 勃林格殷格翰动物保健美国公司 包含直链或支链聚丙烯酸聚合物佐剂的新免疫原性制剂

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Also Published As

Publication number Publication date
AU701024B2 (en) 1999-01-21
CA2197683C (en) 2008-12-30
WO1996005294A1 (fr) 1996-02-22
NZ288254A (en) 1999-01-28
US6048537A (en) 2000-04-11
JPH10504033A (ja) 1998-04-14
AU2741295A (en) 1996-03-07
ZA956797B (en) 1997-02-17
CA2197683A1 (en) 1996-02-22
FR2723740B1 (fr) 1996-11-08
FR2723740A1 (fr) 1996-02-23
MX9701183A (es) 1997-05-31

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