Respiratory syncytial virus (rsv) vaccine

Patent metadata

Field	Value
Publication number	US-2016168207-A1
Application number	US-201615048439-A
Country	US
Kind code	A1
Filing date	Feb 19, 2016
Priority date	Aug 21, 2013
Publication date	Jun 16, 2016
Grant date	—

Abstract

The present invention relates to an mRNA sequence, comprising a coding region, encoding at least one antigenic peptide or protein of RSV infections Respiratory syncytial virus (RSV) 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 RSV infections Respiratory syncytial virus (RSV) 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 RSV infections Respiratory syncytial virus (RSV) infections. The present invention further describes a method of treatment or prophylaxis of RSV infections using the mRNA sequence.

First claim

1 . mRNA sequence comprising a coding region, encoding at least one antigenic peptide or protein derived from the fusion protein F, the glycoprotein G, the short hydrophobic protein SH, the matrix protein M, the nucleoprotein N, the large polymerase L, the M2-1 protein, the M2-2 protein, the phosphoprotein P, the non-structural protein NS1 or the non-structural protein NS2 of Respiratory syncytial virus (RSV), or a fragment, variant or derivative thereof;
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 preferably not being modified compared with the coded amino acid sequence of the wild type mRNA.

2 . The mRNA sequence according to claim 1 , wherein the coding region encodes the full-length protein of fusion protein F, nucleoprotein N or glycoprotein G of Respiratory syncytial virus (RSV).

3 . The mRNA sequence according to any of claims 1 to 2 , wherein the antigenic peptide or protein is derived from the RSV strain ATCC VR-26 long.

4 . The mRNA sequence according to any of claims 1 to 3 comprising additionally
a) a 5′-CAP structure,
b) a poly(A) sequence,
c) and optionally a poly (C) sequence.

5 . The mRNA sequence according to claim 4 , wherein the poly(A) sequence comprises a sequence of about 25 to about 400 adenosine nucleotides, preferably a sequence of about 50 to about 400 adenosine nucleotides, more preferably a sequence of about 50 to about 300 adenosine nucleotides, even more preferably a sequence of about 50 to about 250 adenosine nucleotides, most preferably a sequence of about 60 to about 250 adenosine nucleotides.

6 . The mRNA sequence according to any of claims 1 to 5 comprising additionally at least one histone stem-loop.

7 . The mRNA sequence according to claim 6 , wherein the at least one histone stem-loop is selected from following formulae (I) or (II):
formula (I) (stem-loop sequence without stem bordering elements):

formula (II) (stem-loop sequence with stem bordering elements):

wherein:
stem1 or stem2 bordering elements N 1-6 is a consecutive sequence of 1 to 6, preferably of 2 to 6, more preferably of 2 to 5, even more preferably of 3 to 5, most preferably of 4 to 5 or 5 N, wherein each N is independently from another selected from a nucleotide selected from A, U, T, G and C, or a nucleotide analogue thereof;
stem1 [N 0-2 GN 3-5 ] is reverse complementary or partially reverse complementary with element stem2, and is a consecutive sequence between of 5 to 7 nucleotides;
wherein N 0-2 is a consecutive sequence of 0 to 2, preferably of 0 to 1, more preferably of 1 N, wherein each N is independently from another selected from a nucleotide selected from A, U, T, G and C or a nucleotide analogue thereof;
wherein N 3-5 is a consecutive sequence of 3 to 5, preferably of 4 to 5, more preferably of 4 N, wherein each N is independently from another selected from a nucleotide selected from A, U, T, G and C or a nucleotide analogue thereof, and
wherein G is guanosine or an analogue thereof, and may be optionally replaced by a cytidine or an analogue thereof, provided that its complementary nucleotide cytidine in stem2 is replaced by guanosine;

loop sequence [N 0-4 (U/T)N 0-4 ] is located between elements stem1 and stem2, and is a consecutive sequence of 3 to 5 nucleotides, more preferably of 4 nucleotides;
wherein each N 0-4 is independent from another a consecutive sequence of 0 to 4, preferably of 1 to 3, more preferably of 1 to 2 N, wherein each N is independently from another selected from a nucleotide selected from A, U, T, G and C or a nucleotide analogue thereof; and
wherein U/T represents uridine, or optionally thymidine;

stem2 [N 3-5 CN 0-2 ] is reverse complementary or partially reverse complementary with element stem1, and is a consecutive sequence between of 5 to 7 nucleotides;
wherein N 3-5 is a consecutive sequence of 3 to 5, preferably of 4 to 5, more preferably of 4 N, wherein each N is independently from another selected from a nucleotide selected from A, U, T, G and C or a nucleotide analogue thereof;
wherein N 0-2 is a consecutive sequence of 0 to 2, preferably of 0 to 1, more preferably of 1 N, wherein each N is independently from another selected from a nucleotide selected from A, U, T, G and C or a nucleotide analogue thereof; and
wherein C is cytidine or an analogue thereof, and may be optionally replaced by a guanosine or an analogue thereof provided that its complementary nucleotide guanosine in stem1 is replaced by cytidine;

wherein
stem1 and stem2 are capable of base pairing with each other forming a reverse complementary sequence, wherein base pairing may occur between stem1 and stem2, or
forming a partially reverse complementary sequence, wherein an incomplete base pairing may occur between stem1 and stem2.

8 . The mRNA sequence according to claim 7 , wherein the at least one histone stem-loop is selected from at least one of following formulae (Ia) or (IIa):

9 . The mRNA sequence according to any of claims 1 to 8 comprising additionally a 3′-UTR element.

10 . The mRNA sequence according to claim 9 , wherein the at least one 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 or from a homolog, a fragment or a variant thereof.

11 . The mRNA sequence according to claim 10 , 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, or from a homolog, a fragment or a variant thereof.

12 . The mRNA sequence according to claim 11 , wherein the 3′-UTR element comprises or consists of a nucleic acid sequence derived from a 3′UTR of α-globin gene, preferably comprising the corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO. 29, a homolog, a fragment, or a variant thereof;

13 . The mRNA sequence according to any of claims 9 to 12 ; wherein the mRNA sequence comprises, preferably in 5′- to 3′-direction:
a.) a 5′-CAP structure, preferably m7GpppN;
b.) a coding region encoding at least one antigenic peptide or protein of Respiratory syncytial virus (RSV), preferably derived from the fusion protein F of Respiratory syncytial virus (RSV);
c.) a 3′-UTR element comprising or consisting of a nucleic acid sequence which is derived from a alpha globin gene, preferably comprising the corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO. 29, a homolog, a fragment or a variant thereof;
d.) a poly(A) sequence, preferably comprising 64 adenosines;
e.) a poly(C) sequence, preferably comprising 30 cytosines; and
f.) a histone-stem-loop, preferably comprising the corresponding RNA sequence to the nucleic acid sequence according to SEQ ID No 30.

14 . The mRNA sequence according to claim 13 , wherein the mRNA sequence comprises the RNA sequence according to SEQ ID No. 31.

15 . The mRNA sequence according to claim 9 , wherein the at least one 3′UTR element comprises or consist

Assignees

• Curevac Ag

Inventors

• Kramps Thomas
• Schnee Margit
• Voss Daniel
• Petsch Benjamin

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P37/04

  Immunostimulants · CPC title

• C07K16/11

  Paramyxoviridae (F); Pneumoviridae (F), e.g. respiratory syncytial virus [RSV] · CPC title

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title

• A61K2039/53

  DNA (RNA) vaccination · CPC title