Granted Patent B2

US 12,508,308 · App. 16/098,834 · Granted Dec 30, 2025

Inventors: Edith Jasny (Stuttgart, DE); Susanne Rauch (Tübingen, DE); Kim Ellen Schwendt (Dettenhausen, DE); Benjamin Petsch (Tübingen, DE); Karen Slobod (Somerville, MA)

Assignee: CureVac SE

A61K39/145A61K2039/53A61K2039/54A61K2039/55555A61K2039/70C12N2760/16034

Abstract

Claims (37)

1 . A method for stimulating an anti-influenza immune response in a subject comprising administering to the subject an effective amount of a composition comprising:

(i) at least three mRNAs encoding three different influenza virus hemagglutinin (HA) proteins, or antigenic fragments thereof, wherein said at least three mRNAs encode an HA from influenza B, an HA1 from influenza A, and an HA3 from influenza A; and

(ii) at least three mRNAs encoding three different influenza neuraminidase (NA) proteins, or antigenic fragments thereof, wherein at least one of said at least three mRNAs encodes a NA from influenza B,

wherein each of the mRNAs is formulated with a lipid nanoparticle (LNP) comprising a cationic lipid,

wherein each of said mRNAs comprises a coding sequence encoding the HA or NA protein that has a G/C content that is increased compared to the G/C content of the corresponding coding sequence of a wild type mRNA encoding the HA or NA protein, and

wherein each of said mRNAs comprises: (a) a m7GpppN 5′-CAP structure; (b) a 5′-UTR element; (c) a 3′-UTR element comprising a histone stem loop element having the RNA sequence of SEQ ID NO: 213735; and (d) a poly(A) sequence comprising 60 to 250 consecutive adenosines,

thereby stimulating an anti-influenza immune response in a subject, wherein the composition is administered by intramuscular or intradermal injection.

2 . The method of claim 1 , wherein at least two of the HA proteins are from an influenza A virus.

3 . The method of claim 1 , wherein at least one of the HA proteins and/or the NA proteins is a full-length protein.

4 . The method of claim 1 , wherein said poly(A) sequence is at the 3′ terminus of said mRNAs.

5 . The method of claim 1 , wherein each of said mRNAs comprises a poly (C) sequence.

6 . The method of claim 1 , wherein the lipid nanoparticle (LNP) comprises a cationic lipid, a phospholipid, cholesterol, and a PEGylated lipid.

7 . The method of claim 6 , wherein said at least three mRNAs encoding three different influenza virus HA proteins comprise mRNAs encoding a HA1 protein from a H1N1 influenza virus and HA3 protein from a H3N2 influenza virus.

8 . The method of claim 7 , wherein said at least three mRNAs encoding three different influenza virus HA proteins each encode full-length HA proteins.

9 . The method of claim 6 , wherein the composition is administered by intramuscular injection.

10 . The method of claim 1 , wherein the anti-influenza immune response comprises a CD8+ T-cell response.

11 . The method of claim 10 , wherein the anti-influenza immune response is a protective immune response.

12 . The method of claim 1 , wherein the 5′ UTR element is derived from the 5′-UTR of a TOP gene.

13 . The method of claim 6 , wherein said poly(A) sequence is about 100 consecutive adenosines.

14 . The method of claim 6 , wherein the LNP comprises DSPC.

15 . The method of claim 6 , wherein each of said mRNAs comprises a coding sequence encoding the HA or NA protein that has a G/C content that is increased by at least 7% compared to the G/C content of the corresponding coding sequence of a wild type mRNA encoding the HA or NA protein.

16 . The method of claim 15 , wherein each of said mRNAs comprises a coding sequence encoding the HA or NA protein that has a G/C content that is increased by at least 15% compared to the G/C content of the corresponding coding sequence of a wild type mRNA encoding the HA or NA protein.

17 . The method of claim 6 , wherein each of said mRNAs comprises a nucleotide analog selected from the group consisting of pseudouridine and 1-methyl-pseudouridine.

18 . The method of claim 17 , wherein each of said mRNAs comprises a coding sequence encoding the HA or NA protein that has a G/C content that is increased by at least 7% compared to the G/C content of the corresponding coding sequence of a wild type mRNA encoding the HA or NA protein.

19 . The method of claim 18 , wherein each of said mRNAs comprises a coding sequence encoding the HA or NA protein that has a G/C content that is increased by at least 15% compared to the G/C content of the corresponding coding sequence of a wild type mRNA encoding the HA or NA protein.

20 . The method of claim 19 , wherein each of said mRNAs comprises 1-methyl-pseudouridine substitutions in place of uridine.

21 . The method of claim 20 , comprising administering the composition by intramuscular injection.

22 . The method of claim 21 , wherein said at least three mRNAs encoding three different influenza virus HA proteins each encode full-length HA proteins and wherein said at least three mRNAs encoding three different influenza virus NA proteins each encode full-length NA proteins.

23 . The method of claim 22 , wherein the LNP comprises DSPC.

24 . The method of claim 23 , wherein each of said mRNAs comprises a coding sequence encoding the HA or NA protein that has a G/C content that is increased by at least 7% compared to the G/C content of the corresponding coding sequence of a wild type mRNA encoding the HA or NA protein.

25 . The method of claim 24 , wherein each of said mRNAs comprises a coding sequence encoding the HA or NA protein that has a G/C content that is increased by at least 15% compared to the G/C content of the corresponding coding sequence of a wild type mRNA encoding the HA or NA protein.

26 . The method of claim 25 , wherein each of said mRNAs comprises a nucleotide analog selected from the group consisting of pseudouridine and 1-methyl-pseudouridine.

27 . The method of claim 26 , wherein each of said mRNAs comprises a 1-methyl-pseudouridine nucleotide analog.

28 . The method of claim 7 , wherein the mRNA encoding a HA1 protein comprises a coding sequence at least 85% identical to the HA1 coding sequence of SEQ ID NO: 213577 and encodes a HA1 protein at least 90% identical to the protein encoded by SEQ ID NO: 213577.

29 . The method of claim 7 , wherein the mRNA encoding a HA3 protein comprises a coding sequence at least 85% identical to the HA3 coding sequence SEQ ID NO: 213625 and encodes a HA3 protein at least 90% identical to the protein encoded by SEQ ID NO: 213625.

30 . The method of claim 1 , wherein each of said mRNAs comprises a 5′-UTR element from the dehydrogenase 4 gene (HSD17B4) gene.

31 . The method of claim 1 , wherein each of said mRNAs comprises a Cap1 5′ CAP-structure.

Assignments (4)

Priority Claims (2)

Continuity (1)

References Cited (110)