Hepatitis C virus immunogenic compositions and methods of use thereof

1. An immunogenic composition comprising:

a) a cyclic dinucleotide (CDN); and

b) a hepatitis C virus (HCV) E1/E2 heterodimer; and

c) a heterologous polypeptide comprising a T-cell epitope present in an HCV protein other than E1 and E2,

wherein the heterologous polypeptide comprises:

i) an amino acid sequence having at least 20% amino acid sequence identity to the TP29 amino acid sequence set forth in SEQ ID NO:1, wherein the heterologous polypeptide has a length of from 29 amino acids to 32 amino acids;

ii) an amino acid sequence having at least 20% amino acid sequence identity to the TP50 amino acid sequence set forth in SEQ ID NO:11, wherein the heterologous polypeptide has a length of from 50 amino acids to 55 amino acids;

iii) an amino acid sequence having at least 20% amino acid sequence identity to the TP52 amino acid sequence set forth in SEQ ID NO:2, wherein the heterologous polypeptide has a length of from 52 amino acids to 55 amino acids;

iv) an amino acid sequence having at least 20% amino acid sequence identity to the TP70 amino acid sequence set forth in SEQ ID NO:3, wherein the heterologous polypeptide has a length of from 70 amino acids to 75 amino acids;

v) an amino acid sequence having at least 20% amino acid sequence identity to the TP100 amino acid sequence set forth in SEQ ID NO:4, wherein the heterologous polypeptide has a length of from 100 amino acids to 105 amino acids;

vi) an amino acid sequence having at least 20% amino acid sequence identity to the TP171 amino acid sequence set forth in SEQ ID NO:63, wherein the heterologous polypeptide has a length of from 171 amino acids to 175 amino acids;

vii) an amino acid sequence having at least 20% amino acid sequence identity to the TP228 amino acid sequence set forth in SEQ ID NO:10, wherein the heterologous polypeptide has a length of from 228 amino acids to 232 amino acids;

viii) an amino acid sequence having at least 20% amino acid sequence identity to the TP553 amino acid sequence set forth in SEQ ID NO:12, wherein the heterologous polypeptide has a length of from 553 amino acids to 560 amino acids;

ix) an amino acid sequence having at least 20% amino acid sequence identity to the TP778 amino acid sequence set forth in SEQ ID NO:64, wherein the heterologous polypeptide has a length of about 778 amino acids; or

x) an amino acid sequence having at least 20% amino acid sequence identity to the TP1985 amino acid sequence set forth in SEQ ID NO:13, wherein the heterologous polypeptide has a length of about 1985 amino acids.

2. The immunogenic composition of claim 1 , wherein the CDN is fluorinated.

3. The immunogenic composition of claim 2 , wherein the CDN is 2′-F-c-di-GMP.

4. The immunogenic composition of claim 1 , wherein the CDN is of Formula (I):

wherein:

A is S or O;

X is S, N, O, CH 2 ;

Y, Y′ is NH, CH 2 , O;

Z, Z′ is NH, CH 2 , O;

R1 represents hydrogen or NH 2 which may be substituted;

R2 is hydrogen or absent;

R3 represents NH 2 , O, OH, H, or a halogen;

R4 represents hydrogen, halogen, or a straight or branched C 1 -C 6 alkyl group which may optionally be substituted;

R5 represents hydrogen, OH or a straight or branched C 1 -C 6 alkyl chain or C 1 -C 6 straight or branched alkoxy chain which may optionally be substituted;

is a single or double bond;

or conjugates thereof, and salts or solvates thereof.

5. The immunogenic composition of claim 4 , wherein the CDN is c-diGMP, c-diAMP, c-dilMP, c-dXMP, c-GpAp, c-Gplp, c-GpXp, c-Aplp, c-ApXp, or c-lpXp.

6. The immunogenic composition of claim 1 , wherein the CDN is cyclic-GMP-AMP (cGAMP).

7. The immunogenic composition of claim 6 , wherein the cGAMP is 2′3′-cGAMP, 2′2-cGAMP, 3′2′-cGAMP, or 3′3′-GAMP.

8. The immunogenic composition of claim 1 , wherein the heterologous polypeptide comprises:

i) an amino acid sequence having at least 50% amino acid sequence identity to the TP29 amino acid sequence set forth in SEQ ID NO:1, wherein the heterologous polypeptide has a length of from 29 amino acids to 32 amino acids;

ii) an amino acid sequence having at least 50% amino acid sequence identity to the TP50 amino acid sequence set forth in SEQ ID NO:11, wherein the heterologous polypeptide has a length of from 50 amino acids to 55 amino acids;

iii) an amino acid sequence having at least 50% amino acid sequence identity to the TP52 amino acid sequence set forth in SEQ ID NO:2, wherein the heterologous polypeptide has a length of from 52 amino acids to 55 amino acids;

iv) an amino acid sequence having at least 50% amino acid sequence identity to the TP70 amino acid sequence set forth in SEQ ID NO:3, wherein the heterologous polypeptide has a length of from 70 amino acids to 75 amino acids;

v) an amino acid sequence having at least 50% amino acid sequence identity to the TP100 amino acid sequence set forth in SEQ ID NO:4, wherein the heterologous polypeptide has a length of from 100 amino acids to 105 amino acids;

vi) an amino acid sequence having at least 50% amino acid sequence identity to the TP171 amino acid sequence set forth in SEQ ID NO:63, wherein the heterologous polypeptide has a length of from 171 amino acids to 175 amino acids;

vii) an amino acid sequence having at least 50% amino acid sequence identity to the TP228 amino acid sequence set forth in SEQ ID NO:10, wherein the heterologous polypeptide has a length of from 228 amino acids to 232 amino acids;

viii) an amino acid sequence having at least 50% amino acid sequence identity to the TP553 amino acid sequence set forth in SEQ ID NO:12, wherein the heterologous polypeptide has a length of from 553 amino acids to 560 amino acids;

ix) an amino acid sequence having at least 50% amino acid sequence identity to the TP778 amino acid sequence set forth in SEQ ID NO:64, wherein the heterologous polypeptide has a length of about 778 amino acids; or

x) an amino acid sequence having at least 50% amino acid sequence identity to the TP1985 amino acid sequence set forth in SEQ ID NO:13, wherein the heterologous polypeptide has a length of about 1985 amino acids.

9. The immunogenic composition of claim 1 , wherein the heterologous polypeptide comprises:

i) an amino acid sequence having at least 80% amino acid sequence identity to the TP29 amino acid sequence set forth in SEQ ID NO:1, wherein the heterologous polypeptide has a length of from 29 amino acids to 32 amino acids;

ii) an amino acid sequence having at least 80% amino acid sequence identity to the TP50 amino acid sequence set forth in SEQ ID NO:11, wherein the heterologous polypeptide has a length of from 50 amino acids to 55 amino acids;

iii) an amino acid sequence having at least 80% amino acid sequence identity to the TP52 amino acid sequence set forth in SEQ ID NO:2, wherein the heterologous polypeptide has a length of from 52 amino acids to 55 amino acids;

iv) an amino acid sequence having at least 80% amino acid sequence identity to the TP70 amino acid sequence set forth in SEQ ID NO:3, wherein the heterologous polypeptide has a length of from 70 amino acids to 75 amino acids;

v) an amino acid sequence having at least 80% amino acid sequence identity to the TP100 amino acid sequence set forth in SEQ ID NO:4, wherein the heterologous polypeptide has a length of from 100 amino acids to 105 amino acids;

vi) an amino acid sequence having at least 80% amino acid sequence identity to the TP171 amino acid sequence set forth in SEQ ID NO:63, wherein the heterologous polypeptide has a length of from 171 amino acids to 175 amino acids;

vii) an amino acid sequence having at least 80% amino acid sequence identity to the TP228 amino acid sequence set forth in SEQ ID NO:10, wherein the heterologous polypeptide has a length of from 228 amino acids to 232 amino acids;

viii) an amino acid sequence having at least 80% amino acid sequence identity to the TP553 amino acid sequence set forth in SEQ ID NO:12, wherein the heterologous polypeptide has a length of from 553 amino acids to 560 amino acids;

ix) an amino acid sequence having at least 80% amino acid sequence identity to the TP778 amino acid sequence set forth in SEQ ID NO:64, wherein the heterologous polypeptide has a length of about 778 amino acids; or

x) an amino acid sequence having at least 80% amino acid sequence identity to the TP1985 amino acid sequence set forth in SEQ ID NO:13, wherein the heterologous polypeptide has a length of about 1985 amino acids.

10. The immunogenic composition of claim 1 , wherein:

a) the HCV E2 polypeptide of the HCV E1/E2 heterodimer is derived from an HCV of genotype 1, 2, 3, 4, 5, 6, or 7; and

b) the HCV E1 polypeptide of the HCV E1/E2 heterodimer is derived from an HCV of genotype 1, 2, 3, 4, 5, 6, or 7.

11. A method of inducing an immune response to HCV in an individual, the method comprising administering to the individual an effective amount of the immunogenic composition of claim 1 .

12. The method of claim 11 , wherein said administering is via intramuscular administration, intranasal administration, subcutaneous administration, or a combination thereof.

13. The method of claim 11 , wherein said administering comprises a prime and a boost.

14. The method of claim 11 , wherein the individual is an intravenous drug user.

15. The method of claim 11 , wherein the individual is a recipient of blood or a blood product from a donor.

16. The method of claim 11 , wherein the individual is a recipient of cells, a tissue, or an organ from a donor.