WO2023080718A1 - Composition vaccinale pour la prévention ou le traitement d'une infection par le sars-coronavirus-2 - Google Patents

Composition vaccinale pour la prévention ou le traitement d'une infection par le sars-coronavirus-2 Download PDF

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WO2023080718A1
WO2023080718A1 PCT/KR2022/017256 KR2022017256W WO2023080718A1 WO 2023080718 A1 WO2023080718 A1 WO 2023080718A1 KR 2022017256 W KR2022017256 W KR 2022017256W WO 2023080718 A1 WO2023080718 A1 WO 2023080718A1
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infection
rbd
amino acid
coronavirus
acid sequence
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PCT/KR2022/017256
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Korean (ko)
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홍승혜
강경원
김은솜
백경화
석지현
선보현
안혜빈
이희수
정오석
최우영
김학
박용욱
박호근
백승범
서기원
양선영
이건세
이수진
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에스케이바이오사이언스(주)
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Publication of WO2023080718A1 publication Critical patent/WO2023080718A1/fr

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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
    • 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
    • A61K39/215—Coronaviridae, e.g. avian infectious bronchitis virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins

Definitions

  • the present invention relates to a vaccine composition used for the purpose of preventing Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infection and/or alleviating symptoms expressed during infection.
  • SARS-CoV-2 Severe Acute Respiratory Syndrome-Coronavirus-2
  • the SARS-CoV-2 virus which has been reported worldwide since December 2019, is a virus belonging to the Coronaviridae family, Betacoronavirus genus Sarbecovirus subgenus, and SARS-CoV-2 virus infection is also called COVID-19 (coronavirus disease 2019).
  • the main transmission route is known to be close contact with droplets of an infected person, and direct contact with an infected person or touching a medium such as an item contaminated by droplets of an infected person, then touching the eyes, nose, mouth, etc. without washing hands It is known that viral transmission can be achieved by this.
  • the Receptor Binding Domain (RBD) on the surface of the SARS-CoV-2 virus binds to the ACE2 receptor protein on the surface of human cells, causing infection. It is known. Spike glycoprotein monomers are separated into S1 subunits and S2 subunits by host cell proteases.
  • SARS-CoV-2 virus causes an increase in deaths and enormous social and economic damage, and as the damage rapidly increases, rapid vaccine development is required.
  • Vaccine composition for preventing SARS-CoV-2 infection or alleviating symptoms development is being carried out.
  • the present inventors combine the RBD of the SARS-CoV-2 spike glycoprotein with a protein capable of self-assembling to form a nanostructure to prepare RBD nanoparticles that label multivalent RBD antigens,
  • an immunostimulant capable of further improving the immunogenicity of the RBD nanoparticles was studied.
  • RBD nanoparticles showed excellent immunogenicity at both low and high doses when aluminum hydroxide was used as an immune enhancer.
  • Patent Document 1 US Registered Patent Publication US 9630994 B2
  • Non-Patent Document 1 Science. 2016 Jul 22;353(6297):389-94.
  • a first polypeptide monomer comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 75% identity thereto is an assembled trimer of three; and an RBD (Receptor Binding Domain) nanoparticle comprising a pentamer in which five second polypeptide monomers comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 75% identity thereto, and an immune enhancer It provides a vaccine composition for preventing or treating SARS-coronavirus-2 infection comprising a.
  • RBD Receptor Binding Domain
  • Another aspect of the present invention is a first polypeptide monomer comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 75% identity thereto, a trimer in which three are assembled; And an RBD nanoparticle comprising a pentamer in which five second polypeptide monomers comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 75% identity thereto, and an immune enhancer, SARS - A vaccine composition for preventing or treating coronavirus-2 infection and a kit for preventing or treating SARS-coronavirus-2 infection including instructions for use are provided.
  • the vaccine composition according to the present invention has excellent preventive and therapeutic effects against SARS-coronavirus-2 infection because the IgG antibody titer and neutralizing antibody titer increase after vaccine administration and the increased levels are maintained even after the second vaccination.
  • the term “about” may be presented before a specific numeric value.
  • the term “about” includes not only the exact number that follows the term, but also a range that is or is close to that number. It can be determined whether the number is close to or nearly the specific number mentioned, given the context in which it is presented.
  • the term “about” can refer to a range of -10% to +10% of a numerical value.
  • the term “about” can refer to a range of -5% to +5% of a given numerical value. However, it is not limited thereto.
  • the term “and/or” when used herein is to be understood as specifically disclosing each of the two specified features or elements, either with or without the other.
  • the term “and/or” as used herein in phrases such as “A and/or B” includes “A and B”, “A or B”, “A” (alone), and “B” (alone). ) is intended to include.
  • the term “and/or” as used in phrases such as "A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
  • the term "consisting essentially of” means that a non-specified ingredient may be present if the characteristics of the claimed subject matter are not substantially affected by the presence of the non-specified ingredient.
  • the term “consisting of” means that the percentage of the specified component(s) totals 100%. Ingredients or features that come after the term “consisting of” may be essential or mandatory. In some embodiments, in addition to the ingredients or features that come under “consisting of”, any other ingredients or non-essential ingredients may be excluded.
  • a polypeptide or protein if it has the same or equivalent activity as the polypeptide consisting of the amino acid sequence of the corresponding sequence number, a protein having an amino acid sequence in which some sequences are deleted, modified, substituted, conservatively substituted, or added. It is obvious that can also be used in this application.
  • the amino acid sequence has an addition of a sequence that does not change the function of the protein, a naturally occurring mutation, a silent mutation thereof, or a conservative substitution to the N-terminus and/or C-terminus of the amino acid sequence. It may, but is not limited thereto.
  • Vaccine composition for preventing or treating SARS-CoV-2 infection
  • a first polypeptide monomer comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 75% identity thereto is an assembled trimer of three; and an RBD (Receptor Binding Domain) nanoparticle comprising a pentamer in which five second polypeptide monomers comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 75% identity thereto, and an immune enhancer It provides a vaccine composition for preventing or treating SARS-coronavirus-2 infection comprising a.
  • RBD Receptor Binding Domain
  • the RBD nanoparticle may also be referred to as a "nanostructure", “RBD nanostructure”, or “RBD-NP” as a multimeric protein assembly, and (i) has an amino acid sequence of SEQ ID NO: 1 or at least 75% identity thereto.
  • a trimer in which three first polypeptide monomers comprising an amino acid sequence are assembled; and (ii) a second polypeptide monomer comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 75% identity thereto may comprise a five assembled pentamer.
  • the first polypeptide comprises a SARS-CoV-2 spike glycoprotein receptor binding domain (receptor binding domain, RBD); A first self-assembling polypeptide serving as a structure of nanoparticles; and a linker connecting the RBD and the first self-assembling polypeptide.
  • the first polypeptide monomer may further include an N-terminal phosphatase signal peptide sequence (MGILPSPGMPALLSLVSLLSVLLMGCVA).
  • a plurality of isolated first polypeptide monomers may self-assemble through interactions to form a trimer. This assembly can be achieved through non-covalent protein-protein interaction reactions.
  • the second polypeptide is a second self-assembling polypeptide monomer serving as a structure of nanoparticles, and a plurality of isolated second polypeptide monomers self-assemble through interactions to form a pentamer. can form This assembly can be achieved through non-covalent protein-protein interaction reactions.
  • the first polypeptide may be one of the polypeptides described in International Patent Publication No. 2019-169120.
  • the first polypeptide monomer may be a polypeptide consisting of the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 75% identity thereto, for example, a polypeptide consisting of the amino acid sequence represented by SEQ ID NO: 1 can
  • the polypeptide of SEQ ID NO: 1 may be referred to as "RBD-I53-50A" or "RBD-Component A”.
  • the first polypeptide may be encoded by a gene consisting of the nucleotide sequence represented by SEQ ID NO: 3.
  • the second polypeptide monomer may be a polypeptide consisting of the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 75% identity thereto, for example, a polypeptide consisting of the amino acid sequence represented by SEQ ID NO: 2.
  • the polypeptide of SEQ ID NO: 2 herein may be referred to as "I53-50B" or "Component B”.
  • the second polypeptide monomer may be encoded by a gene consisting of the nucleotide sequence represented by SEQ ID NO: 4.
  • the first polypeptide and the second polypeptide may include any modification that does not disrupt assembly into a multimeric protein assembly, for example, may include addition, deletion, insertion, substitution, or modification of amino acids. .
  • the first polypeptide and the second polypeptide are International Patent Publication No. 2019-169120, US Patent Publication No. 9630994, International Patent Publication No. 2021-163481, International Patent Publication No. 2021-163438, or International Application No. It may be a protein disclosed in PCT/US2021/037341.
  • the first polypeptide is a polypeptide consisting of an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 1, and the amino acid sequence of SEQ ID NOs: 5 to 9 (SEQ ID NO: 7 of International Patent Publication No. 2019-169120, Corresponding to the amino acid sequence of 29, 30, 31 or 39) may be a polypeptide consisting of.
  • the second polypeptide is a polypeptide consisting of an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of SEQ ID NOs: 10 to 17 (SEQ ID NOs: 6 and 8 of International Patent Publication No. 2019-169120) , corresponding to the amino acid sequence of 10, 27, 28, 32, 33 or 38).
  • the RBD nanoparticles may be formed by self-assembly of a trimer of the first polypeptide and a pentamer of the second polypeptide.
  • the RBD nanoparticles of the present invention include (i) 20 trimers of the first polypeptide (Component A) and (ii) 12 pentamers of the second polypeptide (Component B) can have a structure.
  • the multimeric protein assembly of the present invention includes 60 copies of the first polypeptide (Component A) and 60 copies of the second polypeptide (Component B).
  • the RBD nanoparticles of the present invention may have an icosahedral symmetrical structure.
  • the RBD nanoparticles of the present invention have a diameter of about 30 nm to about 70 nm, and in this case, the lumen may be about 15 nm to about 32 nm horizontally.
  • the cell line producing the first polypeptide monomer may be a cell line having an expression vector containing a gene encoding a protein represented by the amino acid sequence represented by SEQ ID NO: 1.
  • the expression vector may be a plasmid vector, but any vector suitable for expressing the first polypeptide monomer in a cell line may be used without limitation.
  • the cell line producing the second polypeptide monomer may be a cell line having an expression vector containing a gene encoding a protein represented by the amino acid sequence represented by SEQ ID NO: 2.
  • the expression vector may be a pET-based vector, for example, a pET29b+ vector, but any vector suitable for expressing the second polypeptide monomer in a cell line may be used without limitation.
  • an expression vector containing a gene encoding a protein represented by the amino acid sequence represented by SEQ ID NO: 1 in the present invention may have a DNA sequence represented by SEQ ID NO: 18.
  • an expression vector containing a gene encoding a protein represented by the amino acid sequence represented by SEQ ID NO: 2 in the present invention may have a DNA sequence represented by SEQ ID NO: 19.
  • amino acid sequence or nucleotide sequence used in the present invention includes sequences showing substantial identity to the sequences described in the sequence listing.
  • substantially identity is 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, It is a sequence having 98% or 99% or more homology, and amino acid sequences or base sequences within these homology ranges are also construed to be included in the scope of the present invention.
  • vector refers to a nucleic acid means comprising a nucleotide sequence that can be introduced into a host cell and recombined and inserted into the genome of the host cell, or can be spontaneously replicated as an episome.
  • Suitable expression vectors include expression control elements such as promoters, initiation codons, stop codons, polyadenylation signals and enhancers, as well as signal sequences or leader sequences for membrane targeting or secretion, and can be prepared in various ways depending on the purpose. . When a genetic construct encoding a target protein is administered, the initiation codon and stop codon must be functional in the subject and must be in frame with the coding sequence.
  • the polynucleotide or vector according to one embodiment of the present invention is an independent molecule outside the genome, specifically a molecule capable of replicating, and may exist in a genetically modified host cell or non-human host organism, or may be present in a host cell or non-human host cell. -Can be stably integrated into the genome of human host organisms.
  • the host cell of the cell line producing the first polypeptide monomer according to one embodiment of the present invention is a eukaryotic cell.
  • the eukaryotic cells include fungus cells, plant cells or animal cells. Examples of the fungal cell may be yeast, specifically yeast of the genus Saccharomyces (Saccharomyces sp.), more specifically S. cerevisiae.
  • animal cells include insect cells or mammalian cells, and specific examples of animal cells include HEK293, 293T, NSO, Chinese hamster ovary cells (CHO), MDCK, U2-OSHela, NIH3T3, MOLT-4, Jurkat, PC-12, PC-3, IMR, NT2N, Sk-n-sh, CaSki, C33A, etc.
  • suitable cell lines well known in the art can be obtained from cell line depositories such as the American Type Culture Collection (ATCC).
  • ATCC American Type Culture Collection
  • the host cell of the cell line producing the first polypeptide monomer may be a Chinese Hamster Ovary (CHO) cell, preferably a recombinant Adeno-Associated Virus (rAAV) HD-BIOP3 GS null CHO-K1 cells in which Exon 6 of the Glutamine Synthetase gene was knocked out by the method can be used.
  • CHO Chinese Hamster Ovary
  • rAAV recombinant Adeno-Associated Virus
  • any method for introducing nucleic acid into the cell may be used, and techniques known in the art may be used depending on the host cell.
  • methods known in the art may be used depending on the host cell.
  • the vaccine composition of the present invention may include a pharmaceutically acceptable carrier together with the RBD nanoparticles.
  • pharmaceutically acceptable carrier refers to any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof. Except that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
  • the vaccine composition of the present invention may include a buffer, a stabilizer, an adsorbent (immunity enhancer) and a solvent in addition to RBD nanoparticles as a main component.
  • a buffer a stabilizer
  • an adsorbent immunophilic adsorbent
  • a solvent in addition to RBD nanoparticles as a main component.
  • Sodium chloride and tromethamine can be used as a buffer
  • L-arginine and sucrose sucrose or sucrose
  • aluminum hydroxide can be used as an adsorbent (immune enhancer).
  • the "immune enhancer" used in the present invention is a substance that non-specifically promotes an immune response to an antigen during the initial activation of immune cells, and the vaccine composition of the present invention is administered together with RBD nanoparticles to enhance the immune response.
  • the immunostimulant may be selected from the group consisting of aluminum phosphate, aluminum sulfate and aluminum hydroxide, and may be aluminum hydroxide (aluminum hydroxide).
  • the vaccine composition may further include aluminum hydroxide, and the aluminum hydroxide may be provided in a pre-mixed state in a drug product.
  • the adjuvant is aluminum hydroxide
  • 750 parts by weight of aluminum hydroxide may be included with respect to 5 parts by weight to 40 parts by weight of the RBD nanoparticles, and 6 to 38 parts by weight and 7 to 36 parts by weight of the RBD nanoparticles. 8 parts by weight to 34 parts by weight, 9 parts by weight to 32 parts by weight, 9 parts by weight to 30 parts by weight, 10 parts by weight to 28 parts by weight, 10 parts by weight to 26 parts by weight, 10 parts by weight to 25 parts by weight
  • For the aluminum hydroxide may be included in 750 parts by weight.
  • aluminum hydroxide is 1000 ⁇ g to 2000 ⁇ g, 1100 ⁇ g to 1900 ⁇ g, 1150 ⁇ g to 1850 ⁇ g, 1200 ⁇ g to 1800 ⁇ g, 1250 ⁇ g to 1750 ⁇ g, 1300 ⁇ g to 1700 ⁇ g, 1350 ⁇ g to 1650 ⁇ g, 1400 ⁇ g to 1600 ⁇ g, 1450 ⁇ g to 1600 ⁇ g, and 1400 ⁇ g to 16 00 ⁇ g can be included as If the aluminum hydroxide is included in less than 1000 ⁇ g, immune activity may be reduced, and if it is included in excess of 2000 ⁇ g, there is a problem in that the possibility of side effects increases.
  • the term "buffer” refers to an agent that serves to maintain the pH of a solution so that the pH does not change rapidly in the solution to which it is added. Buffers applicable to the present invention may include at least one of sodium chloride and tromethamine (Tris). In addition, in addition to sodium chloride and tromethamine, any buffer capable of maintaining pH in a solution can be applied without limitation to the present invention.
  • the buffer may be a phosphate buffer such as sodium phosphate or potassium phosphate, HEPES (2-[4-(2-hydroxyethyl)piperazin-1-yl]ethane-1-sulfonic acid), histidine or citrate buffer. can include
  • the buffer is sodium chloride
  • it may be included in 1 mg to 20 mg, 2 mg to 19 mg, 3 mg for two doses (1 ml) of the RBD nanoparticles, that is, 20 ⁇ g or 50 ⁇ g of the RBD nanoparticles. to 18 mg, 4 mg to 17 mg, 5 mg to 16 mg, 6 mg to 15 mg, 7 mg to 14 mg, 8 mg to 13 mg, 1 mg to 12 mg, 8 mg to 11 mg, 8 mg to 10 mg, 8 mg to 9 mg, and 7 mg to 8.5 mg, for example, 8 mg to 9 mg, 7 mg to 8.5 mg, and 7.5 mg to 8.5 mg.
  • sodium chloride is included within the above range, the stability and homogeneity of the antigenic protein are increased, effectively inducing IgG antibodies and neutralizing antibodies, and the resulting SARS-coronavirus-2 infection prevention effect was confirmed (Example 1).
  • the buffer when it may be included in 0.1 mg to 10 mg, 0.5 mg to 9.5 mg, for 2 doses (1 ml) of the RBD nanoparticles, that is, 20 ⁇ g or 50 ⁇ g of the RBD nanoparticles, 1 mg to 9 mg, 1.5 mg to 8.5 mg, 2 mg to 8 mg, 2.5 mg to 7.5 mg, 3 mg to 7 mg, 3.5 mg to 6.5 mg, 4 mg to 6 mg, 4.5 mg to 6 mg, 5 mg to It may be included in 6 mg, 5.5 mg to 6 mg, for example, 4 mg to 6 mg, 5 mg to 6 mg.
  • stabilizer used in the present invention refers to an agent that allows a poorly soluble immunoactive substance to be easily and reproducibly dispersed in an aqueous solution without a surfactant.
  • Buffers applicable to the present invention may include at least one of L-arginine and sucrose.
  • any stabilizer capable of dispersing poorly soluble immunoactivating substances in an aqueous solution can be applied without limitation to the present invention.
  • the stabilizer may include an amine group in a molecule such as L-lysine or L-histidine and a basic amino acid having alkaline properties, and may include glucose, lactose, maltose, trehalose, sorbitol, mannitol, and combinations thereof. It may contain one or more sugars selected from.
  • the stabilizer is L-arginine
  • it may be included in 8 mg to 24 mg for two doses (1 ml) of the RBD nanoparticles, that is, 20 ⁇ g or 50 ⁇ g of the RBD nanoparticles, 9 mg to 23 mg, 10 mg to 22 mg, 11 mg to 21 mg, 12 mg to 20 mg, 13 mg to 19 mg, 14 mg to 18 mg, 15 mg to 17 mg, 16 mg to 17 mg, for example, 14 mg to 17 mg, 15 mg to 17 mg.
  • L-arginine is included within the above range, the stability and homogeneity of the antigenic protein are increased, effectively inducing IgG antibodies and neutralizing antibodies, and the resulting SARS-coronavirus-2 infection prevention effect was confirmed (Example 1).
  • the stabilizer when the stabilizer is sucrose, it may be included in 35 mg to 55 mg, 36 mg to 54 mg, 37 mg for two doses (1 ml) of the RBD nanoparticles, that is, 20 ⁇ g or 50 ⁇ g of the RBD nanoparticles. to 53 mg, 38 mg to 52 mg, 39 mg to 51 mg, 40 mg to 50 mg, 41 mg to 49 mg, 42 mg to 48 mg, 43 mg to 47 mg, 44 mg to 47 mg, For example, 40 mg to 50 mg, 44 mg to 47 mg, and 45 mg to 47 mg may be included.
  • sucrose is included within the above range, the stability and homogeneity of the antigenic protein are increased, effectively inducing IgG antibodies and neutralizing antibodies, and the resulting SARS-coronavirus-2 infection prevention effect was confirmed (Example 1).
  • the vaccine composition contains 1000 ⁇ g to 2000 ⁇ g of aluminum hydroxide for two doses (1 ml) of the RBD nanoparticles, that is, 20 ⁇ g or 50 ⁇ g of the RBD nanoparticles, and sodium chloride 1 mg to 20 mg of this, 0.1 mg to 10 mg of tromethamine, 8 mg to 24 mg of L-arginine, and 35 mg to 55 mg of sucrose.
  • SARS-coronavirus-2 infection includes not only infection with SARS-coronavirus-2 itself, but also various symptoms (eg, respiratory disease, pneumonia, etc.) resulting from infection with the virus.
  • prevention used in the present invention refers to any action that suppresses or delays the onset of SARS-coronavirus-2 infection by administration of a vaccine composition.
  • the vaccine composition of the present invention contains an immunologically effective amount of RBD nanoparticles.
  • Immunologically effective amount means that administration of said amount to a subject as a single dose or as part of a series of doses is effective for prophylaxis. Such amount may depend on the health and physical condition of the individual being treated, the age of the individual being treated, the taxonomic population (eg, non-human primates, primates, etc.), the ability of the individual's immune system to synthesize antibodies, the degree of protection desired, the vaccine formulation, assessment of the medical condition of the treating physician, and other relevant factors. It is expected that these amounts will fall within a relatively wide range and can be determined through routine testing. Dosage treatment can be a single dose schedule or a multiple dose schedule (eg, including booster doses). The composition may be administered with other immunomodulatory agents.
  • the vaccine composition contains 5 ⁇ g to 40 ⁇ g, 6 ⁇ g to 38 ⁇ g, 7 ⁇ g to 36 ⁇ g, 8 ⁇ g to 34 ⁇ g, 9 ⁇ g to 32 ⁇ g, 9 ⁇ g to 30 ⁇ g to 30 ⁇ g of the RBD nanoparticles as an antigen per dose.
  • the stability and homogeneity of the antigenic protein are increased to effectively induce IgG antibodies and neutralizing antibodies, thereby providing excellent SARS-coronavirus-2 infection prevention effect confirmed (Example 1).
  • Excessive immune response may occur at doses higher than the corresponding dose. Less than the corresponding dose may exhibit insignificant immunogenicity.
  • RBD nanoparticles were described as the weight of recombinant COVID-19 surface antigen protein (RBD) rather than the total weight of RBD nanoparticles (see [Table 3]).
  • the recombinant Corona-19 surface antigen protein (RBD) corresponds to 37% of the RBD nanoparticle weight.
  • the RBD weight is 20ug
  • the total weight of RBD nanoparticles is 135ug
  • the RBD weight is 50ug.
  • Those skilled in the art can easily convert the RBD weight from the RBD nanoparticle weight and the RBD nanoparticle weight from the RBD weight.
  • a single dose of the RBD nanoparticles can be formulated in 0.5 ml.
  • the number of administrations of the vaccine composition is one or more times, preferably twice, and the second inoculation may be performed 4 to 8 weeks after the first inoculation.
  • the vaccine composition may be administered as a booster vaccine.
  • Booster refers to the second antigen stimulation inoculated after the first antigen stimulation during vaccination with a vaccine, and when antibodies are produced, a faster and higher antibody production rate is achieved by the second antigen stimulation compared to the reaction that appears after the first antigen stimulation.
  • the "booster vaccine” is inoculated after the first or second inoculation of the vaccine composition, and may correspond to, for example, the third inoculation, but is not limited thereto, and the immune enhancing effect after the first inoculation It means broadly the inoculation that can be expressed.
  • Vaccination schedules including primary inoculations and booster inoculations, may continue over the course of days, weeks, or years, as needed. Due to the vaccination schedule, vaccines are administered at the highest frequency at the beginning of the vaccine regimen, and for booster effects, the administration of booster vaccines can be gradually reduced in frequency.
  • the vaccine composition may include one or more doses of the booster vaccine, and may include one, two, three, four or five or more doses.
  • the vaccine composition of the present invention can be used to prevent SARS-coronavirus-2 infection in a subject.
  • subject refers to an animal.
  • An animal may be a mammal.
  • Mammal refers to, for example, a primate (eg, human, male or female, infant), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. can
  • the subject for administration of the booster vaccine may be a subject who has been previously administered and / or administered a vaccine composition for preventing or treating SARS-CoV-2 infection once or twice.
  • the vaccine composition may be a vaccine composition according to the present invention, but is not limited thereto.
  • the vaccine composition of the present invention can be prepared in a variety of forms.
  • the composition may be prepared for injectability as a liquid solution or suspension. Solid forms suitable for solution or suspension in liquid vehicles prior to injection may also be prepared.
  • the composition may be prepared for topical administration, for example as an ointment, cream or powder.
  • the composition may be prepared for oral administration, for example as a tablet or capsule, or as a syrup (optionally flavored syrup).
  • the composition may be prepared for pulmonary administration using a fine powder or spray, eg as an inhaler.
  • the composition may be prepared as a suppository or pessary.
  • the composition may be prepared for nasal, otic or ocular administration, for example as drops, sprays or powders.
  • the composition may be included in a hydration agent.
  • the composition may be lyophilized.
  • the vaccine composition of the present invention may be administered through intradermal, intramuscular, intraperitoneal, intravenous, intranasal, epidural or other appropriate routes, and may be prepared for intramuscular injection and administered through the intramuscular route.
  • composition of the present invention may include one selected from the group consisting of 2-phenoxyethanol, formaldehyde, and mixtures thereof as a preservative, and may include 2-phenoxyethanol.
  • Another aspect of the present invention is a first polypeptide monomer comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 75% identity thereto, a trimer in which three are assembled; and an RBD nanoparticle comprising a pentamer assembled of 5 second polypeptide monomers comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 75% identity thereto, and an immune enhancer.
  • a vaccine composition for preventing or treating coronavirus-2 infection and a kit for preventing or treating SARS-coronavirus-2 infection including instructions for use are provided.
  • the immune enhancer may include aluminum hydroxide.
  • the description of the immune enhancer and the content of aluminum hydroxide are described in the description of "1. Vaccine composition for preventing or treating SARS-coronavirus-2 infection", so detailed descriptions are omitted.
  • the vaccine composition may further include a buffer and a stabilizer.
  • buffers and stabilizers are described in the description of "1. Vaccine composition for preventing or treating SARS-CoV-2 infection", so detailed descriptions are omitted.
  • Vaccine booster composition for preventing or treating SARS-CoV-2 infection
  • Another aspect of the present invention is a first polypeptide monomer comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 75% identity thereto, a trimer in which three are assembled; and an RBD (Receptor Binding Domain) nanoparticle comprising a pentamer in which five second polypeptide monomers comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 75% identity thereto, and an immune enhancer It provides a vaccine booster composition for preventing or treating SARS-coronavirus-2 infection comprising a.
  • RBD Receptor Binding Domain
  • RBD nanoparticles The description and dosage of the RBD nanoparticles are described in the description of "1. Vaccine composition for preventing or treating SARS-coronavirus-2 infection", so detailed descriptions are omitted.
  • the immune enhancer may include aluminum hydroxide.
  • the description of the immune enhancer and the content of aluminum hydroxide are described in the description of "1. Vaccine composition for preventing or treating SARS-coronavirus-2 infection", so detailed descriptions are omitted.
  • the vaccine composition may further include a buffer and a stabilizer.
  • buffers and stabilizers are described in the description of "1. Vaccine composition for preventing or treating SARS-CoV-2 infection", so detailed descriptions are omitted.
  • vaccine booster composition means a primer vaccine, that is, a composition capable of enhancing, extending or maintaining the therapeutic effect of a previously administered vaccine, and is required at regular intervals after primer vaccination. It is a composition that can be administered according to.
  • the booster composition may be administered at least one month after inoculation of a primer vaccine composition for preventing or treating SARS-coronavirus-2 infection, and may be additionally inoculated at least every month.
  • boosters may be administered at 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 3 months, 6 months
  • Booster doses may be given at 12 months, 9 months, and 12 months.
  • the interval between administration of the primer vaccine composition and the booster composition of the present invention may be 1 to 3 weeks, 13 to 18 months, and 2 to 20 years.
  • the vaccination schedule may continue over the course of days, weeks, or years, as needed. Due to the vaccination schedule, vaccines are administered at the highest frequency at the beginning of the vaccine regimen, and for booster effects, the administration of booster vaccines can be gradually reduced in frequency.
  • the administration may be performed one or more times, and additional administration may be performed several times, if necessary. For example, it may be administered 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times.
  • the primer vaccine for preventing or treating SARS-CoV-2 infection may be the "1. Vaccine composition for preventing or treating SARS-CoV-2 infection", and a vaccine for preventing or treating SARS-Coronavirus-2 infection. If it can be applied without limitation to the present invention.
  • a subject to be inoculated with the vaccine booster composition, a vaccine booster composition preparation method, an administration route, and a preservative included in the vaccine booster composition are the explanatory part of "1.
  • Vaccine composition for preventing or treating SARS-CoV-2 infection It is the same as that described in , so the description is omitted.
  • Vaccine booster composition kit for preventing or treating SARS-CoV-2 infection
  • vaccine composition for preventing or treating SARS-coronavirus-2 infection
  • vaccine booster composition for preventing or treating SARS-coronavirus-2 infection
  • SARS -Prov ides a vaccine booster composition kit for preventing or treating coronavirus-2 infection.
  • the vaccine composition may include doses required for the first or second inoculation, preferably the first and second inoculations, and the vaccine booster composition may include the doses required for the second or more, preferably the third inoculation, Furthermore, in order to enhance immunogenicity against SARS-coronavirus-2, more additional doses may be optionally included.
  • Another aspect of the present invention is a first polypeptide monomer comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 75% identity thereto, a trimer in which three are assembled; and an RBD (Receptor Binding Domain) nanoparticle comprising a pentamer in which five second polypeptide monomers comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 75% identity thereto, and an immune enhancer
  • a method for preventing or treating SARS-coronavirus-2 infection in a subject comprising administering to a subject in need of prevention or treatment of SARS-coronavirus-2 infection.
  • the method for preventing or treating SARS-coronavirus-2 infection in the subject may include the step of administering a "vaccine booster composition".
  • vaccine composition for preventing or treating SARS-coronavirus-2 infection
  • vaccine booster composition for preventing or treating SARS-coronavirus-2 infection
  • Another aspect of the present invention is a first polypeptide monomer comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 75% identity thereto, a trimer in which three are assembled; and an RBD (Receptor Binding Domain) nanoparticle comprising a pentamer in which five second polypeptide monomers comprising the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 75% identity thereto, and an immune enhancer It provides a use for preventing or treating SARS-coronavirus-2 infection of a vaccine composition or vaccine booster composition comprising a.
  • RBD Receptor Binding Domain
  • vaccine composition for preventing or treating SARS-coronavirus-2 infection
  • vaccine booster composition for preventing or treating SARS-coronavirus-2 infection
  • the trimer glycoprotein on the surface of the SARS-CoV-2 virus is also called spike glycoprotein, and the receptor binding domain (RBD) at the top of the trimer glycoprotein binds to the ACE2 receptor protein on the surface of human cells. By combining, they cause infection.
  • the RBD is combined with nanoparticles to produce RBD nanoparticles.
  • the RBD nanoparticles are formed by self-assembly of 20 RBD-Component A and 12 Component B.
  • the RBD-Component A is a trimer in which three RBD-I53-50A monomers having the amino acid sequence represented by SEQ ID NO: 1 are assembled, and the RBD-I53-50A monomer is the RBD of SARS-CoV-2 spike glycoprotein, nano It consists of I53-50A, which serves as a particle structure, and a linker (GGSGGSGSGGSGGSGSEKAAKAEEAAR) connecting RBD and I53-50A.
  • the component B is a pentamer of I53-50B having an amino acid sequence represented by SEQ ID NO: 2.
  • a CHO cell line (Stable cell line) was used for RBD-Component A protein production, and an E. coli cell line was used for Component B protein production.
  • RBD-Component A protein production RBD-Component A protein production
  • E. coli cell line E. coli cell line
  • RBD-Component A used as an antigen for SARS-CoV-2 vaccine
  • the HD-BIOP3 cell line distributed from HORIZON Discovery, UK was used as a host cell.
  • RBD-Component A cDNA N-SARS-CoV-2RBD-I53-50A-16GS-he
  • SEQ ID NO: 18 Information on the location and function of key genes in the recombinant expression vector plasmid (M-2560) is summarized in Table 1.
  • the CHO cell line-derived Component A intermediate stock solution was obtained by conventional protein expression and purification methods.
  • 100% of the peptide coverage was secured and mutual equivalence to the expected peptide sequence was confirmed, confirming that the intermediate stock solution was the desired Component A protein.
  • Component B protein E. coli BL21 strain distributed by Thermofisher was used.
  • pET29b+ was used as a vector for expressing Component B protein.
  • an I53-50B vector with a total sequence of 5.7 kb (vector: 5.4 kb) is produced.
  • the vector is composed of a kanamycin resistance gene, a Lac operon whose transcription is induced by lactose and its derivatives, a T7 promoter region derived from lambda phage, and a multiple cloning site. there is.
  • the multicloning site has several restriction enzyme sequences, so it is a site that plays a major role in the introduction of antigenic proteins.
  • the I53-50B vector has a DNA sequence represented by SEQ ID NO: 19.
  • the main gene information in the I53-50B vector is shown in Table 2 below.
  • E. coli-derived Component B intermediate stock solutions were obtained by conventional protein expression and purification methods. It was confirmed that the amino acid sequence of the Component B intermediate stock solution was 100% consistent with the theoretical amino acid sequence.
  • a recombinant RBD nanoparticle stock solution (drug substance) was prepared through an assembly process using the prepared Component A intermediate stock solution and Component B intermediate stock solution.
  • Component A stock solution and Component B were mixed and assembled so that the reaction ratio was 1:1.1 on a molar basis.
  • the reaction conditions were room temperature, 1 hour, reaction at a stirring speed of 80 rpm, and when the reaction was completed, the reaction solution was filtered through a 0.2 ⁇ m filter.
  • the filtered assembly reaction solution was concentrated (Ultrafiltration) to 4 kg using a tangential flow filtration system equipped with a 300 kDa MWCO (Molecular weight cut-off) membrane with an area of 0.7 m2, It was recovered by carrying out buffer exchange (Diafiltration) using mM Tris buffer. At this time, the transmembrane pressure (TMP) was maintained at 1 bar or less.
  • the ultrafiltration recovered liquid was filtered through a 0.2 ⁇ m filter and stored in a cryogenic freezer below -70°C.
  • the recombinant RBD nanoparticle stock solution is a particle-type molecule formed by combining the Component A intermediate stock solution and the Component B intermediate stock solution. Molecules in the form of these particles are computer-designed to form molecules of a certain size when appropriate bonding occurs.
  • a commonly used method is a dynamic light scattering method, which measures the molecular size of nanoparticles formed through this method to confirm whether an appropriate structure has been formed.
  • a final stock solution was prepared through a formulation process.
  • aluminum hydroxide was used as an immune enhancer.
  • Aluminum hydroxide was pre-mixed into the final stock solution.
  • the final stock solution was named RBD nanoparticle alum formulation.
  • Vaccination studies included two intramuscular injections of saline placebo (0.5 mL) or RBD nanoparticle alum formulation (RBD 10 ⁇ g or 25 ⁇ g, total injection volume 0.5 mL). 0.5 mL was withdrawn from a vial containing about 0.65 mL of the RBD nanoparticle alum formulation or a 20 mL ampoule of physiological saline. The remaining volume in the vial or ampoule was discarded. This vaccine study was injected into the deltoid muscle of the upper arm every 28 days on day 0 and day 28.
  • Table 5 shows test subjects of alum formulations.
  • the assigned group intention-to-treat set, ITT group
  • safety group safety set
  • all analysis subjects full analysis set, FA group
  • protocol-compliant clinical trial subject group per protocol set, PP group
  • the analysis population refers to a group of subjects included in statistical analysis among subjects participating in a clinical trial.
  • Geometric mean titer is a method of calculating the mean antibody titer for a population of subjects by multiplying all values and taking the nth root of this number, where n is the number of subjects for whom data are available. way.
  • Geometric Mean Fold Rise represents the increase in the geometric mean concentration or geometric mean titer after vaccination compared to the baseline before vaccination.
  • CI 95% confidence interval
  • the GMT of the IgG antibody significantly increased compared to the baseline.
  • the GMT increased significantly compared to the baseline 2 weeks after the second inoculation, and the increased GMT was maintained even after 4 weeks after the second inoculation.
  • the above level is a significantly higher level of antibody compared to the sera of convalescent patients (WHO Reference Panel, First WHO International Reference Panel for anti-SARS-CoV-2 immunoglubulin, NIBSC code: 20/268) of the National Institute of Biomedicine (NIBSC) in the UK.
  • NIBSC National Institute of Biomedicine
  • the second administration of the RBD nanoparticle alum formulation increases the GMT of the IgG antibody, so that the RBD nanoparticle alum formulation can be usefully used as an active ingredient in a vaccine composition for preventing or treating SARS-CoV-2 infection.
  • Table 7 shows the geometric mean titers and seroconversion rates of neutralizing antibodies for the low-content RBD nanoparticle alum formulation and the high-content RBD nanoparticle alum formulation.
  • Neutralizing antibodies are important indicators for confirming immunogenicity because neutralizing antibodies bind to viruses and neutralize them from penetrating into cells.
  • RBD nanoparticle alum formulation 10 ⁇ g (N 18)
  • RBD nanoparticle alum formulation 25 ⁇ g (N 20)
  • Placebo (N 19)
  • the GMT of the neutralizing antibody was significantly increased compared to the baseline.
  • the vaccine composition of the present invention increased the GMT of neutralizing antibodies to 530.90 ⁇ 2.70 and 708.50 ⁇ 2.83 (IU/ml) at 6 weeks after vaccination when 10 ⁇ g or 25 ⁇ g of RBD nanoparticles were inoculated, compared to the effects of conventional vaccines. .
  • the second administration of the RBD nanoparticle alum formulation increases the GMT of neutralizing antibodies, so that the RBD nanoparticle alum formulation can be usefully used as an active ingredient in a vaccine composition for preventing or treating SARS-CoV-2 infection.

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Abstract

La présente invention concerne une composition vaccinale pour la prévention ou le traitement d'une infection par le SARS-Coronavirus-2, comprenant : des nanoparticules RBD (« receptor binding domain », domaine de liaison au récepteur) comprenant un trimère et un pentamère, le trimère étant formé par assemblage de trois premiers monomères polypeptidiques comprenant la séquence d'acides aminés de SEQ ID No : 1, ou une séquence d'acides aminés ayant au moins 75 % d'identité avec celle-ci, et le pentamère étant formé par assemblage de cinq seconds monomères polypeptidiques comprenant la séquence d'acides aminés de SEQ ID No : 2, ou une séquence d'acides aminés ayant au moins 75 % d'identité avec celle-ci ; et un adjuvant. La composition vaccinale, selon la présente invention, présente une excellente immunogénicité lorsqu'elle est inoculée. Ainsi, la composition vaccinale de la présente invention peut être utilisée utilement dans le but de prévenir une infection par le SARS-Coronavirus-2 ou d'atténuer les symptômes lors d'une infection par celui-ci.
PCT/KR2022/017256 2021-11-04 2022-11-04 Composition vaccinale pour la prévention ou le traitement d'une infection par le sars-coronavirus-2 WO2023080718A1 (fr)

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WO2021163438A1 (fr) * 2020-02-14 2021-08-19 University Of Washington Polypeptides, compositions et leur utilisation pour traiter ou limiter le développement d'une infection
KR20210108331A (ko) * 2020-02-25 2021-09-02 (주)지뉴인텍 코로나바이러스감염증-19(covid-19)에 대한 재조합 아데노바이러스 백신 및 이를 이용한 병용요법

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YANG JINGYUN; WANG WEI; CHEN ZIMIN; LU SHUAIYAO; YANG FANLI; BI ZHENFEI; BAO LINLIN; MO FEI; LI XUE; HUANG YONG; HONG WEIQI; YANG : "A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity", NATURE, NATURE PUBLISHING GROUP UK, LONDON, vol. 586, no. 7830, 1 January 1900 (1900-01-01), London, pages 572 - 577, XP037341143, ISSN: 0028-0836, DOI: 10.1038/s41586-020-2599-8 *

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