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JP-7854660-B2 - Multiple antigen peptides against coronavirus and immunostimulatory compositions containing the same

JP7854660B2JP 7854660 B2JP7854660 B2JP 7854660B2JP-7854660-B2

Inventors

  • 増田 健一
  • 齊藤 隆

Assignees

  • 国立研究開発法人理化学研究所
  • 動物アレルギー検査株式会社

Dates

Publication Date
20260507
Application Date
20210521
Priority Date
20200522

Claims (20)

  1. A multi-antigen peptide comprising four to eight peptides consisting of a continuous 11-amino acid sequence of amino acids corresponding to the amino acid sequence described in Sequence ID No. 1, or a peptide consisting of a 11-amino acid sequence of the coronavirus spike protein corresponding to the 11- amino acid sequence, and having antibody-inducing ability against said peptide , wherein the multi-antigen peptide comprises a dendritic polymer backbone and one of the peptides, the peptide being linked to the terminal end of the dendritic polymer backbone .
  2. The multi-antigen peptide according to claim 1, wherein the 11-amino acid sequence of the coronavirus spike protein corresponding to the 11-amino acid sequence has a one-amino acid substitution with respect to the amino acid sequence described in SEQ ID NO: 1.
  3. The multi-antigen peptide according to claim 1 or 2, wherein the 11-amino acid sequence of the coronavirus spike protein corresponding to the 11-amino acid sequence is the amino acid sequence described in SEQ ID NO: 7.
  4. The multi-antigen peptide according to claim 2 or 3, wherein the 11-amino acid sequence of the coronavirus spike protein corresponding to the 11-amino acid sequence is a peptide consisting of the amino acid sequence described in SEQ ID NO: 2.
  5. The multi-antigen peptide according to claim 2 or 3, wherein the 11-amino acid sequence of the coronavirus spike protein corresponding to the 11-amino acid sequence is a peptide consisting of the amino acid sequence described in SEQ ID NO: 8.
  6. The multi-antigen peptide according to claim 1, comprising four or more peptides consisting of a continuous amino acid sequence of 11 amino acids in length, derived from the amino acid sequence described in SEQ ID NO: 1.
  7. The multi-antigen peptide according to claim 6, comprising eight or more 11- amino acid peptides having the amino acid sequence described in any one of claims 1 to 5 or SEQ ID NO: 7.
  8. A multi-antigen peptide according to any one of claims 1 to 7 , wherein a dendritic polymer skeleton and a peptide are linked via a linker.
  9. The multiple antigen peptide according to any one of claims 1 to 8, wherein the dendritic polymer skeleton is composed of lysine, and lysine that forms first-generation branches is peptide-bonded to each of the two amino groups of lysine, and peptides are linked to each of the four amino groups of the lysine that forms the first-generation branches, with or without the linker.
  10. The dendritic polymer skeleton is a lysine molecule, to which lysine molecules forming first-generation branches are peptide-bonded to each of the two amino groups of the lysine molecule, to which lysine molecules forming second-generation branches are peptide-bonded to each of the four amino groups of the resulting first-generation lysine molecule, and to which peptide molecules are linked, with or without a linker, to each of the five, six or more, seven or more, or eight amino groups of the resulting second-generation branching lysine molecule.
  11. A multi-antigen peptide according to any one of claims 6 to 9 , having the following formula (VI): {Here, R is a linker-peptide or a peptide, the peptide is the peptide described in any one of claims 1 to 5, and R2 is hydrogen, an OH group, a substituted or unsubstituted lower alkyl group, an amino group, an amino acid (particularly 3-aminopropanoic acid (β-alanine)), a halogen, or a peptide, the amino acid being linked to the above molecule via an amide bond.}
  12. A vaccine against coronavirus comprising the multi-antigen peptide according to any one of claims 6 to 11 .
  13. The vaccine according to claim 12 , which does not contain an adjuvant.
  14. The vaccine according to claim 12 or 13 , which is used in combination with α-galactosylceramide and not in combination with other adjuvants.
  15. The vaccine according to any one of claims 12 to 14 , wherein the coronavirus is SARS-CoV-2 or a variant virus.
  16. The vaccine according to any one of claims 12 to 14 , wherein the coronavirus is one or more coronaviruses selected from porcine epidemic diarrhea virus (PED), canine coronavirus, and feline infectious peritonitis virus (FIPV).
  17. A pharmaceutical composition comprising a multi-antigen peptide according to any one of claims 1 to 11 .
  18. A pharmaceutical composition according to claim 17 , for use in activating immunity against coronavirus in a target.
  19. A pharmaceutical composition according to claim 17 or 18, for use in inducing antigen-specific immunity against coronavirus in a subject.
  20. A pharmaceutical composition according to any one of claims 17 to 19, for use in inducing antigen-specific IgM antibodies against coronavirus in a target.

Description

This invention relates to a multi-antigen peptide for coronaviruses and an immunostimulatory composition containing the same, particularly to a vaccine for coronaviruses. It has long been known that antibody levels can be increased in vivo without the involvement of T cells by multiple antigen peptides (MAPs) (Non-Patent Document 1). It has been shown that MAPs can induce autoantibodies (anti-IgE antibodies) that are difficult to induce in vivo (Patent Document 1). Furthermore, it has been disclosed that by using this method, a panviral MAP can be created by producing a peptide portion of the Ebola hemorrhagic fever virus, and the target antibody can be induced in the serum of mice by immunizing them (Patent Document 2). Similarly, it has been disclosed that a panviral MAP can be created using a partial peptide of hemagglutinin from the influenza virus, and the target antibody can be induced in the serum of mice by immunizing them (Patent Document 3). US2017-0158738AUS2019-0276495AUS2019-0337989A Saravanan, P. , etc. al. , Acta Virol. , (48) 39-45, 2004 The present invention provides a multi-antigen peptide against coronavirus and an immunostimulatory composition containing the same, particularly a vaccine against coronavirus. According to the present invention, the present invention provides a peptide comprising the amino acid sequence described in SEQ ID NO: 1, or a partial peptide of the coronavirus spike protein comprising an amino acid sequence corresponding to the amino acid sequence of SEQ ID NO: 1 (a peptide comprising the amino acid sequence of the coronavirus spike protein corresponding to an amino acid sequence of 11 to 21 amino acids including the amino acid sequence described in SEQ ID NO: 1), and a multi-antigen peptide comprising any multiple of these peptides. The inventors of this invention found that a multi-antigen peptide (MAP) having a peptide consisting of the amino acid sequence described in SEQ ID NO: 1, or a partial peptide of the coronavirus spike protein consisting of an amino acid sequence corresponding to the amino acid sequence of SEQ ID NO: 1, induced antigen-specific IgM. They also found that this antigen-specific IgM could be maintained in the blood for a long period of time. Furthermore, they revealed that the MAP also induces memory immunity. Moreover, they found that the MAP can directly stimulate antibody production from marginal zone B cells and B1B cells, and induce T cell-independent antibody production. The inventors found that this multi-antigen peptide induces antibody production against a wide range of coronaviruses. Furthermore, in an infection experiment with feline infectious peritonitis virus (FIPV) in cats as an example of a highly pathogenic coronavirus, the inventors found that administering the multi-antigen peptide of this invention early after the onset of symptoms (for example, within 3 days after confirmation of high fever) (in most cases, the initial symptom is high fever) prevented the infection from becoming severe and also had the effect of promoting recovery. This invention provides the following: [1] A peptide consisting of a part of the amino acid sequence described in Sequence ID No. 3, comprising a continuous amino acid sequence of 11 to 21 amino acids in length including the amino acid sequence described in Sequence ID No. 1, or a partial peptide of the coronavirus spike protein consisting of an amino acid sequence corresponding to the 11 to 21 amino acid sequence (or a peptide consisting of the amino acid sequence of the coronavirus spike protein corresponding to the 11 to 21 amino acid sequence). [2] A peptide as described in [1] above, comprising the amino acid sequence described in SEQ ID NO: 1, or a partial peptide of the coronavirus spike protein comprising the amino acid sequence corresponding to the amino acid sequence of SEQ ID NO: 1 (or a peptide comprising the amino acid sequence of the coronavirus spike protein corresponding to the 11-21 amino acid sequence). [3] The peptide according to [2] above, wherein the amino acid sequence corresponding to SEQ ID NO: 1 has one of the following: addition, insertion, substitution, or deletion of one base to the amino acid sequence described in SEQ ID NO: 1. [4] The peptide according to [2] or [3] above, wherein the amino acid sequence corresponding to SEQ ID NO: 1 is a peptide consisting of the amino acid sequence described in SEQ ID NO: 2. [5] A multi-antigen peptide comprising any of the peptides described in [1] to [4] above. [6] The multi-antigen peptide according to [5], comprising four or more peptides having the amino acid sequence described in any of [1] to [4] above or the sequence described in Sequence ID No. 7. [7] A vaccine against coronavirus comprising the multi-antigen peptide described in [6] above. [8] The vaccine described in [7] above, which does not contain an adjuvant. [9] The vaccine described in [6] or [7] above, which is used in combination with α-galactosylceramide a