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EP-4735029-A2 - MULTIVALENT INFLUENZA MRNA VACCINES

EP4735029A2EP 4735029 A2EP4735029 A2EP 4735029A2EP-4735029-A2

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).

Inventors

  • ALEFANTIS, Timothy
  • GIEL-MOLONEY, MARYANN
  • ARVIS, FLORENCE

Assignees

  • Sanofi Vaccines US Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (15)

  1. 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. 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. 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. 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. 5. The composition of any one of claims 1-22, wherein the ratio is expressed in micrograms (μg).
  6. 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. 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. 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. 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. 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. 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 HA Bntigen of the influenza A subtype H3N2, and/or the third mRNA encodes an HA antigen of the influenza BBB Victoria- lineage strain.
  12. 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. 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. 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. 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.

Description

Multivalent Influenza mRNA Vaccines RELATED APPLICATION [001| This application claims priority to European Patent Application Serial No. 23315259.4, filed on June 28, 2023, the disclosures of which are hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [002] Messenger RNA (mRNA) based vaccines provide a promising alternative to traditional subunit vaccines, which contain antigenic proteins derived from a pathogen. Antigen proteins are usually recombinantly made and require bacterial fermentation and/or cell culture, as well as complex purification. Vaccines based on mRNA allow de novo expression of complex antigens in the vaccinated subject, which in turn allows proper post-translational modification and presentation of the antigens in its natural conformation. Unlike traditional technologies, the manufacture of mRNA vaccines does not require complex and costly bacterial fermentation, tissue culture, and purification processes. Moreover, once established, the manufacturing process for mRNA vaccines can be used for a variety of antigens, enabling rapid development and deployment of mRNA vaccines. Further, mRNA vaccines are inherently safe delivery vectors as they express the antigens only transiently and do not integrate into the host genome. Because antigens encoded by mRNAs are produced in vivo in the vaccinated individual, mRNA vaccines are especially effective in eliciting both humoral and T cell mediated immunity. [003] Current mRNA-based multivalent influenza vaccines under investigation encode hemagglutinin (HA) antigens from both the influenza A virus and the B influenza virus in equal ratios (w/w). While these vaccines are immunogenic, ongoing trials indicate that B strain immunogenicity is lower than A strain immunogenicity and immune responses in humans to B strain influenza viruses are sub-optimal with these vaccines. Accordingly, there exists a need for multivalent mRNA-based influenza vaccines with improved B strain immunogenicity. SUMMARY OF THE INVENTION [004] In one aspect, the disclosure provides a composition comprising at least three messenger RNAs (mRN As), 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. [005] In certain embodiments, the composition comprises a fourth mRNA encoding an HA antigen of a second influenza B virus, wherein the first influenza B virus and the second influenza B virus are of different lineages. [006] In certain embodiments, the composition comprises the first mRNA, the second mRNA, and the third mRNA present in the ratio (w/w) of about 1 :1 :2. [007] In certain embodiments, the composition comprises the first mRNA, the second mRNA, and the third mRNA present in the ratio (w/w) of about 1 :1 :3. [008] In certain embodiments, the composition comprises the first mRNA, the second mRNA, and the third mRNA present in the ratio (w/w) of about 1 :1 :4. [009] In certain embodiments, the composition comprises the first mRNA, the second mRNA, and the third mRN A present in the ratio (w/w) of about 1 :1 :5. [0010] In certain embodiments, the composition comprises the first mRNA, the second mRNA, and the third mRNA present in the ratio (w/w) of about 1 :1 :6. [0011] In certain embodiments, the composition comprises the first mRNA, the second mRNA, and the third mRNA present in the ratio (w/w) of about 1:1:7. [0012] In certain embodiments, the composition comprises the first mRNA, the second mRNA, and the third mRNA present in the ratio (w/w) of about 1 :1 :8. [0013] In certain embodiments, the composition comprises the first mRNA, the second mRNA, and the third mRNA present in the ratio (w/w) of about 1 :1 :9. [0014] In certain embodiments, the composition comprises the first mRNA, the second mRNA, and the third mRN A present in the ratio (w/w) of about 1 :1 :10. [0015] In certain embodiments, the composition comprises the first mRNA, the second mRNA, and the third mRNA present in the ratio (w/w) of about 1 : 1 :2 to about 1:1 :10. [0016] In certain embodiments, the composition comprises the first mRNA, the second mRNA, the third mRNA, and the fourth mRNA present in the ratio (w/w) of about 1 : 1 :2:2. [0017] In certain embodiments, the composition comprises the first mRNA, the second mRNA, the third mRNA, and the fourth mRNA present in the ratio (w/w) of about 1 :1 :3:3. [0018] In certain embodiments, the composition comprises the first mRNA, the second mRNA, the third mRNA,