Mutant-based coronavirus vaccine

Abstract

The present disclosure provides coronavirus mRNA vaccines, including vaccines against one or more mutated strains of SARS-CoV-2, and methods of using the vaccines.

Claims

1. A vaccine comprising messenger ribonucleic acid (mRNA) formulated within lipid nanoparticles, wherein the mRNA comprises an open reading frame encoding a fusion protein comprising the N-terminal domain (NTD) of the SARS-CoV-2 spike (S) protein linked to the receptor-binding motif (RBM) of the SARS-CoV-2 spike (S) protein by a first GS linker, and the RBM is linked to a transmembrane domain (TD) by a second GS linker, and the open reading frame The wing frame comprises a nucleoside consisting of N1-methyl-psoiduridine, adenosine, guanosine, and cytidine; the fusion protein has one or more of the following amino acid mutations relative to SEQ ID NO: G142D, ΔN211, L212I, S373P, S375F, N440K, Q498R, and Y505H; and the lipid nanoparticles comprise ionizable aminolipids, neutral lipids, sterols, and polyethylene glycol (PEG)-modified lipids; and the vaccine.

2. A vaccine comprising messenger ribonucleic acid (mRNA) formulated within lipid nanoparticles, wherein the mRNA comprises an open reading frame encoding a fusion protein comprising the N-terminal domain (NTD) of the SARS-CoV-2S protein linked to the receptor-binding motif (RBM) of the SARS-CoV-2 spike (S) protein by a first GS linker, the RBM being linked to a transmembrane domain (TD) by a second GS linker, the open reading frame comprising a nucleoside consisting of N1-methyl-psoidouridine, adenosine, guanosine, and cytidine, the fusion protein having one or more of the following amino acid mutations in the N-terminal domain relative to SEQ ID NO: G142D, ΔN211, and L212I, and the lipid nanoparticles comprising ionizable aminolipids, neutral lipids, sterols, and polyethylene glycol (PEG)-modified lipids.

3. A vaccine comprising messenger ribonucleic acid (mRNA) formulated within lipid nanoparticles, wherein the mRNA comprises an open reading frame encoding a fusion protein comprising the N-terminal domain (NTD) of the SARS-CoV-2 spike (S) protein linked to the receptor-binding motif (RBM) of the SARS-CoV-2 spike (S) protein by a first GS linker, and the RBM is linked to a transmembrane domain (TD) by a second GS linker, and the open reading frame The fusion protein comprises a nucleoside consisting of N1-methyl-psoiduridine, adenosine, guanosine, and cytidine, and the fusion protein has one or more of the following amino acid mutations in the receptor-binding domain (RBD) relative to SEQ ID NO: S373P, S375F, N440K, Q498R, and Y505H, and the lipid nanoparticles comprise ionizable aminolipids, neutral lipids, sterols, and polyethylene glycol (PEG)-modified lipids, in a vaccine.

4. The vaccine according to any one of claims 1 to 3, wherein the TD is an influenza hemagglutinin transmembrane domain.

5. The vaccine according to any one of claims 1 to 4, wherein the fusion protein is an NTD-RBM-TD fusion protein.

6. The vaccine according to any one of claims 1 to 5, wherein the RBM binds to the ACE2 receptor.

7. The vaccine according to any one of claims 1 to 6, wherein the lipid nanoparticles comprise an ionizable amino lipid in a molar ratio of 40 to 55 mol%, a neutral lipid in a ratio of 5 to 15 mol%, a sterol in a ratio of 30 to 45 mol%, and a polyethylene glycol (PEG) modified lipid in a ratio of 1 to 5 mol%.

8. The ionizable amino lipid is defined by formula (I): 【Chemistry 1】 (In the formula, R １ C ５～３０ Alkyl, C ５～２０ Selected from the group consisting of alkenyls and -R''M'R'; R ２ and R ３ C １～１４ Alkyl and C ２～１４ Independently selected from the group consisting of alkenils; R ４ is -(CH ２ ), ｎ where Q is -OR, and n is selected from 1, 2, 3, 4, and 5; R ５ H is; R ６ H is; M and M' are selected independently from -C(O)O- and -OC(O)-; R ７ H is; R is H; R' is C １～１８ Alkyl and C ２～１８ Selected from a group consisting of alkenils; R is C ３～１４ Alkyl and C ３～１４ Selected from the group consisting of alkenils; and m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13. The vaccine according to claim 7, comprising the compound.

9. The ionizable aminolipid has the following structure: 【Chemistry 2】 The vaccine according to claim 7 or 8, comprising a compound having the following properties.

10. The vaccine according to any one of claims 1 to 9, wherein the fusion protein comprises a receptor-binding domain (RBD) containing the RBM.

11. A composition for use in a method for inducing an antigen-specific immune response in a subject, comprising the vaccine according to any one of claims 1 to 10, wherein the method comprises administering the mRNA vaccine to the subject in an amount effective to produce the antigen-specific immune response.

12. A composition for use in the prevention of SARS-CoV-2 infection, comprising the vaccine according to any one of claims 1 to 10.

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