Rabies vaccine
The present invention relates to an mRNA sequence, comprising a coding region, encoding at least one antigenic peptide or protein of Rabies virus or a fragment, variant or derivative thereof. Additionally the present invention relates to a composition comprising a plurality of mRNA sequences comprising a coding region, encoding at least one antigenic peptide or protein of Rabies virus or a fragment, variant or derivative thereof. Furthermore it also discloses the use of the mRNA sequence or the composition comprising a plurality of mRNA sequences for the preparation of a pharmaceutical composition, especially a vaccine, e.g. for use in the prophylaxis or treatment of Rabies virus infections. The present invention further describes a method of treatment or prophylaxis of rabies using the mRNA sequence.
1. A mRNA molecule comprising:
(I) a protein coding region, encoding a rabies virus glycoprotein G (RAV-G), said protein coding region having at least about 95% identity to the protein coding region of SEQ ID NO: 24; and
(II) a 5′-UTR element which comprises a nucleic acid sequence derived from the 5′UTR of a TOP gene.
2. The mRNA molecule according to claim 1 , wherein the protein coding region encodes the full-length protein of glycoprotein G (RAV-G) of Rabies virus.
3. The mRNA molecule according to claim 1 , wherein the RAV-G is from the Pasteur vaccine strain or of the Flury-LEP vaccine strain.
4. The mRNA molecule according to claim 1 , comprising additionally
a) a 5′-CAP structure,
b) a poly(A) sequence,
c) and optionally a poly (C) sequence.
5. The mRNA molecule according to claim 4 , wherein the poly(A) sequence comprises a sequence of about 25 to about 400 adenosine nucleotides.
6. The mRNA molecule according to claim 1 , comprising additionally at least one histone stem-loop.
7. The mRNA molecule according to claim 1 , comprising additionally a 3′-UTR element.
8. The mRNA molecule according to claim 7 , wherein the 3′UTR element comprises or consists of a nucleic acid sequence which is derived from a 3′UTR of a gene providing a stable mRNA.
9. The mRNA molecule according to claim 8 , wherein the 3′UTR element comprises or consists of a nucleic acid sequence derived from a 3′UTR of a gene selected from the group consisting of an albumin gene, an α-globin gene, a β-globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen alpha gene.
10. The mRNA molecule according to claim 9 , wherein the 3′-UTR element comprises or consists of a nucleic acid sequence derived from a 3′UTR of α-globin gene.
11. The mRNA molecule according to claim 1 , wherein the mRNA sequence comprises the RNA sequence according to SEQ ID No. 24.
12. The mRNA molecule according to claim 7 , wherein the at least one 3′UTR element comprises or consist of a nucleic acid sequence which is derived from the 3′UTR of a vertebrate albumin gene.
13. The mRNA molecule according to claim 12 , wherein the 3′UTR element is derived from a nucleic acid sequence according to SEQ ID NO. 18.
14. The mRNA molecule according to claim 1 , wherein the 5′-UTR element lacks the 5′TOP motif.
15. The mRNA molecule according to claim 14 , wherein the 5′UTR element comprises a 5′UTR of a TOP gene encoding a ribosomal protein.
16. The mRNA molecule according to claim 15 , wherein the 5′UTR element comprises or consists of a nucleic acid sequence which is derived from a 5′UTR of a TOP gene encoding a ribosomal Large protein (RPL).
17. The mRNA molecule accordingly to claim 14 , wherein the 5′UTR element comprises or consists of a nucleic acid sequence which is derived from a 5′UTR of a an hydroxysteroid (17-beta) dehydrogenase 4 gene (HSD17B4) gene.
18. The mRNA molecule sequence according to claim 1 , wherein the mRNA sequence comprises, in 5′- to 3′-direction:
(a) a 5′-CAP structure, preferably m7GpppN;
(b) the 5′-UTR element;
(c) the protein coding region encoding;
(d) a 3′-UTR; and
(e) a poly(A) sequence of about 25 to about 400 adenosine nucleotides.
19. A pharmaceutical formulation comprising the mRNA molecule of claim 1 and a pharmaceutically acceptable carrier.
20. The formulation of claim 19 , wherein the formulation comprises a cationic lipid component.