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WO2009111849A1 - Procédé pour la production de vaccin stabilisé - Google Patents

Procédé pour la production de vaccin stabilisé Download PDF

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Publication number
WO2009111849A1
WO2009111849A1 PCT/BR2009/000058 BR2009000058W WO2009111849A1 WO 2009111849 A1 WO2009111849 A1 WO 2009111849A1 BR 2009000058 W BR2009000058 W BR 2009000058W WO 2009111849 A1 WO2009111849 A1 WO 2009111849A1
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WO
WIPO (PCT)
Prior art keywords
poliovirus
hydrostatic pressure
virus
vaccine
mpa
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.)
Ceased
Application number
PCT/BR2009/000058
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English (en)
Inventor
Luciane Pinto Gaspar
Marcos Da Silva Freire
Andréa Chelbe DE OLIVEIRA
Jerson Lima Da Silva
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.)
Universidade Federal do Rio de Janeiro UFRJ
Original Assignee
Universidade Federal do Rio de Janeiro UFRJ
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 Universidade Federal do Rio de Janeiro UFRJ filed Critical Universidade Federal do Rio de Janeiro UFRJ
Publication of WO2009111849A1 publication Critical patent/WO2009111849A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C12N2770/32051—Methods of production or purification of viral material
    • 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
    • C12N2770/32651—Methods of production or purification of viral material

Definitions

  • the present invention relates to vaccines field, more particularly, to stabilization of three Polio vaccine strains, present in oral vaccine against Poliomyelitis (OPV).
  • Poliomyelitis is an acute infection that may manifest as a non- apparent infection, aseptic meningitis or a classic case of flaccid paralysis.
  • the transmission can occur from person to person through fecal-oral and oral-oral interaction. It is caused by a virus that belongs to genus Enterovirus, family Picornaviridae, which has three serotypes: serotype 1 , serotype 2 and serotype 3.
  • the OPV is considered the single vaccine which is able to make the global eradication of Polio, being recommended for countries with low indexes of coverage and heterogeneous vaccination.
  • WHO World Health Organization
  • the OPV containing the Sabin strains is a vaccine unstable to heat, therefore, must be stored frozen (-20 ° C) and used immediately after thawing, to ensure effective immunization against polio.
  • the patent US 5.618.539 describes stabilized viral vaccines, particularly against polio, comprising an aqueous solution of live virus and a stabilizing compound, which has at least two amino or imino groups, such as basic amino acids (eg lysine, arginine etc.).
  • a stabilizing compound which has at least two amino or imino groups, such as basic amino acids (eg lysine, arginine etc.).
  • MgCI 2 magnesium chloride
  • Viruses are a structurally diverse group of microorganisms, which differ widely in their sensitivities to action of high hydrostatic pressure. Studies on picornavirus showed great resistance of this virus to treatment with high hydrostatic pressure. Poliovirus seems to be one of the toughest viruses among all picornaviruses already characterized. High hydrostatic pressure studies on poliovirus are targeted, mostly, for viral inactivation and production of inactivated vaccine (JL Silva, P. Luan, M. Glaser, EW Voss and G. Weber.
  • Treatments to maintain the virus thermal stability, especially poliovirus, are still being made through the use of chemical compounds and biological agents such as magnesium chloride and arginine.
  • the objectives of this invention are: to provide an acquisition of thermal stability for OPV, containing Sabin strains for effective immunization against this infection, and provide the use of a methodology that is extremely safe, clean and economic (characterized by hydrostatic pressure use to obtain thermal stability of three vaccine strains in Sabin vaccine).
  • Figures 1A, 1B and 1C show respectively, a comparison of serotypes 1 ,
  • Figures 2A, 2B and 2C show respectively, high temperature effects, about ability of serotypes 1, 2 and 3 infection, of attenuated poliovirus. Circles represent stabilized virus with MgC ⁇ (91 mg/mL) and L-arginine (10 mg/mL), triangles represent virus without stabilizers. All symbols represent average of three independent experiments. Titres from infectivity test were determined by TCID50 in Vero cells.
  • Hep2C and Vero cells (African green monkey cells) (CCL 81) were obtained from "American Type Collection” (ATTC). Both were maintained in medium 199 supplemented with Earle salts (Gibco) with fetal bovine serum
  • the attenuated viruses poliovirus serotype 1
  • LSC, 2ab poliovirus serotype 2 (P712 CH ab) and poliovirus serotype 3 (Leon 12 a 1b), used in this invention, are from vaccine Glaxo Smithkline (GSK), containing the following identification: poliovirus serotype 1-SB 1003A; poliovirus serotype 2 SB-238B, and poliovirus serotype 3-SB 359A.
  • GSK vaccine Glaxo Smithkline
  • Virus titre (TCID 50 /mL) was calculated using the method described by Reed and Muench (LJ. Reed and HA Muench. A simple Method of Estimating Fifty Percent End Points. American Journal Hygiene. 1938; 493-497), which allows an analysis of virus biological characteristics from cell culture and under different temperature and pressurization time conditions.
  • poliovirus serotypes were cultivated in Vero cells. Confluent cell monolayers were inoculated at different Multiplicities of Infection (MOI) in growing medium 199. Then the virus was adsorbed for 1 hour at 37 0 C and monolayers were fed with 100 ml_ of maintenance medium. To obtain the virus that were used in the study with hydrostatic pressure, i.e. poliovirus serotypes (1 , 2 and 3), they were cultivated in Vero cells in a MOI of 0,01 for the poliovirus serotype 1 and serotype 2, 0,001 to poliovirus serotype 3. Each experiment was performed three times to ensure results reproducibility and standard deviation was calculated for each condition tested, as described in the state of the art for other viruses (T.
  • MOI Multiplicities of Infection
  • virus showed mild reduction of viral titre and total loss only to 52 0 C. This behavior was expected in light of current knowledge about thermostability of these three viruses: it is known that the
  • MgCI 2 increases poliovirus capsid conformation rigidity and decreases extent of water penetration in the capsid.
  • virus serotypes 1 , 2 and 3 samples were subjected to 310 MPa hydrostatic pressure for different time intervals (8, 17 and 65 hours) and in different temperatures (-10, 4, 25, 37 0 C). Hydrostatic pressure was unable to induce a detectable reduction in infectivity of three polioviruses, even after 65 hours at 37 0 C or -10 0 C. Table 1 shows these results.
  • Results show that stability in relation to pressurization of each of the three poliovirus strains is similar in all conditions tested, including pressurization at 310 MPa for 8 to 65 hours and incubation at 37 0 C or -10 0 C (Table 1).
  • virus stability investigation at 310 MPa for 65 hours at 37 0 C showed that pressurized particles resisted at temperature of 37 0 C for 65 hours in absence and presence of stabilizers (MgCb and L-arginine) (Table 2). This stability occurred with three polioviruses strains as observed by virus titre in cell culture evaluated by TCIDs 0 .
  • High hydrostatic pressure is a technology that is extremely safe, clean and economical. Furthermore, a commercial vaccine stabilized by high hydrostatic pressure action would avoid the need of electrical energy for material storage.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne le domaine des vaccins, plus particulièrement, la stabilisation des trois souches de vaccin de la poliomyélite, présentes dans un vaccin oral contre la poliomyélite (OPV). Une pression hydrostatique élevée est une technologie qui est extrêmement sûre, propre et économique. De plus, un vaccin commercial stabilisé par une haute pression hydrostatique évite la nécessité d’énergie électrique pour le stockage des matières.
PCT/BR2009/000058 2008-03-10 2009-03-10 Procédé pour la production de vaccin stabilisé Ceased WO2009111849A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRPI0800357-2A BRPI0800357A2 (pt) 2008-03-10 2008-03-10 método para produção de uma vacina estabilizada
BRPI0800357-2 2008-03-10

Publications (1)

Publication Number Publication Date
WO2009111849A1 true WO2009111849A1 (fr) 2009-09-17

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Application Number Title Priority Date Filing Date
PCT/BR2009/000058 Ceased WO2009111849A1 (fr) 2008-03-10 2009-03-10 Procédé pour la production de vaccin stabilisé

Country Status (2)

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BR (1) BRPI0800357A2 (fr)
WO (1) WO2009111849A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9169302B2 (en) 2012-08-30 2015-10-27 Merial, Inc. Hyperbaric device and methods for producing inactivated vaccines and for refolding/solubilizing recombinant proteins
US9283270B2 (en) 2012-01-20 2016-03-15 Serum Institute Of India Ltd. Method for stabilization of biological molecules
US10080791B2 (en) 2012-08-30 2018-09-25 Merial Inc. Hyperbaric device and methods for producing inactivated vaccines and for refolding/solubilizing recombinant proteins

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5618539A (en) * 1989-08-15 1997-04-08 Massachusetts Institute Of Technology Stabilized vaccine compositions
WO1997033612A1 (fr) * 1996-03-15 1997-09-18 Immunotherapy, Inc. Dialdehydes servant d'adjuvants immunostimulants et de reticulants pour la production de preparations immunogenes, pour la generation de cellules soumises a pression et reticulation afin de renforcer et d'augmenter la reponse immunitaire contre le cancer, les tumeurs et les affections pathogenes
CN1247090A (zh) * 1998-09-04 2000-03-15 中国科学院上海生物化学研究所 鸡传染性法氏囊病病毒疫苗、制备方法及其应用
WO2000048641A1 (fr) * 1998-06-15 2000-08-24 Bbi Bioseq, Inc. Sterilisation cryogenique rapide et preparation de vaccin
WO2004042001A2 (fr) * 2002-05-17 2004-05-21 Emory University Particules pseudovirales, procede de fabrication et compositions immunogeniques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5618539A (en) * 1989-08-15 1997-04-08 Massachusetts Institute Of Technology Stabilized vaccine compositions
WO1997033612A1 (fr) * 1996-03-15 1997-09-18 Immunotherapy, Inc. Dialdehydes servant d'adjuvants immunostimulants et de reticulants pour la production de preparations immunogenes, pour la generation de cellules soumises a pression et reticulation afin de renforcer et d'augmenter la reponse immunitaire contre le cancer, les tumeurs et les affections pathogenes
WO2000048641A1 (fr) * 1998-06-15 2000-08-24 Bbi Bioseq, Inc. Sterilisation cryogenique rapide et preparation de vaccin
CN1247090A (zh) * 1998-09-04 2000-03-15 中国科学院上海生物化学研究所 鸡传染性法氏囊病病毒疫苗、制备方法及其应用
WO2004042001A2 (fr) * 2002-05-17 2004-05-21 Emory University Particules pseudovirales, procede de fabrication et compositions immunogeniques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Derwent World Patents Index; AN 2000-476846 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9283270B2 (en) 2012-01-20 2016-03-15 Serum Institute Of India Ltd. Method for stabilization of biological molecules
US9169302B2 (en) 2012-08-30 2015-10-27 Merial, Inc. Hyperbaric device and methods for producing inactivated vaccines and for refolding/solubilizing recombinant proteins
US10080791B2 (en) 2012-08-30 2018-09-25 Merial Inc. Hyperbaric device and methods for producing inactivated vaccines and for refolding/solubilizing recombinant proteins

Also Published As

Publication number Publication date
BRPI0800357A2 (pt) 2009-10-27

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