Combination vaccine
The present invention relates to a vaccine, especially a combination vaccine providing at least a first and a second antigenic function, the combination vaccine comprising at least one RNA encoding at least one or more proteins or fragments, variants or derivatives of proteins awarding antigenic function, wherein the first antigenic function being a Fusion (F) protein or a fragment, variant or derivative of a Fusion (F) protein derived from the virus family Paramyxoviridae and the second antigenic function being an Hemagglutinin (HA) protein or a fragment, variant or derivative of an Hemagglutinin (HA) protein derived from the virus family Orthomyxoviridae. Furthermore, the present invention is directed to a kit or kit of parts comprising the components of said combination vaccine and to said combination vaccine for use in a method of prophylactic or therapeutic treatment of diseases, particularly in the prevention or treatment of infectious diseases like RSV and influenza.
1. A method of stimulating an antigen-specific CTL and antibody immune response in a subject comprising administering by injection a composition comprising a cocktail of (i) an mRNA encoding a Fusion (F) protein derived from the virus family Paramyxoviridae and (ii) an mRNA encoding a Hemagglutinin (HA) protein derived from the virus family Orthomyxoviridae, wherein the F-protein specific CTL and antibody response is enhanced by the cocktail.
2. The method of claim 1 , wherein the mRNA encoding the F protein and the RNA encoding HA protein are separate monocistronic RNA molecules.
3. The method of claim 1 , wherein the mRNA encoding the F protein and the mRNA encoding HA protein are comprised in the same bicistronic or a multicistronic mRNA molecule.
4. The method of claim 1 , wherein the mRNA encoding the F protein and the mRNA encoding HA protein encode a fusion protein of the F protein and the HA protein.
5. The method of claim 1 , wherein the Fusion (F) protein is derived from viruses selected from: Avulavirus, Ferlavirus, Henipavirus, Morbillivirus, Respirovirus, Rubulavirus, TPMV-like viruses, Pneumovirus, Metapneumovirus, Atlantic salmon paramyxovirus, Beilong virus, J virus, Mossman virus, Nariva virus, Salem virus, or Pacific salmon paramyxovirus.
6. The method of claim 1 , wherein the Fusion (F) protein is derived from human respiratory syncytial virus (RSV).
7. The method of claim 6 , wherein the human respiratory syncytial virus (RSV) is selected from RSV Long or RSV A2.
8. The method of claim 1 , wherein the Hemagglutinin (HA) protein is derived from an Influenza virus.
9. The method of claim 1 , wherein the mRNA comprises at least two monocistronic mRNAs selected from the group consisting of:
a) at least one monocistronic mRNA encoding SEQ ID No.: 1 and at least one monocistronic mRNA encoding SEQ ID No.: 3, and
(b) at least one monocistronic mRNA encoding SEQ ID No.: 2 and at least one monocistronic mRNA encoding SEQ ID No.: 3.
10. The method of claim 1 , wherein the mRNA comprises at least two monocistronic mRNAs each having at least 80% homology to the sequences of the monocistronic mRNAs selected from the group consisting of:
(a) at least one monocistronic mRNA according to SEQ ID No.: 13 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21,
(b) at least one monocistronic mRNA according to SEQ ID No.: 14 and at least one monocistronic mRNA according to SEQ ID No.: 18 or according to SEQ ID No.: 21,
(c) at least one monocistronic mRNA according to SEQ ID No.: 15 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21,
(d) at least one monocistronic mRNA according to SEQ ID No.: 16 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21,
(e) at least one monocistronic mRNA according to SEQ ID No.: 17 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21,
(f) at least one monocistronic mRNA according to SEQ ID No.: 19 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21, and
(g) at least one monocistronic mRNA according to SEQ ID No.: 20 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21.
11. The method of claim 1 , wherein at least one mRNA comprises at least one of the following structural elements: a histone-stem-loop structure a 5′-Cap structure, a poly(C) sequence, a poly-A tail and/or a polyadenylation signal.
12. The method of claim 1 , wherein at least one mRNA is a stabilized, sugar modified and/or base modified mRNA.
13. The method of claim 1 , wherein at least one mRNA is optimized for translation.
14. The method of claim 1 , wherein at least one mRNA is associated with or complexed with a cationic or polycationic compound or a polymeric carrier, optionally in a weight ratio selected from a range of about 6:1 (w/w) to about 0.25:1 (w/w).
15. The method of claim 14 , wherein at least one mRNA is associated or complexed with a cationic protein or peptide.
16. The method of claim 1 , further comprising administering an adjuvant component.
17. The method of claim 1 , wherein the composition comprises:
a) an adjuvant component, comprising or consisting at least one adjuvant nucleic acid, complexed with a cationic or polycationic compound and/or with a polymeric carrier, and
b) optionally a pharmaceutically acceptable carrier.
18. The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable vehicle.
19. The method of claim 11 , wherein the histone-stem-loop structure is a histone-stem-loop in its 3′ untranslated region.
20. The method of claim 12 , wherein the stabilized mRNA is stabilized by backbone modifications, sugar modifications and/or base modifications.
21. The method of claim 20 , wherein the stabilized mRNA is stabilized by modification of the G/C-content.
22. The method of claim 13 , wherein the mRNA optimized for translation is optimized for translation by replacing codons for less frequent tRNAs of a given amino acid by codons for more frequently occurring tRNAs for said amino acid.
23. The method of claim 15 , wherein at least one mRNA is associated or complexed with protamine.
24. The method of claim 10 , wherein the mRNA comprises at least two monocistronic mRNAs selected from the group consisting of:
(a) at least one monocistronic mRNA according to SEQ ID No.: 13 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21,
(b) at least one monocistronic mRNA according to SEQ ID No.: 14 and at least one monocistronic mRNA according to SEQ ID No.: 18 or according to SEQ ID No.: 21,
(c) at least one monocistronic mRNA according to SEQ ID No.: 15 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21,
(d) at least one monocistronic mRNA according to SEQ ID No.: 16 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21,
(e) at least one monocistronic mRNA according to SEQ ID No.: 17 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21,
(f) at least one monocistronic mRNA according to SEQ ID No.: 19 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21, and
(g) at least one monocistronic mRNA according to SEQ ID No.: 20 and at least one monocistronic mRNA according to SEQ ID No.: 18 or SEQ ID No.: 21.
25. The method of claim 1 , wherein the Hemagglutinin (HA) protein is derived from an Influenza virus and the Fusion (F) protein is derived from human respiratory syncytial virus (RSV).