WO2016063291A1 - Improved methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof - Google Patents

Improved methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof Download PDF

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Publication number
WO2016063291A1
WO2016063291A1 PCT/IN2015/000376 IN2015000376W WO2016063291A1 WO 2016063291 A1 WO2016063291 A1 WO 2016063291A1 IN 2015000376 W IN2015000376 W IN 2015000376W WO 2016063291 A1 WO2016063291 A1 WO 2016063291A1
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Prior art keywords
dose
type
inactivation
polioviruses
atleast
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PCT/IN2015/000376
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English (en)
French (fr)
Inventor
Rajeev Mhalasakant DHERE
Sambhaji Shankar PISAL
Jagdish Kamalaji ZADE
Rajendra Narayan SABALE
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Serum Institute of India Pvt Ltd
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Serum Institute of India Pvt Ltd
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Priority to NZ731341A priority Critical patent/NZ731341B2/en
Priority to KR1020177012227A priority patent/KR102219638B1/ko
Priority to PL15831237T priority patent/PL3204494T3/pl
Priority to UAA201704367A priority patent/UA125788C2/uk
Priority to SG11201702838SA priority patent/SG11201702838SA/en
Priority to KR1020217004836A priority patent/KR102510744B1/ko
Priority to CN201580066368.0A priority patent/CN106999569B/zh
Priority to EP20154738.7A priority patent/EP3663396A1/en
Priority to EA201700187A priority patent/EA201700187A1/ru
Priority to CU2017000044A priority patent/CU24510B1/es
Priority to DK15831237.1T priority patent/DK3204494T3/da
Priority to BR112017007089-8A priority patent/BR112017007089B1/pt
Priority to JP2017518817A priority patent/JP6755243B2/ja
Priority to SI201531223T priority patent/SI3204494T1/sl
Priority to CA2963897A priority patent/CA2963897C/en
Application filed by Serum Institute of India Pvt Ltd filed Critical Serum Institute of India Pvt Ltd
Priority to AU2015334495A priority patent/AU2015334495B2/en
Priority to LTEP15831237.1T priority patent/LT3204494T/lt
Priority to MX2017004534A priority patent/MX388525B/es
Priority to ES15831237T priority patent/ES2803578T3/es
Priority to MYPI2017703783A priority patent/MY204389A/en
Priority to US15/517,225 priority patent/US10485862B2/en
Priority to EP15831237.1A priority patent/EP3204494B1/en
Publication of WO2016063291A1 publication Critical patent/WO2016063291A1/en
Priority to PH12017500627A priority patent/PH12017500627A1/en
Anticipated expiration legal-status Critical
Priority to US16/597,964 priority patent/US11793869B2/en
Priority to CY20201100591T priority patent/CY1123078T1/el
Priority to AU2021269395A priority patent/AU2021269395B2/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/125—Picornaviridae, e.g. calicivirus
    • A61K39/13—Poliovirus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • 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
    • C12N7/04—Inactivation or attenuation; Producing viral sub-units
    • C12N7/045—Pseudoviral particles; Non infectious pseudovirions, e.g. genetically engineered
    • 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
    • C12N7/04—Inactivation or attenuation; Producing viral sub-units
    • C12N7/06—Inactivation or attenuation by chemical treatment
    • 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)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5254—Virus avirulent or attenuated
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • A61K2039/55505—Inorganic 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • 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
    • A61K2039/70—Multivalent vaccine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • 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
    • C12N2770/32311—Enterovirus
    • C12N2770/32334—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
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32611—Poliovirus
    • C12N2770/32634—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • 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
    • C12N2770/32661—Methods of inactivation or attenuation
    • C12N2770/32663—Methods of inactivation or attenuation by chemical treatment
    • 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
    • C12N2770/32671—Demonstrated in vivo effect
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • cVDPVs are transmissible and can become neurovirulent (similar to wild polioviruses) resulting in vaccine associated paralytic poliomyelitis.Such strains can potentially re-seed the world with polioviruses and negate the eradication accomplishments.
  • IPV is delivered by intramuscular (IM) or deep subcutaneous (SC) injection.
  • IPV is currently available either as a non-adjuvanted stand-alone formulation, or in various combinations, including DT-IPV (with diphtheria and tetanus toxoids) and hexavalentDTPHepB- Hib-IPV vaccines(additionalIy with pertussis, hepatitis B, and Haemophilus influenzae b.
  • the currently acceptable standard dose of polio vaccines contains D antigens as 40 Units of inactivated poliovirus type 1 (Mahoney), 8 units of inactivated poliovirus type 2 (MEF-I) and 32 units of inactivated poliovirus type 3 (Saukett) (e.g.
  • Infanrix-IPVTM Infanrix-IPVTM.Existing preparations of stand-alone IPV do not contain adjuvant. Most experts agree that worldwide use of IPV is preferable because of its proven protective track- record and safety. However, when compared to OPV, the cost-prize for I PV is significantly higher . This is mainly due to requirements for: (i) more virus per dose; (ii) additional downstream processing (i.e. concentration, purification and inactivation), and the related QC-testing (iii) loss of antigen or poor recovery in downstream and iv) containment.
  • Reduced-dose efficacious vaccine formulations which provide protection against infection using a lower dose of IPV antigen are desirable in situations where the supply of conventional vaccine is insufficient to meet global needs or where the cost of manufacture of the conventional vaccine prevents the vaccine being sold at a price which is affordable for developing countries. Also the exposure to lower dose of IPV; compared to the existing marketed formulations could be more safer.Thus.various strategies to make IPV available at more affordable prices need to be evaluated.
  • Emulsion adjuvants (MF-59,AS03,AF3) have been previously reported to provide a strong dose- reduction effect (> 30fold] for Influenza and Hepatitis B vaccines. These adjuvants work by forming a depot at the site of injection, enabling the meted release of antigenic material and the stimulation of antibody producing plasma cells.However, these adjuvants have been deemed too toxic for widespread human prophylactic vaccine use and are usually reserved for those severe and/or terminal conditions such as cancer where there is a higher tolerance of side-effects.
  • Aluminum salts have been considered safe, are already being used in combination vaccines containing sIPV, have the lowest development hurdles and are inexpensive to manufacture.However aluminium adjuvants are not known for permitting significant dose- reduction.
  • the present inventors have surprisingly found that D-antigen losses post-formaldehyde inactivation could be due to presence of phosphate buffer that unexpectedly causes undesirable aggregation of polio viruses.
  • the instant invention provides an improved process of formaldehyde inactivation in presence of TRIS buffer thereby ensuring minimal epitopic modifications and subsequently minimizing D-antigen losses. Subsequently significantly dose reduced Sabin IPV vaccine compositions with atleast 8 fold dose reduction for Sabin Type I and 3 fold dose reduction for Sabin Type III can be obtained .
  • Fig l Alum phosphate gel prepared in 0.9% NaCI(pH Vs Zeta potential at different concentrations of Alum phosphate gel)
  • Fig 2 Alum phosphate gel prepared in WFl[p ⁇ Vs Zeta potential at different concentrations of Alum phosphate gel)
  • Fig 3 Alum Hydroxide gel prepared in 0.9% NaCI[pU Vs Zeta potential at different concentrations of Alum hydroxide gel)
  • Fig 4 Alum Hydroxide gel prepared in WFI (pH Vs Zeta potential at different concentrations of Alum hydroxide gel) Detailed Description:
  • Step (c) Incubating mixture obtained in Step (c) at 37°C from 5 to 13 days on magnetic stirrer, e) Subjecting post-incubation mixture to intermediate 0.22 ⁇ filtration on day 7 and final filtration on day 13,
  • step (a) wherein formalin inactivation of step (a) does not occur in presence of phosphate buffer
  • a first embodiment of instant invention is that said buffer to be used during formaldehyde inactivation can be selected from the group consisting of TRIS, TBS, MOPS, HEPES, and bicarbonate buffers.
  • a preferred aspect of first embodiment is that said formaldehyde inactivation can occur in presence of TRIS Buffer or TBS(TR1S Buffered saline) having concentration selected from 30mM,40mM and 50mM, preferably 40mM and at a pH selected from 6.8,6.9,7,7.1 and 7.2 preferably between 6.8 and 7.2 wherein said inactivation does not utilize any phosphate buffer.
  • TRIS Buffer or TBS(TR1S Buffered saline) having concentration selected from 30mM,40mM and 50mM, preferably 40mM and at a pH selected from 6.8,6.9,7,7.1 and 7.2 preferably between 6.8 and 7.2 wherein said inactivation does not utilize any phosphate buffer.
  • a second embodiment of the instant invention is that adsorption of formalin inactivated sIPV can be done on aluminium hydroxide having concentration selected from 1.5mg/dose, 1.8mg/dose,2.2 mg/dose, preferably between 2mg/dose to 2.4 mg/dose and at a pH selected from 6.2,6.3,6.4 and 6.5, preferably 6.5.
  • a third embodiment of instant invention is that said improved process of formalin inactivation and aluminium hydroxide adsorption can result in D- Antigen recovery post-inactivation between 50% and 80% and percent adsorption of aluminium hydroxide can be between 85 and 99% .
  • One aspect of third embodiment is that present invention provides an improved process of formalin inactivation and aluminium hydroxide adsorption resulting in dose reduction of atleast 8 fold for Sabin Type I, atleast 3 fold for Sabin Type 111 as compared to standard dose of 40 DU-8DU-32DU.
  • Second aspect of third embodiment is that instant invention provides improved formaldehyde inactivation and aluminium hydroxide, adsorption methods that result in vaccine compositions comprising of i) inactivated poliovirus type 1 at a dose of atleast 5D-antigen units, ii) inactivated poliovirus type 2 at a dose of atleast 8D-antigen units and iii) inactivated poliovirus type 3 at a dose of atleast l OD-antigen units.
  • a fourth embodiment of instant invention is that said aluminium salt adjuvant is an aluminium hydroxide having concentration between 1.5mg/0.5 ml dose and 2.5 mg/0.5 ml dose, preferably between 2.100 mg/0.5ml dose and 2.4mg/0.5 ml dose at a pH of about 6.5.
  • total aluminium content in the trivalent vaccine(Type 1,2 and 3) can be between 800-1000 ⁇ g, preferably 800 g Al 3+ per 0.5mL dose characterized in that atleast 400 g Al 3+ for Type l.atleast 200 ⁇ g Al 3+ for Type 2,atleast 200 ⁇ g Al 3+ for Type 3.
  • said dose reduced polio virus vaccine composition can consist of Type 1 and Type 3 and is devoid of Type 2 wherein the dose volume can be between 0.1
  • the non-IPV antigen(s) may be adsorbed onto an aluminium salt such as aluminium hydroxide, an aluminium salt such as aluminium phosphate or onto a mixture of both aluminium hydroxide and aluminium phosphate, or may be unadsorbed.
  • an aluminium salt such as aluminium hydroxide
  • an aluminium salt such as aluminium phosphate
  • aluminium phosphate or onto a mixture of both aluminium hydroxide and aluminium phosphate, or may be unadsorbed.
  • Poliovirus may be grown in cell culture.
  • the cell culture may be a VERO cell line or P KC, which is a continuous cell line derived from monkey kidney.
  • VERO cells can conveniently be cultured microcarriers.
  • virions may be purified using techniques such as ultrafiltration, diafiltration, and chromatography. Prior to administration to patients, the viruses must be inactivated, and this can be achieved by treatment with formaldehyde.
  • compositions may be presented in vials, or they may be presented in ready filled syringes.
  • the syringes may be supplied with or without needles.
  • a syringe will include a single dose of the composition, whereas a vial may include a single dose or multiple doses (e.g. 2 doses).
  • I n one embodiment the dose is for human. In a further embodiment the dose is for an adult, adolescent, toddler, infant or less than one year old human and may be administered by injection.
  • Vaccines of the invention may be packaged in unit dose form or in multiple dose form (e.g. 2 doses).
  • the said multidose composition can be selected from a group consisting of 2 dose,5 dose and 10 dose .
  • vials are preferred to pre-filled syringes.
  • Effective dosage volumes can be routinely established, but a typical human dose of the composition for injection has a volume of 0.5mL.
  • Clarified harvest pool was concentrated to 10X using tangential flow filtration system with lOOKda cassettes(0.5m 2 ) and then diafiltered 3 times of harvest volume with phosphate buffer (40 mM , pH : 7.0)
  • IEC Ion Exchange Chromatography
  • 10X TFF concentrate was passed through DEAE Sepharose fast flow (Weak- Anion exchanger) packed in column xk- 26 using Akta explorer (GE Healthcare). Negatively charged impurities was found to bind to the column whereas polio virus was collected in flow through with phosphate buffer 40 mM.
  • purified virus pool was buffer exchanged from phosphate buffer to TRIS buffer (40mM ,pH: 7) with TFF system [100 KDa ,0.1 m2).
  • TFF system 100 KDa ,0.1 m2
  • Type 2 140 140 DU/ml 165.16 DU/ml 155 DU/ml
  • TRIS Buffer at a concentration of 40mM was found to be most efficient in terms of D Antigen content preservation for sIPV 1,2 and 3.
  • Microtiter plate was sealed and incubated overnight at room temperature.
  • Desired volume of A1(0H)3/A1P0 was taken to get the required concentration of alum in a 100 ml glass bottle.
  • Desired volume of A1(0H)3/A1P0 was taken to get the required concentration of alum in a 100 ml glass bottle.
  • Inactivated polio virus bulk with known D-Ag Unit was added and volume make up was done with diluent.
  • Sabin polio virus type-3 shows only 50-60% adsorption with aluminium phosphate (AlPCUj.Whereas, Sabin polio virus type-3 shows atleast 90% adsorption with Al(OH) 3 .Thus, Alum hydroxide was found to be more efficient as compared to Alum phosphate with respect to adsorption of Sabin Type 1,2 and 3.
  • SNT test was carried out. Sera was separated and used to test the presence of neutralizing antibodies for type specific polio virus. Control sera used to validate the test. Virus back-titration was also performed to get the number of challenge virus particles added.
  • Animal Model Wistar rat (8 weeks, approx 200 gm) 50% male and 50 % female per group.
  • Alum hydroxide adjuvanted Type 1 Sabin IPV having 5 DU/dose gave better seroconversion as compared to Salk IPV vaccine with 40DU/dose and Alum phosphate 5 adjuvanted Sabin IPV having 5 DU/dose.
  • Type 2 sIPV having 8 DU/dose with adjuvant gave equivalent sero conversion as compared to Salk IPV vaccine with 8DU/ dose.
  • Type 3 sIPV having lODU/dose with adjuvant gave equivalent sero conversion as compared to Salk IPV vaccine with 32DU/ dose.

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PCT/IN2015/000376 2014-10-07 2015-10-06 Improved methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof Ceased WO2016063291A1 (en)

Priority Applications (26)

Application Number Priority Date Filing Date Title
CA2963897A CA2963897C (en) 2014-10-07 2015-10-06 Improved methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof
PL15831237T PL3204494T3 (pl) 2014-10-07 2015-10-06 Ulepszone metody inaktywacji wirusa polio i adsorpcji na adiuwancie
UAA201704367A UA125788C2 (uk) 2014-10-07 2015-10-06 Спосіб інактивації ентеровірусу, ад'ювант адсорбції та композиція із зменшеною дозою вакцини, одержана з ним
SG11201702838SA SG11201702838SA (en) 2014-10-07 2015-10-06 Improved methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof
KR1020217004836A KR102510744B1 (ko) 2014-10-07 2015-10-06 엔테로바이러스 불활화 및 보강제 흡착 방법과 이로부터 수득되는 저용량 백신 조성물
CN201580066368.0A CN106999569B (zh) 2014-10-07 2015-10-06 肠道病毒灭活的改进的方法、佐剂吸附及其获得的剂量减少的疫苗组合物
EP20154738.7A EP3663396A1 (en) 2014-10-07 2015-10-06 Dose reduced povlio virus vaccine compositions and methods for its production
EA201700187A EA201700187A1 (ru) 2014-10-07 2015-10-06 Способ получения композиции, содержащей энтеровирусные частицы
CU2017000044A CU24510B1 (es) 2014-10-07 2015-10-06 Método para la composición de una vacuna contra la poliomielitis, con poliovirus inactivados y adsorción en coadyuvantes
DK15831237.1T DK3204494T3 (da) 2014-10-07 2015-10-06 Forbedrede fremgangsmåder til inaktivering af poliovirus, adsorption af adjuvans
BR112017007089-8A BR112017007089B1 (pt) 2014-10-07 2015-10-06 Método para a produção de uma composição compreendendo partículas enterovirais
JP2017518817A JP6755243B2 (ja) 2014-10-07 2015-10-06 エンテロウイルス不活化およびアジュバント吸着のための改良された方法、ならびに、それから得られる投与量減量ワクチン組成物
SI201531223T SI3204494T1 (sl) 2014-10-07 2015-10-06 Izboljšane metode za neaktivacijo poliovirusa, adjuvans adsorpcije
NZ731341A NZ731341B2 (en) 2015-10-06 Improved methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof
MYPI2017703783A MY204389A (en) 2014-10-07 2015-10-06 Improved methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof
EP15831237.1A EP3204494B1 (en) 2014-10-07 2015-10-06 Improved methods for poliovirus inactivation, adjuvant adsorption
LTEP15831237.1T LT3204494T (lt) 2014-10-07 2015-10-06 Polioviruso inaktyvavimo, adjuvanto adsorpcijos pagerinti būdai
MX2017004534A MX388525B (es) 2014-10-07 2015-10-06 Métodos mejorados para inactivación de enterovirus, composiciones de vacuna con adsorción de adyuvante y reducida en dosis obtenida de los mismos.
ES15831237T ES2803578T3 (es) 2014-10-07 2015-10-06 Métodos mejorados para la inactivación del enterovirus, adsorción de adjuvante y composiciones de vacuna de dosis reducida obtenidas de los mismos
KR1020177012227A KR102219638B1 (ko) 2014-10-07 2015-10-06 엔테로바이러스 불활화 및 보강제 흡착 방법과 이로부터 수득되는 저용량 백신 조성물
US15/517,225 US10485862B2 (en) 2014-10-07 2015-10-06 Methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof
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US16/597,964 US11793869B2 (en) 2014-10-07 2019-10-10 Methods for enterovirus inactivation, adjuvant adsorption and dose reduced vaccine compositions obtained thereof
CY20201100591T CY1123078T1 (el) 2014-10-07 2020-06-25 Βελτιωμενες μεθοδοι για την αδρανοποιηση του ιου της πολιομυελιτιδας, την προσροφηση ανοσοενισχυτικου
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