# US 2019/0314486 A1 · Influenza hemagglutinin protein vaccines

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- Number: US 2019/0314486 A1
- Document ID: US20190314486A1
- Status: Published application
- Kind: A1
- Application number: 16/343,272
- Filed: 2017-10-18
- Published: 2019-10-17
- Earliest claimed: 2016-10-21
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Jessica Anne Flynn; Lan Zhang; Kerim Babaoglu; Arthur Fridman; David Nickle
- Web page: https://patentgrep.com/patent/US20190314486A1

## CPC

- A61K 39/12: Viral antigens
- A61K 39/145: Orthomyxoviridae, e.g. influenza virus
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61P 31/16: for influenza or rhinoviruses
- C07K 14/11: Orthomyxoviridae, e.g. influenza virus
- A61K 2039/53: {DNA (RNA) vaccination}
- A61K 2039/55555: {Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers}
- C12N 2760/16134: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2760/16234: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The disclosure relates to influenza virus hemagglutinin protein and DNA vaccines, as well as methods of using the vaccines and compositions comprising the vaccines.

## Claims

### Claim 1

An influenza virus vaccine, comprising at least one isolated antigenic polypeptide:
wherein the at least one antigenic polypeptide comprises an amino acid sequence that has at least 90% identity to a mature amino acid sequence in any one of SEQ ID NOs: 1-4, 8-11, 14-19, 41-61, and 83-88.

### Claim 2

(canceled)

### Claim 3

(canceled)

### Claim 4 (depends on 1)

The vaccine of claim 1, wherein the polypeptide has conservative mutations compared to a mature amino acid sequence in any one of SEQ ID NOs: 1-4, 8-11, 14-19, 41-61, and 83-88.

### Claim 5 (depends on 1)

The vaccine of claim 1, wherein the polypeptide comprises the mature amino acid sequence that is identified in any one of SEQ ID NOs: 1-4, 8-11, 14-19, 41-61, and 83-88.

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The vaccine of claim 1, wherein the polypeptide comprises a mature amino acid sequence that is the extracellular domain of SEQ ID NO: 8 or 10.

### Claim 8

An influenza virus vaccine comprising two isolated antigenic polypeptides, wherein the first polypeptide comprises an amino acid sequence that has at least 90% identity to the mature amino acid sequence of any one of SEQ ID NOs: 1-5, 8-11, 14-19, 41-63, and 83-88 and the second polypeptide comprises an amino acid sequence that has at least 90% identity to the mature amino acid sequence of SEQ ID NO: 20.

### Claim 9

(canceled)

### Claim 10

(canceled)

### Claim 11 (depends on 8)

The vaccine of claim 8, wherein the first and second polypeptide has conservative mutations compared to the mature amino acid sequence in any one of SEQ ID NOs: 1-5, 8-11, 14-19, 41-63, 83-88 and 20.

### Claim 12 (depends on 8)

The vaccine of claim 8, wherein the first polypeptide comprises the mature amino acid sequence in SEQ ID NO: 4, and the second polypeptide comprises the mature amino acid sequence in SEQ ID NO: 20.

### Claim 13

(canceled)

### Claim 14 (depends on 1)

The vaccine of claim 1, wherein the vaccine is multivalent.

### Claim 15 (depends on 1)

The vaccine of claim 1 formulated in an effective amount to produce an antigen-specific immune response.

### Claim 16 (depends on 1)

The vaccine of claim 1, formulated with a Lipid Nanoparticle (LNP) comprising one or more cationic lipids and a poly(ethyleneglycol)-lipid (PEG-lipid).

### Claim 17 (depends on 16)

The vaccine of claim 16, wherein the one or more cationic lipids are ionizable cationic lipids.

### Claim 18 (depends on 17)

The vaccine of claim 17, wherein the ionizable cationic lipids are selected from DLinDMA; DlinKC2DMA; DLin-MC3-DMA; CLinDMA; S-Octyl CLinDMA;
(2S)-1-{7-[(3β)-cholest-5-en-3-yloxy]heptyloxy}-3-[(4Z)-dec-4-en-1-yloxy]-N,N-dimethylpropan-2-amine;
(2R)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-[(4Z)-dec-4-en-1-yloxy]-N,N-dimethylpropan-2-amine;
1-[(2R)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-(octyloxy)propan-2-yl]guanidine;
1-[(2R)-1-{7-[(3β)-cholest-5-en-3-yloxy]heptyloxy}-N,N-dimethyl-3-[(9 Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine;
1-[(2R)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-N,N-dimethyl-3-[(9 Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine;
(2S)-1-({6-[(3β))-cholest-5-en-3-yloxy]hexyl}oxy)-N,N-dimethyl-3-[(9 Z)-octadec-9-en-1-yloxy]propan-2-amine;
(3β)-3-[6-{[(2S)-3-[(9Z)-octadec-9-en-1-yloxyl]-2-(pyrrolidin-1-yl)propyl]oxy}hexyl)oxy]cholest-5-ene;
(2R)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-(octyloxy)propan-2-amine;
(2R)-1-({8-[(3β)-cholest-5-en-3-yloxy]octyl)}oxy)-N,N-dimethyl-3-(pentyloxy)propan-2-amine;
(2R)-1-({8-[(3β)-cholest-5-en-3-yloxy]octyl)}oxy)-3-(heptyloxy)-N,N-dimethylpropan-2-amine;
(2R)-1-({8-[(3β)-cholest-5-en-3-yloxy]octyl})oxy)-N,N-dimethyl-3-[(2Z)-pent-2-en-1-yloxy]propan-2-amine;
(2S)-1-butoxy-3-({8-[(3β)-cholest-5-en-3-yloxy]octyl})oxy)-N,N-dimethylpropan-2-amine;
(2S-1-({8-[(3(3)-cholest-5-en-3-yloxy]octyl}oxy)-3-[2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecafluorononyl)oxy]-N,N-dimethylpropan-2-amine;
2-amino-2-{[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}propane-1,3-diol;
2-amino-3-((9-(((3S,10R,13R)-10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)nonyl)oxy)-2-((((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)methyl)propan-1-ol;
2-amino-3-((6-(((3S,10R,13R)-10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)hexyl)oxy)-2-((((Z)-octadec-9-en-1-yl)oxy)methyl)propan-1-ol;
(20Z,23Z)-N,N-dimethylnonacosa-20,23-dien-10-amine;
(17Z,20Z)-N,N-dimethylhexacosa-17,20-dien-9-amine;
(16Z,19Z)-N,N-dimethylpentacosa-16,19-dien-8-amine;
(12Z,15Z)-N,N-dimethylhenicosa-12,15-dien-4-amine;
(14Z,17Z)-N,N-dimethyltricosa-14,17-dien-6-amine;
(15Z,18Z)-N,N-dimethyltetracosa-15,18-dien-7-amine;
(18Z,21Z)-N,N-dimethylheptacosa-18,21-dien-10-amine;
(15Z,18Z)-N,N-dimethyltetracosa-15,18-dien-5-amine;
(14Z,17Z)-N,N-dimethyltricosa-14,17-dien-4-amine;
(19Z,22Z)-N,N-dimethyloctacosa-19,22-dien-9-amine;
(18Z,21Z)-N,N-dimethylheptacosa-18,21-dien-8-amine;
(17Z,20Z)-N,N-dimethylhexacosa-17,20-dien-7-amine;
(16Z,19Z)-N,N-dimethylpentacosa-16,19-dien-6-amine;
(22Z,25Z)-N,N-dimethylhentriaconta-22,25-dien-10-amine;
(21Z,24Z)-N,N-dimethyltriaconta-21,24-dien-9-amine;
(18Z)-N,N-dimethylheptacos-18-en-10-amine;
(17Z)-N,N-dimethylhexacos-17-en-9-amine;
(19Z,22Z)-N,N-dimethyloctacosa-19,22-dien-7-amine;
N,N-dimethylheptacosan-10-amine;
(20Z,23Z)-N-ethyl-N-methylnonacosa-20,23-dien-10-amine;
1-[(11Z,14Z)-1-nonylicosa-11,14-dien-1-yl]pyrrolidine;
(20Z)-N,N-dimethylheptacos-20-en-10-amine;
(15Z)-N,N-dimethylheptacos-15-en-10-amine;
(14Z)-N,N-dimethylnonacos-14-en-10-amine;
(17Z)-N,N-dimethylnonacos-17-en-10-amine;
(24Z)-N,N-dimethyltritriacont-24-en-10-amine;
(20Z)-N,N-dimethylnonacos-20-en-10-amine;
(22Z)-N,N-dimethylhentriacont-22-en-10-amine;
(16Z)-N,N-dimethylpentacos-16-en-8-amine;
(12Z,15Z)-N,N-dimethyl-2-nonylhenicosa-12,15-dien-1-amine;
(13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine;
N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]heptadecan-8-amine;
1-[(1S,2R)-2-hexylcyclopropyl]-N,N-dimethylnonadecan-10-amine;
N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]nonadecan-10-amine;
N,N-dimethyl-21-[(1S,2R)-2-octyl cyclopropyl]henicosan-10-amine;
N,N-dimethyl-1-[(1S,2S)-2-{[(1R,2R)-2-pentylcyclopropyl]methyl} cyclopropyl]nonadecan-10-amine;
N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]hexadecan-8-amine;
N,N-dimethyl-1-[(1R,2S)-2-undecylcyclopropyl]tetradecan-5-amine;
N,N-dimethyl-3-{7-[(1S,2R)-2-octylcyclopropyl]heptyl} dodecan-1-amine;
1-[(1R,2S)-2-heptylcyclopropyl]-N,N-dimethyloctadecan-9-amine;
1-[(1S,2R)-2-decylcyclopropyl]-N,N-dimethylpentadecan-6-amine;
N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]pentadecan-8-amine; and
(11E,20Z,23Z)-N,N-dimethylnonacosa-11,20,23-trien-10-amine;
or a pharmaceutically acceptable salt thereof, or a stereoisomer of any of the foregoing.

### Claim 19

(canceled)

### Claim 20 (depends on 17)

The vaccine of claim 17, which comprises 30-75 mole % ionizable cationic lipid and 0.1-20 mole % PEG-lipid.

### Claim 21 (depends on 17)

The vaccine of claim 17, further comprising one or more non-cationic lipids selected from a phospholipid, a phospholipid derivative, a fatty acid, a sterol, or a combination thereof.

### Claim 22 (depends on 21)

The vaccine of claim 21, wherein the sterol is cholesterol, stigmasterol or stigmastanol.

### Claim 23 (depends on 21)

The vaccine of claim 21, wherein the phospholipid is selected from phosphatidylserine, 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), dilauroylphosphatidylcholine (DLPC), 1,2-dieicosenoyl-sn-glycero-3-phosphocholine, and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC).

### Claim 24 (depends on 23)

The vaccine of claim 23, wherein the PEG-lipid is 1,2-Dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG), PEG-disteryl glycerol (PEG-DSG), PEG-dipalmetoleyl, PEG-dioleyl, PEG-distearyl, PEG-diacylglycamide (PEG-DAG), PEG- dipalmitoyl phosphatidylethanolamine (PEG-DPPE), or PEG-1,2-dimyristyloxlpropyl-3-amine (PEG-c-DMA).

### Claim 25 (depends on 24)

The vaccine of claim 24, which comprises 20-99.8 mole % ionizable cationic lipids, 0.1-65 mole % non-cationic lipids, and 0.1-20 mole % PEG-lipid.

### Claim 26 (depends on 25)

The vaccine of claim 25, wherein the non-cationic lipids comprise a mixture of cholesterol and DSPC.

### Claim 27 (depends on 16)

The vaccine of claim 16, which comprises 34-59 mole % ionizable cationic lipids selected from the group consisting of (2S)-1-({6-[(3β)-cholest-5-en-3-yloxy]hexyl}oxy)-N,N-dimethyl-3-[(9 Z)-octadec-9-en-1-yloxy]propan-2-amine; (13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine; and N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]heptadecan-8-amine, 30-48 mole % cholesterol, 10-24% DSPC and 1-2 mole % PEG-DMG.

### Claim 28

(canceled)

### Claim 29 (depends on 1)

A method of inducing an immune response in a subject, the method comprising administering to the subject the vaccine of claim 1 in an amount effective to produce an antigen-specific immune response in the subject.

### Claim at position 30

-36. (canceled)

### Claim 37 (depends on 1)

A method of inducing cross-reactivity against a variety of influenza strains in a mammal, the method comprising administering to the mammal in need thereof the vaccine of claim 1.

### Claim 38

(canceled)