WO2015179979A1 - Viral particles as immunogens against enterovirus infection and production thereof - Google Patents

Viral particles as immunogens against enterovirus infection and production thereof Download PDF

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WO2015179979A1
WO2015179979A1 PCT/CA2015/050484 CA2015050484W WO2015179979A1 WO 2015179979 A1 WO2015179979 A1 WO 2015179979A1 CA 2015050484 W CA2015050484 W CA 2015050484W WO 2015179979 A1 WO2015179979 A1 WO 2015179979A1
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viral particles
enterovirus
cva6
cvaio
coxsackievirus
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PCT/CA2015/050484
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English (en)
French (fr)
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Pele Choi-Sing Chong
Chia-Chyi Liu
Hsiao-Yu Lin
Yen-Hung Chow
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National Health Research Institutes
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Priority to CN201580028292.2A priority Critical patent/CN106661102B/zh
Priority to JP2017514745A priority patent/JP6774149B2/ja
Publication of WO2015179979A1 publication Critical patent/WO2015179979A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1009—Picornaviridae, e.g. hepatitis A virus
    • 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
    • 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
    • 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
    • A61K2039/5258—Virus-like particles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • 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
    • C12N2770/32311—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
    • C12N2770/32311—Enterovirus
    • C12N2770/32351—Methods of production or purification of viral material

Definitions

  • the present invention relates to viral particles as immunogens against enterovirus infection and a method of producing the same by using human embryo kidney 293 (HEK 293) cells.
  • the present invention also relates to an immunogenic composition against enterovirus infection for human use, and a method of inducing an immune response against enterovirus infection or a disease as caused, particularly Hand-Foot-Mouth diseases (HFMD).
  • HFMD Hand-Foot-Mouth diseases
  • Enterovirus within the Picornaviridae family, is a genus of small, non-enveloped viruses containing positive-strand RNAs.
  • the Enterovirus genus now comprises 12 species: Enterovirus A, Enterovirus B, Enterovirus C, Enterovirus D, Enterovirus E, Enterovirus F, Enterovirus Q Enterovirus H, Enterovirus J Rhinovirus A, Rhinovirus B and Rhinovirus C.
  • These viruses infect the intestinal tract but can cause various types of diseases.
  • Typical enterovirus diseases are meningitis, paralysis, myocarditis, hand, foot and mouth-disease (HFMD), herpangina, pleurodynia, hepatitis, rash and respiratory diseases including pneumonia.
  • the only enterovirus vaccine for use in human beings is vaccine of poliovirus which belongs to Enterovirus C. Currently, vaccines against non-polio enteroviruses are not available for human use.
  • the Enteroviruses have a RNA genome including the 5' untranslated region (UTR), the protein coding regions, the 3 ' UTR and a variable length poly-A tract is located at the terminus of the 3 ' end.
  • the RNA genome size is 7.4 Kbp and the single open reading frame (ORF) encodes a polyprotein.
  • the polyprotein is subdivided into three regions, PI, P2 and P3.
  • PI encodes four viral structural proteins VP4, VP2, VP3 and VP1, while P2 and P3 encode seven non- structural proteins 2A to 2C and 3A to 3D.
  • Coxsackieviruses are divided into 23 serotypes (1-22, 24) of group A and six serotypes (1-6) of group B (Knipe and Howley, 2001). Recently, human scavenger receptor class B, member 2 (SCARB2) was identified to be important receptor for EV71 and CVA16 infection (Yamayoshi et al. , 2009).
  • SCARB2 human scavenger receptor class B, member 2
  • Taiwan Sentinel Physician Surveillance Based on the Taiwan Sentinel Physician Surveillance, the epidemiology of major Enterovirus serotypes was systematically examined and monitored Enterovirus infections in Taiwan (Tseng et al , 2007). The information shows that there are different prevalent
  • CVA16 and EV71 Enterovirus serotypes every year, especially CVA16 and EV71 which primarily manifest as hand-foot-and-mouth disease (HFMD).
  • HFMD hand-foot-and-mouth disease
  • other common circulating serotypes including E30, E6, El l, CB3, CB4, CB5, CVA4, CVA6 and CVA10, had been identified to cause HFMD outbreaks during 2000-2005. This study also demonstrates the repeated cyclic epidemic pattern of these serotypes that have important public health
  • WO 99/53034 provides modified viral genomes for use as vaccines or vectors, which are improved in their ability to retain attenuating mutations.
  • WO2010139193 Al discloses a hand- foot-mouth disease vaccine obtained by inactivating purified EV71 virus type B and type C, and CoxA16 virus.
  • US20120045468 Al provides immunogenic compositions (e.g., vaccines) against EV71 infection and related methods.
  • an immunogenic composition as described herein for manufacturing a human vaccine against enterovirus infection or a disease as caused.
  • the CVA6 viral particles and the CVA10 viral particles, produced and collected from cultures of HEK 293 cells are combined together to form a multivalent immunogenic composition.
  • Coxsackievirus A2 (CVA2)
  • Coxsackievirus A3 (CVA3)
  • Coxsackievirus A4 (CVA4)
  • the viral particles according to the present invention after collected from cell cultures are subjected to purification and/or inactivation.
  • the inactivation is conducted by a formalin treatment.
  • Fig. 3 shows that both CVA6 and CVAIO only infected HEK293 cells (6 days postinfection).
  • Fig. 5 shows (A) CVAIO virus purification by sucrose gradient zonal ultracentrifugation; (B) Silver-stain of each fractions analyzed by SDS-PAGE.
  • Fig. 7 shows protein bands of CVA6, CVAIO and EVA71 viral particles.
  • coxsackievirus strains CVA6 and CVAIO unlike EVA71 and CVA16 would not infect cell lines used in human vaccine production such as Vero cells, MRC-5 cells and MDCK cells; and in contrast, these viruses (CVA6 and CVAIO) replicated well in HEK293 cells.
  • the virus title can reach 10 6 to 10 8 TCID50/ml.
  • the viral particles of the invention can be used as effective immunogens and are useful for preparing an immunogenic composition, especially for human use, against enterovirus infections, including CVA6 or CVAIO or both or further Enterovirus A other than CVA6 or CVAIO, e.g. CVA16 or EVA71.
  • the species Enterovirus A includes the serotypes as follows:
  • Coxsackievirus A5 CVA5
  • Coxsackievirus A6 CVA6
  • Coxsackievirus A7 CVA7
  • Coxsackievirus A8 (CVA8), Coxsackievirus A10 (CVAIO), Coxsackievirus A12 (CVA12), Coxsackievirus A14 (CVA14), Coxsackievirus A16 (CVA16), Enterovirus A71 (EVA71), Enterovirus A76 (EVA76), Enterovirus A89 (EVA89), Enterovirus A90 (EVA90), Enterovirus A91 (EVA91), Enterovirus A92 (EVA92), Enterovirus A114 (EVA 114) and Enterovirus A119 (EVA119).
  • empty particle refers to a viral particle that does not contain a nucleic acid, vector or plasmid, and is therefore not infectious.
  • sub-particle refers to noninfectious subparticles of a virus empty particle.
  • the sub-particle refers to a virus particle having a different capsid protein composition as compared to that of a full particle.
  • a sub-particle can (1) contain less capsid protein than VPl, VP2, VP3 and VP4, (2) contain more capsid proteins than VPl, VP2, VP3 and VP4, and/or (3) contain one or more incompletely processed capsid proteins.
  • the "antigen” refers to a particle or a molecule containing one or more epitopes that will stimulate a host's immune system to make a humoral and/or cellular antigen- specific response.
  • the term “antigen” is used interchangeably with "immunogen. "
  • an antigen induces a state of sensitivity or immune responsiveness and reacts in a demonstrable way with antibodies or immune cells of the sensitized subject in vivo or in vitro.
  • An antigen can be specifically recognized and bound by antibodies in an organism.
  • An antigen in association with a major histocompatibility complex can also be recognized and bound by receptors on the surface of T lymphocytes (T-cells), leading to the activation of the T-cells.
  • T-cells T lymphocytes
  • epitopope refers to the site on an antigen to which a specific antibody molecule or a T-cell receptor binds.
  • the term is used herein interchangeably with “antigenic determinant” or "antigenic determinant site.”
  • immune response refers to any reaction of the immune system in response to an antigen in a subject.
  • examples of an immune response in a vertebrate include, but are not limited to, antibody production, induction of cell- mediated immunity, and complement activation.
  • the immune response to a subsequent stimulus by the same antigen also named the secondary immune response, is more rapid than in the case of the primary immune response.
  • immunogenic refers to a capability of producing an immune response in a host animal against an antigen or antigens. This immune response forms the basis of the protective immunity elicited by a vaccine against a specific infectious organism.
  • adjuvant refers to a substance added to an immunogenic composition, such as a vaccine, that while not having any specific antigenic effect in itself, can stimulate the immune system and increase the immune response to the immunogenic composition.
  • the Enterovirus A other than CVA6 and CVA10 is selected from the group consisting of:
  • Coxsackievirus A5 CVA5
  • Coxsackievirus A7 CVA7
  • Coxsackievirus A8 CVA8
  • Coxsackievirus A12 (CVA12), Coxsackievirus A14 (CVA14), Coxsackievirus A16 (CVA16), Enterovirus A71 (EVA71), Enterovirus A76 (EVA76), Enterovirus A89 (EVA89), Enterovirus A90 (EVA90), Enterovirus A91 (EVA91), Enterovirus A92 (EVA92), Enterovirus A114 (EVA114) and Enterovirus Al 19 (EVA119).
  • a multivalent immunogenic composition of the present invention can comprise viral particles of four types of enterovirus, CVA6 viral particles, CVAIO viral particles, CVA16 viral particles, and EVA71 viral particles, at a weight ratio of about 1 : 1 : 1 : 1. The ratio can be adjusted as needed.
  • the CVA6 or CVAIO viral particles or other viral particles are further subjected to purification or inactivation or both.
  • a fraction of empty particles can be identified at 25-35%) sucrose gradient.
  • a fraction of sub-particles can be identified at less than 25% sucrose gradient.
  • the immunogenic composition of the invention can comprise (i) a fraction of full particles, a fraction of empty particles, a fraction of sub-particles of CVA6 or any combination thereof; (ii) a fraction of full particles, a fraction of empty particles, a fraction of sub-particles of CVAIO or any combination thereof; (iii) a fraction of full particles, a fraction of empty particles, a fraction of sub-particles of Enterovirus A other than CVA6 and CVAIO (e.g. CVA16 or EVA71) or any combination thereof; or (iv) any combination of (i), (ii) and (iii).
  • the empty particles of the enterovirus are detected to have PI polypeptide that is incompletely processed during viral assembly and packaging, having a molecular weight of 65-95 kDa.
  • the full particles of the enterovirus are detected to have VP1 (32-35 kDa), VP2 (24-28 kDa), VP3 (24-28 kDa) and VP4 (6-8 kDa).
  • the method of the invention further comprises a step of determining the amount of the purified enterovirus particles.
  • an effective amount of the immunogen or composition described above may be administered parenterally, e.g., subcutaneous injection or intramuscular injection.
  • binders and carriers may include, for example, polyalkalene glycols or triglycerides.
  • Oral immunogens or compositions may include normally employed excipients such as pharmaceutical grades of saccharine, cellulose, magnesium carbonate and the like. These immunogens or compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders.
  • the enterovirus infection is caused by Enterovirus A, selected from the group consisting of: Coxsackievirus A2 (CVA2), Coxsackievirus A3 (CVA3),
  • an isolated antibody that selectively binds to a peptide having one of the sequences mentioned above or viral particles as described herein. Further provided is a method of producing the antibody by immunizing an animal with the above-described
  • immunogen or immunogenic composition which elicits an immune response in the animal to produce the antibody; and isolating the antibody or a cell producing the antibody from the animal.
  • Enterovirus (EV71, CVA16, CVA6 and CVA10) was cultivated in either Vero cell or HEK293 cell using serum-free VP-SFM medium, Dulbecco's modified Eagle's medium + 10%FBS and other appropriate serum-free medium in T-flak. Cell density reached 1 to 2.5 ⁇ 10 6 cells per mL after six days of cultivation. The cells were infected with virus at a MOI of 10 "2 to 10 "5 . Virus was harvested and collected from the culture supernatants at 6 days post-infection (DPI).
  • DPI days post-infection
  • the virus culture supernatant was harvested from the T-flask culture.
  • the cell debris was removed by passage through a 0.65 ⁇ filter (Sartorius, Germany), and the supernatant was concentrated 20-fold with a 100K TFF capsule (Pall).
  • the crude virus concentrate (-50 mL) was loaded onto a 10-60% continuous sucrose gradient and centrifuged at 32,000 rpm for three hours using a zonal rotor in a Hitachi CP80 ultracentrifuge.
  • the fractions (50 mL per fraction) at 10 to 60%) sucrose were collected and individually dialyzed against three exchanges of 1 L PBS at pH 7.4 (Gibco/Life Technologies, Taipei, Taiwan), then stored at 4°C.
  • the infectivity of the purified virus fraction was assessed by a tissue culture's infectious dose (TCID 50 ) assay.
  • the fractions were also subjected to SDS-PAGE and Western blot analyses.
  • the fractions identified to contain virus were pooled and concentrated by diafiltration using an Amicon 100K tube (Millipore, Belerica, MA USA) and centrifuged at 3,000 x g, then stored at 4°C.
  • concentration of the purified virus fractions was determined by a BCA protein assay.
  • Half of the purified virus fractions (15 mL) was stored at -80°C in 0.5 mL aliquots; the other half was inactivated by 1/4000 (v/v) formalin at 37°C for 3 days and stored at 4°C.
  • Viral titers were determined using the TCID 50 median endpoint. Serially-diluted virus samples (from 10 "1 to 10 "8 ) were added to RD cells grown in 96-well plates, and 6 replicate samples were used for each dilution. The 96-well plates were incubated for six days at 37 C, and TCID 50 values were measured by counting cytopathic effects (CPE) on infected RD cells. The TCID 50 values were calculated using the Reed-Muench method.
  • Binding of the respective antibodies to the viral particles was detected by adding 1 mL PBS buffer containing a horseradish peroxidase (HRP)- conjugated donkey anti-mouse secondary antibody (Jackson ImmunoResearch) at a dilution of 1 : 5,000. Afterl-hour incubation at room temperature, the membrane was washed 6 times with assay buffer and blotted dry. The dots were revealed by adding TMB substrate solution (KPL).
  • HRP horseradish peroxidase
  • Example 3 irus cultivation using HEK293 cell culture
  • CVA6 and CVAIO that could not infect Vero cells and RD cells are not for human vaccine production, so other potential GMP-grade certified cell-lines such as MDCK, MRC-5, CHO and HEK293 were tested and used to propagate CVA6 and/or CVAIO.
  • GMP-grade certified cell-lines such as MDCK, MRC-5, CHO and HEK293 were tested and used to propagate CVA6 and/or CVAIO.
  • both CVA6 and CVAIO only infected HEK293 cells (Fig. 3).
  • Table 3 Virus titers of enterovirus produced in HEK293 cells.
  • Example 9 The recognition of mice anti-sera that immunized with viral particles

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PCT/CA2015/050484 2014-05-28 2015-05-28 Viral particles as immunogens against enterovirus infection and production thereof WO2015179979A1 (en)

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CN201580028292.2A CN106661102B (zh) 2014-05-28 2015-05-28 作为对抗肠病毒感染之免疫原的病毒颗粒及其制造
JP2017514745A JP6774149B2 (ja) 2014-05-28 2015-05-28 エンテロウイルス感染に対する免疫原としてのウイルス粒子およびその生産

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WO2016205389A1 (en) * 2015-06-15 2016-12-22 Emory University Multivalent enterovirus vaccine compositions and uses related thereto
CN110184242A (zh) * 2019-06-11 2019-08-30 武汉生物制品研究所有限责任公司 柯萨奇病毒a组6型（cva6）的小鼠强毒力攻毒株及其应用
CN111139233A (zh) * 2020-01-19 2020-05-12 中国医学科学院医学生物学研究所 广谱中和抗EV71、CA16、CA10和CA6人-鼠嵌合IgM型单克隆抗体及应用
CN113122551A (zh) * 2021-03-30 2021-07-16 新乡医学院 一种柯萨奇病毒a组19型vp1基因重组表达蛋白、多克隆抗体的制备方法及其应用
CN113564132A (zh) * 2021-09-23 2021-10-29 北京民海生物科技有限公司 柯萨奇病毒a16型毒株及其应用
CN114807060A (zh) * 2022-06-23 2022-07-29 北京民海生物科技有限公司 柯萨奇病毒a6型毒株及其免疫原性组合物和应用
CN114990075A (zh) * 2022-04-20 2022-09-02 中国医学科学院医学生物学研究所 一株可适用于人用疫苗细胞基质培养的柯萨奇病毒a组10型疫苗株及其应用
CN115707778A (zh) * 2021-08-20 2023-02-21 华淞(上海)生物医药科技有限公司 重组柯萨奇病毒a10病毒样颗粒及其用途
CN115960220A (zh) * 2022-11-25 2023-04-14 华淞(上海)生物医药科技有限公司 特异性结合柯萨奇病毒a6的单克隆抗体及其用途
CN117783524A (zh) * 2024-02-26 2024-03-29 中国医学科学院医学生物学研究所 一种双抗体夹心法间接定量检测柯萨奇a10型病毒抗原的建立与应用

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CN112011572B (zh) * 2020-07-17 2022-05-06 北京科兴生物制品有限公司 柯萨奇病毒a7的病毒样颗粒及其制备方法和应用
CN113564130B (zh) * 2021-09-23 2022-01-07 北京民海生物科技有限公司 柯萨奇病毒a10型毒株及其应用

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