Multivalent influenza mRNA vaccines

Abstract

The present disclosure provides multivalent influenza vaccine compositions comprising at least three messenger RNAs (mRNAs) encoding a combination of influenza A and influenza B hemagglutinin (HA) antigens, wherein the mRNA encoding the HA antigen of the influenza A virus is present in a different ratio (w / w) than the mRNA encoding the influenza B virus, and methods of eliciting an immune response by administering said compositions. In particular, the disclosures relate to mRNA encoding these antigens formulated in a lipid nanoparticle (LNP).

Description

This disclosure provides multivalent influenza vaccine compositions and methods for inducing an immune response by administering said compositions, the multivalent influenza vaccine compositions comprising at least three messenger RNAs (mRNAs) encoding a combination of influenza A and influenza B hemagglutinin (HA) antigens, wherein the mRNA encoding the HA antigen of influenza A virus is present in different ratios (w / w) with the mRNA encoding the influenza B virus. In particular, this disclosure relates to mRNAs encoding these antigens formulated into lipid nanoparticles (LNPs). Abstract

Claims

CLAIMSWhat is claimed is:

1. A composition comprising at least three messenger RNAs (mRNAs), wherein the at least three mRNAs comprise an open reading frame (ORF) encoding a hemagglutinin (HA) antigen selected from the group consisting of:(i) a first mRNA encoding an HA antigen of a first influenza A virus;(ii) a second mRNA encoding an HA antigen of a second influenza A virus, wherein the first influenza A virus and the second influenza A virus are of different subtypes; and(iii) a third mRNA encoding an HA antigen of a first influenza B virus, wherein the mRNA encoding the HA antigen of the influenza A virus is present in a different ratio (w / w) than the mRNA encoding the HA antigen of the influenza B virus.

2. The composition of claim 1, further comprising a fourth mRNA encoding an HA antigen of a second influenza B virus, and wherein the first influenza B virus and the second influenza B virus are of different lineages.

3. The composition of claim 1 , wherein the first mRNA, the second mRNA, and the third mRNA are present in the ratio (w / w) of about 1 : 1 :2, about 1 :1 :3, about 1 : 1 :4, about 1 :1 :5, about 1 :1 :6, about 1 : 1 :7, about 1 :1 :8, about 1 : 1 :9 or about 1 :1 : 10.

4. The composition of claim 2, wherein the first mRNA, the second mRNA, the third mRNA, and the fourth mRNA are present in the ratio (w / w) of about 1 :1 :2:2, about 1 :1 :3:3, about 1 :1 :4:4, about 1 :1 :5:5, about 1 :1 :6:6, about 1 :1 :7:7, about 1 :1 :8:8, about 1 :1 :9:9 or about 1 :1 :10:10.

5. The composition of any one of claims 1-22, wherein the ratio is expressed in micrograms (μg).

6. The composition of any one of the preceding claims, wherein the first mRNA, the second mRNA, the third mRNA, and / or the fourth mRNA are formulated into a LNP.

7. The composition of claim 6, wherein the LNP comprises at least one cationic lipid, optionally selected from the group consisting of OF-02, cKK-E10, GL-HEPES-E3-E10-DS-3- E18-1, GL-HEPES-E3-E12-DS-4-E10, GL-HEPES-E3-E 12-DS-3-E 14, (4- hydroxybutyl)azanediyl]di(hexane-6,l-diyl) bis(2 -hexyldecanoate) (ALC-0315) and IM-001.

8. The composition of claim 6 or claim 7, wherein the LNP further comprises a polyethylene glycol (PEG) conjugated (PEGylated) lipid, a cholesterol-based lipid, and a helper lipid.

9. The composition of any one of claims 6 to 8, wherein the LNP comprises: a cationic lipid at a molar ratio of 35% to 55%; a polyethylene glycol (PEG) conjugated (PEGylated) lipid at a molar ratio of 0.25% to 2.75%; a cholesterol-based lipid at a molar ratio of 20% to 45%; and a helper lipid at a molar ratio of 5% to 35%, wherein all of the molar ratios are relative to the total lipid content of the LNP; optionally wherein the LNP comprises: a cationic lipid at a molar ratio of 40%; a PEGylated lipid at a molar ratio of 1 .5%; a cholesterol-based lipid at a molar ratio of 28.5%; and a helper lipid at a molar ratio of 30%, wherein all of the molar ratios are relative to the total lipid content of the LNP.

10. The composition of claim 8 or claim 9, wherein the PEGylated lipid is dimyristoyl- PEG2000 (DMG-PEG2000) or 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159); and / or the cholesterol-based lipid is cholesterol; and / or the helper lipid is 1,2- dioleoyl-SN-glycero-3-phosphoethanolamine (DOPE) or 1 ,2-distearoyl-sn-glycero-3- p hosphocho li ne (D S PC) .

11. The composition of any one of the preceding claims, wherein the first mRNA encodes an HA antigen of the influenza A subtype H1N1, and / or the second mRNA encodes an HABntigen of the influenza A subtype H3N2, and / or the third mRNA encodes an HA antigen of the influenza BBB Victoria- lineage strain.

12. The composition of any one of claims 2-11 , wherein the fourth mRNA encodes an HA antigen of the influenza B Yamagata-lineage strain .

13. A composition comprising at least three messenger RNAs (mRNAs), wherein:(i) a first mRNA encodes a hemagglutinin (HA) antigen of a first influenza A virus;(ii) a second mRNA encodes an HA antigen of a second influenza A virus, wherein the first influenza A virus and the second influenza A virus are of different subtypes; and(iii) a third mRNA encodes an HA antigen of a first influenza B virus, wherein the first mRNA, the second mRNA, and the third mRNA are formulated into a lipid nanoparticle (LNP) comprising IM-001.

14. A composition of any one of claims 1-14 for use in a method of eliciting an immune response to influenza A or protecting a subject against influenza A infection.

15. A composition of any one of claims 1-14 for use in a method of eliciting an immune response to influenza β or protecting a subject against influenza B infection.