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 method of treatment or prophylaxis of rabies virus infections comprising the steps:
a) providing an mRNA having a sequence comprising a coding region encoding glycoprotein G (RAV-G) of Rabies virus, wherein the G/C content of the coding region is increased compared with the G/C content of the coding region of the wild type mRNA, and wherein the coded amino acid sequence of said GC-enriched mRNA is not being modified compared with the coded amino acid sequence of the wild type mRNA, and wherein:
(i) the mRNA comprises a sequence at least 95% identical to SEQ ID No: 24; or
(ii) wherein the mRNA further comprises a 5′-UTR element which comprises a nucleic acid sequence which is derived from the 5′UTR of a TOP gene;
b) applying or administering the mRNA to a tissue or an organism;
c) optionally administering rabies immune globulin.
2. The method of claim 1 , wherein the coding region encodes the full-length protein of glycoprotein G (RAV-G) of Rabies virus.
3. The method of claim 1 , wherein the glycoprotein G (RAV-G) is from a Rabies vaccine strain.
4. The method of claim 1 , wherein the mRNA further comprises
a) a 5′-CAP structure,
b) a poly(A) sequence,
c) and optionally a poly (C) sequence.
5. The method of claim 4 , wherein the poly(A) sequence comprises a sequence of about 25 to about 400 adenosine nucleotides.
6. The method of claim 1 , wherein the mRNA further comprises at least one histone stem-loop.
7. The method of claim 1 , wherein the mRNA further comprises a 3′-UTR element.
8. The method of claim 7 , wherein the 3′UTR element comprises a nucleic acid sequence which is derived from a 3′UTR of a gene providing a stable mRNA or from a homolog.
9. The method of claim 8 , wherein the 3′UTR element comprises 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 method of claim 9 , wherein the 3′-UTR element comprises a nucleic acid sequence derived from a 3′UTR of α-globin gene.
11. The method of claim 7 , wherein the at least one 3′UTR element comprises a nucleic acid sequence which is derived from the 3′UTR of a vertebrate albumin gene.
12. The method of claim 11 , wherein the 3′UTR element is derived from a nucleic acid sequence according to SEQ ID NO. 18.
13. The method of claim 1 , wherein the mRNA comprises, in 5′- to 3′-direction:
a) a 5′-CAP structure;
b) a coding region encoding at least one of glycoprotein G (RAV-G) of Rabies virus;
c) a 3′-UTR element comprising or consisting of a nucleic acid sequence which is derived from an alpha globin gene or an albumin gene;
d) a poly(A) sequence;
e) a poly(C) sequence; and
f) a histone-stem-loop.
14. The method of claim 13 , wherein the mRNA comprises the RNA sequence of SEQ ID No. 24.
15. The method of claim 1 , wherein the mRNA further comprises a 5′-UTR element which comprises a nucleic acid sequence which is derived from the 5′UTR of a TOP gene.
16. The method of claim 15 , wherein the 5′UTR element comprises a nucleic acid sequence which is derived from a 5′UTR of a TOP gene encoding a ribosomal protein.
17. The method of claim 16 , wherein the 5′UTR element comprises a nucleic acid sequence which is derived from a 5′UTR of a TOP gene encoding a ribosomal Large protein (RPL).