# US 2018/0021258 A1 · Novel multivalent nanoparticle-based vaccines

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- Number: US 2018/0021258 A1
- Document ID: US20180021258A1
- Status: Published application
- Kind: A1
- Application number: 15/540,898
- Filed: 2015-12-31
- Published: 2018-01-25
- Earliest claimed: 2014-12-31
- Assignees: The U.S.A., as represented by the Secretary, Department of Health and Human Services
- Applicants: The USA, as represented by the Secretary Department of Health and Human Services
- Inventors: Barney S. GRAHAM; Masaru KANEKIYO; Hadi M. YASSINE
- Web page: https://patentgrep.com/patent/US20180021258A1

## CPC

- A61K 9/167: {with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface (with further drug-free outer coating A61K9/5073)}
- A61K 39/12: Viral antigens
- A61K 39/145: Orthomyxoviridae, e.g. influenza virus
- A61P 31/16: for influenza or rhinoviruses
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- A61K 2039/575: {humoral response}
- A61K 2039/6031: {Proteins}
- A61K 2039/6068: {Other bacterial proteins, e.g. OMP}
- A61K 2039/6075: {Viral proteins}
- A61K 2039/70: {Multivalent vaccine}
- C12N 2760/16134: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2760/16171: Demonstrated in vivo effect
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Novel, nanoparticle-based vaccines are provided that elicit an immune response to a broad range of infectious agents, such as influenza viruses. The nanoparticles comprise a heterogeneous population of fusion proteins, each comprising a monomeric subunit of a self-assembly protein, such as ferritin, joined to one or more immunogenic portions of a protein from an infectious agent, such as influenza virus. The fusion proteins self-assemble to form nanoparticles that display a heterogeneous population of immunogenic portions on their surface. When administered to an individual, such nanoparticles elicit an immune response to different strains, types, subtypes and species with in the same taxonomic family. Thus, such nanoparticles can be used to vaccinate an individual against infection by different Types, subtypes and/or strains of infectious agents. Also provided are specific fusion proteins, nucleic acid molecules encoding such fusion proteins and methods of using nanoparticles of the invention to vaccinate individuals.

## Claims

### Claim at position 1

1-13. (canceled)

### Claim 14

A nanoparticle comprising a heterogeneous population of self-assembling fusion proteins, wherein the nanoparticle displays, on its surface, immunogenic portions of corresponding proteins from at least two different infectious agents, and wherein the at least two different infectious agents are from different genera, types, subtypes or species, within the same taxonomic order.

### Claim 15 (depends on 14)

The nanoparticle of claim 14, wherein each fusion protein comprises at least a portion of a monomeric subunit protein capable of self-assembling into a nanoparticle, joined to an immunogenic portion from a corresponding protein from one of the infectious agents, wherein the heterogeneous population comprises at least two different species of fusion proteins, and wherein the difference between the species of fusion proteins is due, at least in part, to sequence differences in the immunogenic portion of corresponding proteins.

### Claim 16 (depends on 15)

The nanoparticle of claim 15, wherein the monomeric subunit protein is selected from the group consisting of a monomeric ferritin subunit protein, a monomeric encapsulin protein, a monomeric 03-33 protein, a monomeric SOR protein, a monomeric LS protein, a monomeric PDC protein and a Chikungunya virus structural polyprotein.

### Claim 17 (depends on 15)

The nanoparticle of claim 15, wherein the monomeric subunit protein is selected from the group consisting of:
a. a monomeric subunit protein comprising at least 25 contiguous amino acids from an amino acid sequence selected from a sequence selected from the group consisting of SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:76, SEQ ID NO:79, SEQ ID NO:82, SEQ ID NO:85, SEQ ID NO:88, SEQ ID NO:91 and SEQ ID NO:94; and,
b. a monomeric subunit protein comprising an amino acid sequence at least about 80% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:76, SEQ ID NO:79, SEQ ID NO:82, SEQ ID NO:85, SEQ ID NO:88, SEQ ID NO:91 and SEQ ID NO:94.

### Claim 18 (depends on 14)

The nanoparticle of claim 14, wherein the infectious agents are influenza viruses.

### Claim 19 (depends on 18)

The nanoparticle of claim 18, wherein the corresponding proteins are influenza hemagglutinin proteins.

### Claim 20 (depends on 19)

The nanoparticle of claim 19, wherein the immunogenic portions each comprise at least 10 contiguous amino acid residues from the receptor-binding domain of an influenza hemagglutinin protein.

### Claim 21 (depends on 19)

The nanoparticle of claim 19, wherein the at least two species of fusion proteins comprise immunogenic portions selected from the group consisting of:
a. immunogenic portions from HA proteins from two different types of influenza virus;
b. immunogenic portions from HA protein from two different subtypes of influenza virus; and,
c. immunogenic portions from HA protein from two different strains of influenza virus.

### Claim 22 (depends on 19)

The nanoparticle of claim 19, wherein each fusion protein comprises an amino acid sequence at least 80% identical to a sequence selected from the group consisting of SEQ ID NO:97, SEQ ID NO:100, SEQ ID NO:103, SEQ ID NO:106, SEQ ID NO:109, SEQ ID NO:112, SEQ ID NO:115, SEQ ID NO:118, SEQ ID NO:121, SEQ ID NO:124, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:133, SEQ ID NO:136, SEQ ID NO:139, SEQ ID NO:142, SEQ ID NO:145, SEQ ID NO:148, SEQ ID NO:151, SEQ ID NO:154, SEQ ID NO:157, SEQ ID NO:160, SEQ ID NO:163, SEQ ID NO:166, SEQ ID NO:169, SEQ ID NO:172, SEQ ID NO:175, SEQ ID NO:178, SEQ ID NO:181, SEQ ID NO:184, SEQ ID NO:187 and SEQ ID NO:190.

### Claim 23 (depends on 1)

A method of eliciting in an individual, a broadly neutralizing immune response against an infectious agent, comprising administering to the individual the nanoparticle of claim 1.

### Claim 24 (depends on 1)

A method of vaccinating an individual against an infectious agent, comprising administering to the individual the nanoparticle of claim 1.

### Claim 25

A method of producing a nanoparticle comprising a heterogeneous population of self-assembling fusion proteins, wherein the nanoparticle displays, on its surface, immunogenic portions of corresponding proteins from at least two different infectious agents, and wherein the at least two different infectious agents are from different genera, types, subtypes or species, within the same taxonomic order, the method comprising culturing a cell comprising at least two nucleic acid molecules, each nucleic acid molecule encoding a unique species of fusion protein, under conditions suitable for expressing the encoded proteins and forming nanoparticles,
wherein each encoded fusion protein comprises at least a portion of a monomeric subunit protein capable of self-assembling into a nanoparticle, joined to an immunogenic portion of a corresponding protein from one of the infectious agents, and
wherein the difference between unique species of fusion proteins is due, at least in part, to sequence differences in the immunogenic portions of the corresponding proteins.

### Claim 26 (depends on 25)

The method of claim 25, wherein the monomeric subunit protein is selected from the group consisting of a monomeric ferritin subunit protein, a monomeric encapsulin protein, a monomeric 03-33 protein, a monomeric SOR protein, a monomeric LS protein, a monomeric PDC protein and a Chikungunya virus structural polyprotein.

### Claim 27 (depends on 25)

The method of claim 25, wherein the monomeric subunit protein is selected from the group consisting of:
a. a monomeric subunit protein comprising at least 25 contiguous amino acids from an amino acid sequence selected from a sequence selected from the group consisting of SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:76, SEQ ID NO:79, SEQ ID NO:82, SEQ ID NO:85, SEQ ID NO:88, SEQ ID NO:91 and SEQ ID NO:94; and,
b. a monomeric subunit protein comprising an amino acid sequence at least about 80% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:70, SEQ ID NO:73, SEQ ID NO:76, SEQ ID NO:79, SEQ ID NO:82, SEQ ID NO:85, SEQ ID NO:88, SEQ ID NO:91 and SEQ ID NO:94.

### Claim 28 (depends on 25)

The method of claim 25, wherein the infectious agents are influenza viruses.

### Claim 29 (depends on 28)

The method of claim 28, wherein the corresponding proteins are influenza hemagglutinin proteins.

### Claim 30 (depends on 29)

The method of claim 29, wherein the immunogenic portions each comprise at least 10 contiguous amino acid residues from the receptor-binding domain of an influenza hemagglutinin protein.

### Claim 31

A fusion protein comprising an amino acid sequence at least 80% identical to a sequence selected from the group consisting of SEQ ID NO:97, SEQ ID NO:100, SEQ ID NO:103, SEQ ID NO:106, SEQ ID NO:109, SEQ ID NO:112, SEQ ID NO:115, SEQ ID NO:118, SEQ ID NO:121, SEQ ID NO:124, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:133, SEQ ID NO:136, SEQ ID NO:139, SEQ ID NO:142, SEQ ID NO:145, SEQ ID NO:148, SEQ ID NO:151, SEQ ID NO:154, SEQ ID NO:157, SEQ ID NO:160, SEQ ID NO:163, SEQ ID NO:166, SEQ ID NO:169, SEQ ID NO:172, SEQ ID NO:175, SEQ ID NO:178, SEQ ID NO:181, SEQ ID NO:184, SEQ ID NO:187 and SEQ ID NO:190.

### Claim 32 (depends on 31)

A nucleic acid molecule comprising a nucleic acid sequence encoding the fusion protein of claim 31.

### Claim 33 (depends on 32)

The nucleic acid molecule of claim 32, wherein nucleic acid molecule comprises a nucleic acid sequence at least 80% identical to a sequence selected from the group consisting of SEQ ID NO:96, SEQ ID NO:99, SEQ ID NO:102, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:111, SEQ ID NO:114, SEQ ID NO:117, SEQ ID NO:120, SEQ ID NO:123, SEQ ID NO:126, SEQ ID NO:129, SEQ ID NO:132, SEQ ID NO:135, SEQ ID NO:138, SEQ ID NO:141, SEQ ID NO:144, SEQ ID NO:147, SEQ ID NO:150, SEQ ID NO:153, SEQ ID NO:156, SEQ ID NO:159, SEQ ID NO:162, SEQ ID NO:165, SEQ ID NO:168, SEQ ID NO:171, SEQ ID NO:174, SEQ ID NO:177, SEQ ID NO:180, SEQ ID NO:183, SEQ ID NO:186 and SEQ ID NO:189.