Universal influenza vaccine using nucleoside-modified mRNA

Inventors: Norbert Pardi (Philadelphia, PA); Drew Weissman (Wynnewood, PA); Raffael Nachbagauer (New York, NY); Scott Hensley (Philadelphia, PA); Peter Palese (New York, NY); Florian Krammer (New York, NY); Adolfo Garcia-Sastre (New York, NY); Alec W. Freyn (New York, NY)

Assignees: The Trustees of the University of Pennsylvania; Icahn School of Medicine at Mount Sinai

A61K39/145 A61P31/16

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Quick Facts

Patent No.: US 12685764
App. No.: 17/995,207
Granted: Jul 21, 2026
Kind: B2

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Abstract

The present invention relates to compositions and methods for inducing an immune response against influenza virus in a subject. In some embodiments, the present invention provides a composition comprising a nucleoside-modified nucleic acid molecule encoding at least one influenza virus antigen, such as a hemagglutinin antigen or a fragment thereof, neuraminidase antigen or a fragment thereof, nucleoprotein antigen or a fragment thereof, matrix protein 1 antigen or a fragment thereof, or matrix-2 ion channel antigen or a fragment thereof.

Claims (35)

1 . A composition for inducing an immune response against one or more influenza viruses in a subject, the composition comprising a combination of isolated nucleoside-modified RNA molecules encoding at least four influenza viral antigens selected from:

a) a full length HA antigen or a fragment thereof comprising at least the HA-stalk domain or HA-head domain,

b) a full length NA antigen or a fragment thereof comprising at least the NA-stalk domain or NA-head domain,

c) a full length NP antigen or a fragment thereof,

d) a full length M1 antigen or a fragment thereof, and

e) a full length M2 ion channel antigen or a fragment thereof comprising at least the M2 ion channel-extracellular domain or M2 ion channel-intracellular domain, and

further wherein the isolated nucleoside-modified RNA molecules comprise RNA molecules in which all of the uridines have been replaced with pseudouridine or 1-methyl pseudouridine.

2 . The composition of claim 1 , wherein the composition comprises at least four influenza virus antigens comprising amino acid sequences selected from the group consisting of:

a) an HA antigen comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, and any combination thereof;

b) an NA antigen comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, and any combination thereof;

c) an NP antigen comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, and any combination thereof;

d) an M2 ion channel antigen comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, and any combination thereof; and

e) an M1 antigen comprises an amino acid sequence as set forth in SEQ ID NO: 107 and any combination thereof.

3 . The composition of claim 1 , wherein the at least one influenza virus antigen is a combination of a HA-stalk domain comprising an amino acid sequence as set forth in SEQ ID NO: 27, full length NA antigen comprising an amino acid sequence as set forth in SEQ ID NO: 41, full length NP antigen comprising an amino acid sequence as set forth in SEQ ID NO: 67, and full length M2 ion channel antigen comprising an amino acid sequence as set forth in SEQ ID NO: 93.

4 . The composition of claim 1 , wherein the composition comprises at least four nucleoside-modified RNA molecules comprising nucleic acid sequences that are encoded by a combination of at least four DNA sequences sequence selected from the group consisting of:

a) at least one nucleoside-modified RNA comprises a nucleic acid sequence that is encoded by a DNA sequence comprising at least one nucleotide sequence selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, and SEQ ID NO: 28;

b) at least one nucleoside-modified RNA comprises a nucleic acid sequence that is encoded by a DNA sequence comprising at least one nucleotide sequence selected from the group consisting of: SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, and SEQ ID NO: 54;

c) at least one nucleoside-modified RNA comprises a nucleic acid sequence that is encoded by a DNA sequence comprising at least one nucleotide sequence selected from the group consisting of: SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, and SEQ ID NO: 80;

d) at least one nucleoside-modified RNA comprises a nucleic acid sequence that is encoded by a DNA sequence comprising at least one nucleotide sequence selected from the group consisting of: SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, and SEQ ID NO: 106; and

e) at least one nucleoside-modified RNA comprises a nucleic acid sequence that is encoded by a DNA sequence comprising at least one nucleotide sequence as set forth in SEQ ID NO: 108.

5 . The composition of claim 4 , wherein the at least one nucleoside-modified RNA comprises a nucleic acid sequence that is encoded by a DNA sequence comprising a combination of a nucleotide sequence as set forth in SEQ ID NO: 28, nucleotide sequence as set forth in SEQ ID NO: 42, nucleotide sequence as set forth in SEQ ID NO: 68, and nucleotide sequence as set forth in SEQ ID NO: 94.

6 . The composition of claim 1 , wherein the composition further comprises an adjuvant, or

wherein the at least one nucleoside-modified RNA further encodes at least one adjuvant.

7 . The composition of claim 1 , wherein the composition further comprises a lipid nanoparticle (LNP), or wherein the at least one nucleoside-modified RNA is encapsulated within an LNP.

8 . The composition of claim 1 , wherein the at least one isolated nucleoside-modified RNA is a purified nucleoside-modified mRNA.

9 . A method of inducing an immune response against influenza virus in a subject comprising administering to the subject an effective amount of a composition of claim 1 .

10 . The method of claim 9 , wherein the at least one influenza virus antigen is selected from the group consisting of a full length HA antigen or a fragment thereof, HA-stalk domain or a fragment thereof, HA-head domain or a fragment thereof, full length NA antigen or a fragment thereof, NA-stalk domain or a fragment thereof, NA-head domain or a fragment thereof, full length NP antigen or a fragment thereof, full length M1 antigen or a fragment thereof, full length M2 ion channel antigen or a fragment thereof, M2 ion channel-extracellular domain or a fragment thereof, M2 ion channel-intracellular domain or a fragment thereof, and any combination thereof.

11 . The method of claim 10 , wherein the at least one influenza virus antigen comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, SEQ ID NO: 95, SEQ ID NO: 97, SEQ ID NO: 99, SEQ ID NO: 101, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 107, and any combination thereof.

12 . The method of claim 10 , wherein the at least one influenza virus antigen is a combination of a HA-stalk domain comprising an amino acid sequence as set forth in SEQ ID NO: 27, full length NA antigen comprising an amino acid sequence as set forth in SEQ ID NO: 41, full length NP antigen comprising an amino acid sequence as set forth in SEQ ID NO: 67, and full length M2 ion channel antigen comprising an amino acid sequence as set forth in SEQ ID NO: 93.

13 . The method of claim 9 , wherein the at least one nucleoside-modified RNA comprises a nucleic acid sequence that is encoded by a DNA sequence comprising at least one nucleotide sequence selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, and SEQ ID NO: 108.

14 . The method of claim 13 , wherein the at least one nucleoside-modified RNA comprises a nucleic acid sequence that is encoded by a DNA sequence comprising a combination of a nucleotide sequence as set forth in SEQ ID NO: 28, nucleotide sequence as set forth in SEQ ID NO: 42, nucleotide sequence as set forth in SEQ ID NO: 68, and nucleotide sequence as set forth in SEQ ID NO: 94.

15 . The method of claim 9 , wherein the method further comprises administering to the subject an effective amount of an adjuvant.

16 . The method of claim 9 , wherein the at least one nucleoside-modified RNA is a purified nucleoside-modified mRNA, and further wherein the mRNA molecule comprises at least one selected from the group consisting of pseudouridine and 1-methyl-pseudouridine.

17 . The method of claim 9 , wherein the influenza virus is selected from the group consisting of an influenza virus A, influenza virus B, influenza virus C, influenza virus D, and any combination thereof.

18 . The method of claim 9 , wherein the method treats or prevents an infection, disease, disorder, or any combination thereof associated with influenza virus in the subject.