VARIANT STRAIN-BASED CORONAVIRUS VACCINES
The disclosure provides coronavirus mRNA vaccines, including vaccines directed against one or more variant strains of SARS-CoV-2, as well as methods of using the vaccines.
1 . A nucleic acid encoding a SARS-CoV-2 antigen of a second circulating SARS-CoV-2 virus strain, wherein the antigen has an amino acid sequence with at least one amino acid mutation with respect to an antigen of a first circulating SARS-CoV-2 virus strain, wherein the mutation is an amino acid substitution, deletion or insertion, wherein the antigen is not a full length stabilized spike protein having a 2P mutation and wherein the nucleic acid is in a lipid nanoparticle.
2 . The nucleic acid of claim 1 , wherein the first and second virus strains are in circulation for at least a portion of 1 year.
3 . The nucleic acid of claim 1 , wherein the first and second virus strains are in circulation during the same pandemic period or endemic period.
4 . The nucleic acid of any one of claims 1 - 3 , wherein the SARS-CoV-2 antigen has a second amino acid mutation with respect to the antigen of the first circulating SARS-CoV-2 virus strain, wherein the mutation is an amino acid substitution, deletion or insertion, and the second mutation corresponds to a third virus strain in circulation.
5 . The nucleic acid of any one of claims 1 - 4 , wherein the lipid nanoparticle comprises an ionizable amino lipid, a sterol, a neutral lipid, and a polyethylene glycol (PEG)-modified lipid.
6 . The nucleic acid of claim 5 , wherein the lipid nanoparticle comprises 40-55 mol % ionizable amino lipid, 30-45 mol % sterol, 5-15 mol % neutral lipid, and 1-5 mol % PEG-modified lipid.
7 . The nucleic acid of any one of claims 1 - 6 , wherein the SARS-CoV-2 antigen is a receptor binding domain (RBD) of spike protein.
8 . The nucleic acid of any one of claims 1 - 6 , wherein the SARS-CoV-2 antigen is an N-terminal domain (NTD).
9 . The nucleic acid of any one of claims 1 - 6 , wherein the SARS-CoV-2 antigen is a combination of an RBD and NTD.
10 . The nucleic acid of any one of claims 1 - 6 , wherein the SARS-CoV-2 antigen is an NTD, RBD, and transmembrane domain joined by linkers.
11 . The nucleic acid of claim 10 , wherein the SARS-CoV-2 antigen is an NTD, RBD, and influenza hemagglutinin transmembrane (HATM) domain joined by linkers (NTD-RBD-HATM).
12 . The nucleic acid of any one of claims 1 - 6 , wherein the SARS-CoV-2 antigen is an NTD-RBD fusion.
13 . The nucleic acid of any one of claims 1 - 6 , wherein the SARS-CoV-2 antigen is an S1 protein subunit.
14 . The nucleic acid of any one of claims 1 - 13 , wherein the amino acid mutation in the antigen is associated with a structure or function of the virus that is different in quantity or kind from a corresponding structure or function in the first virus.
15 . The nucleic acid of claim 14 , wherein the function of the amino acid mutation is ACE2 receptor binding, virus transmissibility, viral uptake, viral pathogenesis, altered furin cleavage, or viral replication.
16 . The nucleic acid of any one of claims 1 - 15 , wherein the nucleic acid comprises messenger RNA (mRNA).
17 . A composition comprising:
a first messenger ribonucleic acid (mRNA) encoding a first SARS-CoV-2 antigen of a first SARS-CoV-2 virus and a second mRNA encoding a second SARS-CoV-2 antigen of a second SARS-CoV-2 virus, wherein the second SARS-CoV-2 virus has an amino acid sequence with at least one amino acid mutation with respect to an amino acid sequence of the first SARS-CoV-2 virus, wherein the mutation is an amino acid substitution, deletion or insertion, wherein each of the first and second antigens are not full length stabilized spike proteins having a 2P mutation.
18 . The composition of claim 17 , wherein the first SARS-CoV-2 virus is a first circulating SARS-CoV-2 virus strain, and the second SARS-CoV-2 virus is a second circulating SARS-CoV-2 virus strain, and wherein the first and second virus strains are spreading in the population for at least a portion of 1 year.
19 . The composition of any one of claims 17 - 18 , wherein the mRNAs are present at about a 1:1 ratio relative to each other mRNA in the composition.
20 . The composition of any one of claims 17 - 19 , wherein the mRNAs are in a lipid nanoparticle and wherein the lipid nanoparticle comprises an ionizable amino lipid, a sterol, a neutral lipid, and a polyethylene glycol (PEG)-modified lipid.
21 . The composition of claim 20 , wherein the lipid nanoparticle comprises 40-55 mol % ionizable amino lipid, 30-45 mol % sterol, 5-15 mol % neutral lipid, and 1-5 mol % PEG-modified lipid.
22 . The composition of any one of claims 20 - 21 , wherein the lipid nanoparticle comprises 40-50 mol % ionizable amino lipid, 35-45 mol % sterol, 10-15 mol % neutral lipid, and 2-4 mol % PEG-modified lipid.
23 . The composition of any one of claims 20 - 22 , wherein the lipid nanoparticle comprises 45 mol %, 46 mol %, 47 mol %, 48 mol %, 49 mol %, or 50 mol % ionizable amino lipid.
24 . The composition of any one of claims 20 - 23 , wherein the ionizable amino lipid has the structure of Compound 1:
25 . The composition of any one of claims 20 - 24 , wherein the sterol is cholesterol or a variant thereof.
26 . The composition of any one of claims 20 - 25 , wherein the neutral lipid is 1,2 distearoyl-sn-glycero-3-phosphocholine (DSPC).
27 . The composition of any one of claims 20 - 26 , wherein the PEG-modified lipid is 1,2 dimyristoyl-sn-glycerol, methoxypolyethyleneglycol (PEG2000 DMG).
28 . A method comprising
administering to a subject a second effective dose of a second vaccine comprising a second nucleic acid encoding a second SARS-CoV-2 antigen, wherein the subject has previously been administered a first effective dose of a first vaccine comprising a first nucleic acid encoding a first SARS-CoV-2 antigen,
wherein the second vaccine is administered in an effective amount to induce an immune response specific for the second antigen, wherein the second SARS-CoV-2 antigen has an amino acid sequence with at least one mutation, with respect to a corresponding amino acid sequence of the first SARS-CoV-2 antigen, wherein the mutation is an amino acid substitution, deletion or insertion and wherein each of the first and second antigens are not full length stabilized spike proteins having a 2P mutation.
29 . The method of claim 28 , wherein the first encoded SARS-CoV-2 antigen is of a first circulating SARS-CoV-2 virus and wherein the second encoded SARS-CoV-2 antigen is of a second circulating SARS-CoV-2 virus.
30 . The method of claim 28 , wherein the first encoded SARS-CoV-2 antigen is representative of a first circulating SARS-CoV-2 virus and wherein the second encoded SARS-CoV-2 antigen is representative of a second circulating SARS-CoV-2 virus.
31 . The method of claim 28 , wherein the first encoded SARS-CoV-2 antigen is representative of a plurality of first circulating SARS-CoV-2 viruses and/or wherein the second encoded SARS-CoV-2 antigen is representative of a second plurality of circulating SARS-CoV-2 viruses.
32 . The method of any one of claims 29 - 32 , wherein the second circulating SARS-CoV-2 virus is an immunodominant emerging strain or variant of concern detected during a period when the first circulating SARS-CoV-2 virus is present in a subject population.
33 . The method of any one of claims 29 - 32 , wherein the second circulating SARS-CoV-2 virus and the first circulating SARS-CoV-2 virus are detectable in a subject population within at least one year.
34 . The method of any one of claims 29 - 32 , wherein the second circulating SARS-CoV-2 virus and the first circulating SARS-CoV-2 virus are detectable in a subject population during a same season.
35 . The method of any one of claims 29 - 32 , wherein the second circulating SARS-CoV-2 virus and the first circulating SARS-CoV-2 virus are detectable in a subject population during a same pandemic period or endemic period.
36 . The method of any one of claims 28 - 35 , wherein the first nucleic acid encoding the first SARS-CoV-2 antigen is a DNA or a messenger RNA (mRNA).
37 . The method of any one of claims 28 - 36 , wherein the first nucleic acid encoding a first SARS-CoV-2 antigen is a messenger RNA (mRNA).
38 . The method of any one of claims 28 - 36 wherein the second nucleic acid encoding a second SARS-CoV-2 antigen is a messenger RNA (mRNA).
39 . The method of any one of claims 28 - 38 , wherein the second vaccine further comprises the first nucleic acid encoding a first SARS-CoV-2 antigen.
40 . The method of claim 39 , wherein the first nucleic acid encoding a first SARS-CoV-2 antigen and the second nucleic acid encoding a second SARS-CoV-2 antigen are present in the second vaccine in a 1:1 ratio.
41 . The method of any one of claims 28 - 38 , wherein the first and/or second vaccine is a monovalent vaccine.
42 . The method of any one of claims 28 - 40 , wherein the first and/or second vaccine is a multivalent vaccine, comprising more than one nucleic acids encoding antigens representative of a plurality of variants of concern.
43 . The method of any one of claims 28 - 42 , wherein the first encoded SARS-CoV-2 antigen is administered to the subject as a first vaccine comprised of one or more doses and the second encoded SARS-CoV-2 antigen is administered to the subject as a boost in one or more doses.
44 . The method of any one of claims 28 - 42 , wherein the second encoded SARS-CoV-2 antigen is administered to the subject as first vaccine comprised of one or more doses and the first encoded SARS-CoV-2 antigen is administered to the subject as a boost in one or more doses.
45 . The method of any one of claims 28 - 42 , wherein the first and second encoded SARS-CoV-2 antigens are administered to the subject together as a boost dose, optionally wherein the first and second encoded SARS-CoV-2 antigens are present in the boost dose in a 1:1 ratio.
46 . The method of any one of claims 28 - 42 , wherein the first encoded SARS-CoV-2 antigen is administered to the subject as a prime dose and as a boost dose to complete a vaccination and wherein the second encoded SARS-CoV-2 antigen is administered to the subject as a booster regimen at least 3 months after the first vaccination is complete.
47 . The method of any one of claims 28 - 42 , wherein the first encoded SARS-CoV-2 antigen is administered to the subject as a prime dose and as a boost dose in an initial vaccination and the second encoded SARS-CoV-2 antigen is administered to the subject as a boost dose more than 6 months after the initial vaccination.
48 . The method of any one of claims 46 - 47 , wherein the boost dose is a seasonal boost or a pandemic shift boost to provide protection for a plurality of variants of concern.
49 . A method comprising
administering to a subject a vaccine comprising a first nucleic acid encoding a SARS-CoV-2 antigen of a first SARS-CoV-2 virus, wherein the first SARS-CoV-2 virus is an emerging variant of a primary SARS-CoV-2 virus, wherein the antigen has an amino acid sequence with at least one amino acid mutation with respect to a corresponding protein antigen of the primary SARS-CoV-2 virus, and wherein the mutation is an amino acid substitution, deletion or insertion, and wherein the subject is seropositive for a SARS-CoV-2 antigen of the primary SARS-CoV-2 virus.
50 . A method comprising
administering to a subject a vaccine comprising a first nucleic acid encoding a SARS-CoV-2 antigen of a first SARS-CoV-2 virus, wherein the first SARS-CoV-2 virus is an emerging variant of a primary SARS-CoV-2 virus, wherein the antigen has an amino acid sequence with at least one amino acid mutation with respect to a corresponding protein antigen of the primary SARS-CoV-2 virus, and wherein the mutation is an amino acid substitution, deletion or insertion, and wherein the subject is seronegative for a SARS-CoV-2 antigen of the primary SARS-CoV-2 virus.
51 . The method of claim 49 or 50 , wherein the subject is administered a second dose of the vaccine between 2 weeks and 1 year after the first dose of vaccine is administered.
52 . The method of claim 49 or 50 , wherein the subject is administered a second vaccine between 2 weeks and 1 year after the vaccine is administered, wherein the second vaccine comprises a second nucleic acid encoding the corresponding protein antigen of the primary SARS-CoV-2 virus.
53 . The method of claim 52 , wherein the second vaccine comprises a mixture of the first and second nucleic acids, wherein the first nucleic acid and the second nucleic acid are present in the second vaccine at a ratio of 1:1.
54 . A method comprising
administering to a subject a booster vaccine comprising a nucleic acid encoding a first SARS-CoV-2 antigen from a first SARS-CoV-2 virus, wherein the subject has previously been administered at least one prime dose of a first vaccine comprising a first nucleic acid encoding the SARS-CoV-2 antigen of the first the SARS-CoV-2 virus, wherein the booster vaccine is administered in an effective amount to induce a neutralizing immune response against a second SARS-CoV-2 virus, wherein the second SARS-CoV-2 virus comprises a second SARS-CoV-2 antigen, wherein the second BARS-CoV-2 antigen has an amino acid sequence with at least one amino acid mutation with respect to a corresponding protein antigen of the first BARS-CoV-2 virus, wherein the booster vaccine is administered in a dosage of 25-100 μg at least 6 months after a first dose of the first vaccine, and wherein each of the first and second antigens are not full length stabilized spike proteins having a 0.2P mutation.
55 . The method of claim 54 , wherein the booster vaccine is administered in a dosage of 50 μg.
56 . The method of claim 54 or 55 , wherein the booster vaccine is administered at least about 6 months after a second dose of the first vaccine.
57 . The method of claim 54 or 55 , wherein the booster vaccine is administered 6-12 months after a second dose of the first vaccine.
58 . The method of claim 54 or 55 , wherein the booster vaccine is administered at least about 8 months after a second dose of the first vaccine.
59 . The method of any one of claims 54 - 58 , wherein the boost dose is a seasonal boost or a pandemic shift boost to provide a neutralizing immune response against a plurality of variants of concern.