Methods and compositions for norovirus blockade epitopes

1. A chimeric norovirus capsid protein consisting of a norovirus VP1 major capsid protein backbone from norovirus strain GII.4.1974 (SEQ ID NO:14), norovirus strain GII.4.1987 (SEQ ID NO:2), norovirus strain GII.4.1997 (SEQ ID NO:3), norovirus strain GII.4.2002 (SEQ ID NO:4), norovirus strain GII.4.2002a (SEQ ID NO:5), norovirus strain GII.4.2004 (SEQ ID NO:6), norovirus strain GII.4.2005 (SEQ ID NO:7), norovirus strain GII.4.2006 (SEQ ID NO:8), norovirus strain GII.4.2007 (SEQ ID NO:9), norovirus strain GII.4.2008a (SEQ ID NO:10), norovirus strain GII.4.2008s (SEQ ID NO:11), norovirus strain GII.4.2009 (SEQ ID NO:12), or norovirus strain GII.4.2012 (SEQ ID NO:13) in which two or more, in any combination, of the following sets of amino acid residues (a)-(i):

a) amino acid residues 294, 296, 297, 298, 368 and 372 (Epitope A);

b) amino acid residues 333 and 382 (Epitope B);

c) amino acid residues 340 and 376 (Epitope C);

d) amino acid residues 393, 394 and 395 (Epitope D);

e) amino acid residues 407, 412 and 413 (Epitope E); and

f) amino acid residues 310, 316, 484 and 493 (Epitope F), wherein amino acid residue numbering of (a)-(f) is based on the amino acid sequence of any of SEQ ID NOs:4-13; and

g) amino acid residues 393 and 394 (Epitope D);

h) amino acid residues 406, 411 and 412 (Epitope E); and

i) amino acid residues 310, 316, 483 and 492 (Epitope F), wherein amino acid residue numbering of (g)-(i) is based on the amino acid sequence of SEQ ID NOs:2, 3 or 14, are substituted into the capsid protein backbone to introduce at least one epitope from each of two or more different norovirus strains of the above norovirus strains, each of which is different from one another and each of which is different from the norovirus strain of the capsid protein backbone.

2. A synthetic backbone molecule comprising two or more sets of amino acid residues wherein each set of amino acid residues forms a norovirus conformational epitope, wherein the two or more sets of amino acid residues each form a conformational epitope from two or more norovirus strains that are different from one another and wherein the two or more sets of amino acid residues are selected in any combination from the group consisting of the following sets of amino acid residues (a)-(i):

a) amino acid residues 294, 296, 297, 298, 368 and 372 (Epitope A);

b) amino acid residues 333 and 382 (Epitope B);

c) amino acid residues 340 and 376 (Epitope C);

d) amino acid residues 393, 394 and 395 (Epitope D);

e) amino acid residues 407, 412 and 413 (Epitope E); and

f) amino acid residues 310, 316, 484 and 493 (Epitope F), wherein amino acid residue numbering of (a)-(f) is based on the amino acid sequence of any of SEQ ID NOs:4-13; and

g) amino acid residues 393 and 394 (Epitope D);

h) amino acid residues 406, 411 and 412 (Epitope E); and

i) amino acid residues 310, 316, 483 and 492 (Epitope F), wherein amino acid residue numbering of (g)-(i) is based on the amino acid sequence of SEQ ID NOs:2, 3 or 14, from two or more norovirus strains that are different from one another, wherein the synthetic backbone molecule allows for formation of two or more norovirus conformational epitopes, and

wherein the synthetic backbone molecule is not a norovirus capsid protein.

3. A norovirus P particle consisting of multiple copies of a norovirus P domain backbone from norovirus strain GII.4.1974 (SEQ ID NO:14), norovirus strain GII.4.1987 (SEQ ID NO:2), norovirus strain GII.4.1997 (SEQ ID NO:3), norovirus strain GII.4.2002 (SEQ ID NO:4), norovirus strain GII.4.2002a (SEQ ID NO:5), norovirus strain GII.4.2004 (SEQ ID NO:6), norovirus strain GII.4.2005 (SEQ ID NO:7), norovirus strain GII.4.2006 (SEQ ID NO:8), norovirus strain GII.4.2007 (SEQ ID NO:9), norovirus strain GII.4.2008a (SEQ ID NO:10), norovirus strain GII.4.2008s (SEQ ID NO:11), norovirus strain GII.4.2009 (SEQ ID NO:12), or norovirus strain GII.4.2012 (SEQ ID NO:13) in which two or more, in any combination, of the following sets of amino acid residues (a)-(i):

a) amino acid residues 294, 296, 297, 298, 368 and 372 (Epitope A);

b) amino acid residues 333 and 382 (Epitope B);

c) amino acid residues 340 and 376 (Epitope C);

d) amino acid residues 393, 394 and 395 (Epitope D);

e) amino acid residues 407, 412 and 413 (Epitope E); and

f) amino acid residues 310, 316, 484 and 493 (Epitope F), wherein amino acid residue numbering of (a)-(f) is based on the amino acid sequence of any of SEQ ID NOs:4-13; and

g) amino acid residues 393 and 394 (Epitope D);

h) amino acid residues 406, 411 and 412 (Epitope E); and

i) amino acid residues 310, 316, 483 and 492 (Epitope F), wherein amino acid residue numbering of (g)-(i) is based on the amino acid sequence of SEQ ID NOs:2, 3 or 14, are substituted into the P domain backbone to introduce at least one epitope from each of two or more norovirus strains of the above norovirus strains, each of which is different from one another and each of which is different from the norovirus strain of the P domain backbone, wherein the epitopes are presented on the P particle surface.

4. The chimeric norovirus capsid protein of claim 1 , wherein the norovirus VP1 major capsid protein backbone is from GII.4.2006.

5. The chimeric norovirus capsid protein of claim 4 , comprising Epitope A from GII.4.1987 and Epitope E from GII.4.2002.

6. A virus like particle (VLP) comprising the chimeric norovirus capsid protein of claim 1 .

7. A composition comprising the chimeric norovirus capsid protein of claim 1 in a pharmaceutically acceptable carrier.

8. A method of producing an immune response to a norovirus in a subject, comprising administering to the subject an effective amount of the chimeric norovirus capsid protein of claim 1 .