Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus

MOLLER; Niels Iversen ;   et al.

Patent Application Summary

U.S. patent application number 15/101791 was filed with the patent office on 2016-12-22 for proteins and nucleic acids useful in vaccines targeting staphylococcus aureus. This patent application is currently assigned to Evaxion Biotech ApS. The applicant listed for this patent is Evaxion Biotech ApS. Invention is credited to Andreas Holm MATTSSON, Niels Iversen MOLLER.

Application Number20160368952 15/101791
Document ID /
Family ID49680922
Filed Date2016-12-22
United States Patent Application 20160368952
Kind Code A1
MOLLER; Niels Iversen ;   et al. December 22, 2016
Proteins and nucleic acids useful in vaccines targeting staphylococcus aureus

Abstract

The present invention relates to proteins and nucleic acids derived from Staphylococcus aureus as well as therapeutic and diagnostic uses of the proteins and nucleic acids.

Inventors: MOLLER; Niels Iversen; (Copenhagen, DK) ; MATTSSON; Andreas Holm; (Copenhagen, DK)
Applicant:
Name City State Country Type

Evaxion Biotech ApS
Copenhagen
DK
Assignee: Evaxion Biotech ApS
Family ID: 49680922
Appl. No.: 15/101791
Filed: December 3, 2014
PCT Filed: December 3, 2014
PCT NO: PCT/EP2014/076398
371 Date: June 3, 2016
Current U.S. Class: 1/1
Current CPC Class: C12Q 1/689 20130101; A61K 39/085 20130101; C07K 14/31 20130101; G01N 33/56938 20130101; G01N 2333/31 20130101; G01N 2500/04 20130101; C07K 16/1271 20130101; A61K 2039/55505 20130101
International Class: C07K 14/31 20060101 C07K014/31; C12Q 1/68 20060101 C12Q001/68; G01N 33/569 20060101 G01N033/569; A61K 39/085 20060101 A61K039/085; C07K 16/12 20060101 C07K016/12
Foreign Application Data
Date Code Application Number
Dec 3, 2013 EP 13195472.9
Claims


1. A polypeptide comprising a) an amino acid sequence selected from the group consisting of any one of SEQ ID NOs: 5, 14, 6-16 and 49, or b) an amino acid sequence consisting of at least or exactly or at most 5 contiguous amino acid residues from any one of SEQ ID NOs: 5, 1-4, 6-16 and 49, or c) an amino acid sequence having a sequence identity of at least 60% with the amino acid sequence of a), d) an amino acid sequence having a sequence identity of at least 60% with the amino acid sequence of b), or e) an assembly of amino acids derived from any one of SEQ ID NOs: 5, 1-4, 6-16 and 49, which has essentially the same 3D conformation as in the protein from which said assembly is derived so as to constitute a B-cell epitope, said polypeptide being antigenic in a mammal.

2. The polypeptide according to claim 1, wherein the at least or exactly or at most 5 contiguous amino acids are at least or exactly or at most 6, such as at least or exactly or at most 7, at least or exactly or at most 8, at least or exactly or at most 9, at least or exactly or at most 10, at least or exactly or at most 11, at least or exactly or at most 12, at least or exactly or at most 13, at least or exactly or at most 14, at least or exactly or at most 15, at least or exactly or at most 16, at least or exactly or at most 17, at least or exactly or at most 18, at least or exactly or at most 19, at least or exactly or at most 20, at least or exactly or at most 21, at least or exactly or at most 22, at least or exactly or at most 23, at least or exactly or at most 24, at least or exactly or at most 25, at least or exactly or at most 26, at least or exactly or at most 27 at least or exactly or at most 28, at least or exactly or at most 29, at least or exactly or at most 30, at least or exactly or at most 31, at least or exactly or at most 32, at least or exactly or at most 33, at least or exactly or at most 34, and at least or exactly or at most 35 contiguous amino acid residues.

3. The polypeptide according to claim 1 or 2, wherein the sequence identity with the amino acid sequence of a) is at least 65%, such as at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99%.

4. The polypeptide according to claim 1 or 2, wherein the sequence identity with the amino acid sequence of b) is at least 60%, such as at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99%.

5. The polypeptide according to any one of the preceding claims, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135 and 136 in any one of SEQ ID NOs: 1-16 and 49.

6. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188 and 189 in any on of SEQ ID NOs: 2-16 and 49.

7. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204 and 205 in any one of SEQ ID NOs: 3-16 and 49.

8. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237 and 238 in any one of SEQ ID NOs: 4-16 and 49.

9. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322 and 323 in any one of SEQ ID NOs: 5-16 and 49.

10. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352 and 353 in any one of SEQ ID NOs: 6-16 and 49.

11. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394 and 395 in any one of SEQ ID NOs: 7-16 and 49.

12. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, and 408 in any one of SEQ ID NOs: 8-16 and 49.

13. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490 and 491 in any one of SEQ ID NOs: 8-16.

14. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502 and 503 in any one of SEQ ID NOs: 9-16.

15. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 504 and 505 in any one of SEQ ID NOs: 10-16.

16. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 506, 507, 508, 509, 510 and 511 in any one of SEQ ID NOs: 11-16.

17. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560 and 561 in any one of SEQ ID NOs: 12-16.

18. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614 and 615 in any one of SEQ ID NOs: 13-16.

19. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676 and 677 in any one of SEQ ID NOs: 14-16.

20. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801 and 802 in any one of SEQ ID NOs: 15-16.

21. The polypeptide according to any one of claims 1-4, wherein the at least or exactly or at most 5 contiguous amino acid residues has an N-terminal amino acid residue corresponding to any one of amino acid residues 803 and 804 in SEQ ID NOs: 16.

22. A polypeptide comprising a) the amino acid sequence SEQ ID NO: 5, or b) an amino acid sequence consisting of at least or exactly or at most 5 contiguous amino acid residues from one SEQ ID NO: 5, or c) an amino acid sequence having a sequence identity of at least 60% with the amino acid sequence of a), d) an amino acid sequence having a sequence identity of at least 60% with the amino acid sequence of b), or e) an assembly of amino acids derived from SEQ ID NOs: 5 which has essentially the same 3D conformation as in the protein from which said assembly is derived so as to constitute a B-cell epitope, said polypeptide being antigenic in a mammal.

23. The polypeptide according to claim 21, which is as defined in any one of claims 2-9.

24. The polypeptide according to any one of the preceding claims, which is fused or conjugated to an immunogenic carrier molecule.

25. The polypeptide according to claim 24, wherein the immunogenic carrier molecule is a polypeptide that induces T-helper lymphocyte responses in a majority of humans, such as immunogenic carrier proteins selected from the group consisting of keyhole limpet hemocyanin or a fragment thereof, tetanus toxoid or a fragment thereof, diphtheria toxoid or a fragment thereof.

26. The polypeptide according to any one of the preceding claims, which is capable of inducing an adaptive immune response against the polypeptide in a mammal, in particular in a human being.

27. The polypeptide according to claim 26, which is capable of inducing, in the mammal, a protective adaptive immune response against infection with S. aureus.

28. The polypeptide according to claim 26 or 27, which induces a humoral and/or a cellular immune response.

29. An isolated nucleic acid fragment, which comprises i) a nucleotide sequence encoding a polypeptide according to any one of the preceding claims, or ii) a nucleotide sequence consisting of the amino acid encoding part of any one of SEQ ID NOs: 17-48, 50, and 51. iii) a nucleotide sequence consisting of at least or exactly or at most 10 consecutive nucleotides in the amino acid encoding part of any one of SEQ ID NOs: 17-48, 50, and 51, iv) a nucleotide sequence having a sequence identity of at least 60% with the nucleotide sequence in i) or ii), v) a nucleotide sequence having a sequence identity of at least 60% with the nucleotide sequence in iii), vi) a nucleotide sequence complementary to the nucleotide sequence in i)-v), or vii) a nucleotide sequence which hybridizes under stringent conditions with the nucleotide sequence in i)-vi).

30. The nucleic acid fragment according to claim 29, which is a DNA or an RNA fragment.

31. The nucleic acid fragment according to claim 29 or 30, wherein the nucleotide sequence consists of at least or exactly or at most 11, such as at least or exactly or at most 12, at least or exactly or at most 13, at least or exactly or at most 14, at least or exactly or at most 15, at least or exactly or at most 16, at least or exactly or at most 17 at least or exactly or at most 18, at least or exactly or at most 19, at least or exactly or at most 20, at least or exactly or at most 21, at least or exactly or at most 22, at least or exactly or at most 23, at least or exactly or at most 24, at least or exactly or at most 25, at least or exactly or at most 26, at least or exactly or at most 27, at least or exactly or at most 28, at least or exactly or at most 29, at least or exactly or at most 30, at least or exactly or at most 31, at least or exactly or at most 32, at least or exactly or at most 33, at least or exactly or at most 34, at least or exactly or at most 35, at least or exactly or at most 36, at least or exactly or at most 37, at least or exactly or at most 38, at least or exactly or at most 39, at least or exactly or at most 40, at least or exactly or at most 41, at least or exactly or at most 42, at least or exactly or at most 43, at least or exactly or at most 44, at least or exactly or at most 45, at least or exactly or at most 46, at least or exactly or at most 47, at least or exactly or at most 48, at least or exactly or at most 49, at least or exactly or at most 50, at least or exactly or at most 51, at least or exactly or at most 52, at least or exactly or at most 53, at least or exactly or at most 54, at least or exactly or at most 55, at least or exactly or at most 56, at least or exactly or at most 57, at least or exactly or at most 58, at least or exactly or at most 59, at least or exactly or at most 60, at least or exactly or at most 61, at least or exactly or at most 62, at least or exactly or at most 63, at least or exactly or at most 64, at least or exactly or at most 65, at least or exactly or at most 66, at least or exactly or at most 67, at least or exactly or at most 68, at least or exactly or at most 69, at least or exactly or at most 70, at least or exactly or at most 71, at least or exactly or at most 72, at least or exactly or at most 73, at least or exactly or at most 74, at least or exactly or at most 75, at least or exactly or at most 76, at least or exactly or at most 77, at least or exactly or at most 78, at least or exactly or at most 79, at least or exactly or at most 80, at least or exactly or at most 81, at least or exactly or at most 82, at least or exactly or at most 83, at least or exactly or at most 84, at least or exactly or at most 85, at least or exactly or at most 86, at least or exactly or at most 87, at least or exactly or at most 88, at least or exactly or at most 89, at least or exactly or at most 90, at least or exactly or at most 91, at least or exactly or at most 92, at least or exactly or at most 93, at least or exactly or at most 94, at least or exactly or at most 95, at least or exactly or at most 96, at least or exactly or at most 97, at least or exactly or at most 98, at least or exactly or at most 99, at least or exactly or at most 100, at least or exactly or at most 101, at least or exactly or at most 102, at least or exactly or at most 103, at least or exactly or at most 104, at least or exactly or at most 105, at least or exactly or at most 106, at least or exactly or at most 107, at least or exactly or at most 108, at least or exactly or at most 109, at least or exactly or at most 110, at least or exactly or at most 111, at least or exactly or at most 112, at least or exactly or at most 113, at least or exactly or at most 114, at least or exactly or at most 115, at least or exactly or at most 116, at least or exactly or at most 117, at least or exactly or at most 118, at least or exactly or at most 119, at least or exactly or at most 120, at least or exactly or at most 121, at least or exactly or at most 122, at least or exactly or at most 123, at least or exactly or at most 124, at least or exactly or at most 125, at least or exactly or at most 126, at least or exactly or at most 127, at least or exactly or at most 128, at least or exactly or at most 129, at least or exactly or at most 130, at least or exactly or at most 131, at least or exactly or at most 132, at least or exactly or at most 133, at least or exactly or at most 134, at least or exactly or at most 135, at least or exactly or at most 136, at least or exactly or at most 137, at least or exactly or at most 138, at least or exactly or at most 139, at least or exactly or at most 140, at least or exactly or at most 141, at least or exactly or at most 142, at least or exactly or at most 143, at least or exactly or at most 144, at least or exactly or at most 145, at least or exactly or at most 146, at least or exactly or at most 147, at least or exactly or at most 148, at least or exactly or at most 149, at least or exactly or at most 150, at least or exactly or at most 151, at least or exactly or at most 152, at least or exactly or at most 153, at least or exactly or at most 154, at least or exactly or at most 155, at least or exactly or at most 156, at least or exactly or at most 157, at least or exactly or at most 158, at least or exactly or at most 159, at least or exactly or at most 160, at least or exactly or at most 171, at least or exactly or at most 172, at least or exactly or at most 173, at least or exactly or at most 174, at least or exactly or at most 175, at least or exactly or at most 176, at least or exactly or at most 177, at least or exactly or at most 178, at least or exactly or at most 179, at least or exactly or at most 180, at least or exactly or at most 181, at least or exactly or at most 182, at least or exactly or at most 183, at least or exactly or at most 184, at least or exactly or at most 185, at least or exactly or at most 186, at least or exactly or at most 187, at least or exactly or at most 188, at least or exactly or at most 189, at least or exactly or at most 190, at least or exactly or at most 191, at least or exactly or at most 192, at least or exactly or at most 193, at least or exactly or at most 194, at least or exactly or at most 195, at least or exactly or at most 196, at least or exactly or at most 197, at least or exactly or at most 198, at least or exactly or at most 199, at least or exactly or at most 200, at least or exactly or at most 201, at least or exactly or at most 202, at least or exactly or at most 203, at least or exactly or at most 204, at least or exactly or at most 205, at least or exactly or at most 206, at least or exactly or at most 207, at least or exactly or at most 208, at least or exactly or at most 209, at least or exactly or at most 210, at least or exactly or at most 211, at least or exactly or at most 212, at least or exactly or at most 213, at least or exactly or at most 214, at least or exactly or at most 215, at least or exactly or at most 216, at least or exactly or at most 217, at least or exactly or at most 218, at least or exactly or at most 219, at least or exactly or at most 220, at least or exactly or at most 221, at least or exactly or at most 222, at least or exactly or at most 223, at least or exactly or at most 224, at least or exactly or at most 225, at least or exactly or at most 226, at least or exactly or at most 227, at least or exactly or at most 228, at least or exactly or at most 229, at least or exactly or at most 230, at least or exactly or at most 231, at least or exactly or at most 232, at least or exactly or at most 233, at least or exactly or at most 234, at least or exactly or at most 235, at least or exactly or at most 236, at least or exactly or at most 237, at least or exactly or at most 238, at least or exactly or at most 239, at least or exactly or at most 240, at least or exactly or at most 241, at least or exactly or at most 242, at least or exactly or at most 243, at least or exactly or at most 244, at least or exactly or at most 245, at least or exactly or at most 246, at least or exactly or at most 247, at least or exactly or at most 248, at least or exactly or at most 249, at least or exactly or at most 250, at least or exactly or at most 251, at least or exactly or at most 252, at least or exactly or at most 253, at least or exactly or at most 254, at least or exactly or at most 255, at least or exactly or at most 256, at least or exactly or at most 257, at least or exactly or at most 258, at least or exactly or at most 259, at least or exactly or at most 260, at least or exactly or at most 271, at least or exactly or at most 272, at least or exactly or at most 273, at least or exactly or at most 274, at least or exactly or at most 275, at least or exactly or at most 276, at least or exactly or at most 277, at least or exactly or at most 278, at least or exactly or at most 279, at least or exactly or at most 280, at least or exactly or at most 281, at least or exactly or at most 282, at least or exactly or at most 283, at least or exactly or at most 284, at least or exactly or at most 285, at least or exactly or at most 286, at least or exactly or at most 287, at least or exactly or at most 288, at least or exactly or at most 289, at least or exactly or at most 290, at least or exactly or at most 291, at least or exactly or at most 292, at least or exactly or at most 293, at least or exactly or at most 294, at least or exactly or at most 295, at least or exactly or at most 296, at least or exactly or at most 297, at least or exactly or at most 298, at least or exactly or at most 299, at least or exactly or at most 300, at least or exactly or at most 301, at least or exactly or at most 302, at least or exactly or at most 303, at least or exactly or at most 304, at least or exactly or at most 305, at least or exactly or at most 306, at least or exactly or at most 307, at least or exactly or at most 308, at least or exactly or at most 309, at least or exactly or at most 310, at least or exactly or at most 311, at least or exactly or at most 312, at least or exactly or at most 313, at least or exactly or at most 314, at least or exactly or at most 315, at least or exactly or at most 316, at least or exactly or at most 317, at least or exactly or at most 318, at least or exactly or at most 319, at least or exactly or at most 320, at least or exactly or at most 321, at least or exactly or at most 322, at least or exactly or at most 323, at least or exactly or at most 324, at least or exactly or at most 325, at least or exactly or at most 326, at least or exactly or at most 327, at least or exactly or at most 328, at least or exactly or at most 329, at least or exactly or at most 330, at least or exactly or at most 331, at least or exactly or at most 332, at least or exactly or at most 333, at least or exactly or at most 334, at least or exactly or at most 335, at least or exactly or at most 336, at least or exactly or at most 337, at least or exactly or at most 338, at least or exactly or at most 339, at least or exactly or at most 340, at least or exactly or at most 341, at least or exactly or at most 342, at least or exactly or at most 343, at least or exactly or at most 344, at least or exactly or at most 345, at least or exactly or at most 346, at least or exactly or at most 347, at least or exactly or at most 348, at least or exactly or at most 349, at least or exactly or at most 350, at least or exactly or at most 351, at least or exactly or at most 352, at least or exactly or at most 353, at least or exactly or at most 354, at least or exactly or at most 355, at least or exactly or at most 356, at least or exactly or at most 357, at least or exactly or at most 358, at least or exactly or at most 359, at least or exactly or at most 360, at least or exactly or at most 361, at least or exactly or at most 362, at least or exactly or at most 363, at least or exactly or at most 364, at least or exactly or at most 365, at least or exactly or at most 366, at least or exactly or at most 367, at least or exactly or at most 368, at least or exactly or at most 369, at least or exactly or at most 370, at least or exactly or at most 371, at least or exactly or at most 372, at least or exactly or at most 373, at least or exactly or at most 374, at least or exactly or at most 375, at least or exactly or at most 376, at least or exactly or at most 377, at least or exactly or at most 378, at least or exactly or at most 379, at least or exactly or at most 380, at least or exactly or at most 381, at least or exactly or at most 382, at least or exactly or at most 383, at least or exactly or at most 384, at least or exactly or at most 385, at least or exactly or at most 386, at least or exactly or at most 387, at least or exactly or at most 388, at least or exactly or at most 389, at least or exactly or at most 390, at least or exactly or at most 391, at least or exactly or at most 392, at least or exactly or at most 393, at least or exactly or at most 394, at least or exactly or at most 395, at least or exactly or at most 396, at least or exactly or at most 397, at least or exactly or at most 398, at least or exactly or at most 399, at least or exactly or at most 400, at least or exactly or at most 401, at least or exactly or at most 402, at least or exactly or at most 403, at least or exactly or at most 404, at least or exactly or at most 405, at least or exactly or at most 406, at least or exactly or at most 407, at least or exactly or at most 408, at least or exactly or at most 409, at least or exactly or at most 410, at least or exactly or at most 411, at least or exactly or at most 412, at least or exactly or at most 413, at least or exactly or at most 414, at least or exactly or at most 415, at least or exactly or at most 416, at least or exactly or at most 417, at least or exactly or at most 418, at least or exactly or at most 419, at least or exactly or at most 420, at least or exactly or at most 421, at least or exactly or at most 422, and at least or exactly or at most 423 consecutive nucleotides in the amino acid encoding part of any one of SEQ ID NOs: 17-48, 50, and 51.

32. The nucleic acid fragment according to any one of claims 29-31, wherein the sequence identity with the nucleotide sequence in i) or ii) is at least 65%, such as at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99%.

33. The nucleic acid fragment according to any one of claims 29-31, wherein the sequence identity with the nucleotide sequence in iii) is at least 65%, such as at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99%.

34. A vector comprising the nucleic acid according to any one of claims 29-33, such as a cloning vector or an expression vector.

35. The vector according to claim 34, which comprises in operable linkage and in the 5'-3' direction, an expression control region comprising an enhancer/promoter for driving expression of the nucleic acid fragment defined in claim 29-i), optionally a signal peptide coding sequence, a nucleotide sequence defined in claim 29-i), and optionally a terminator.

36. The vector according to claim 34 or 35, wherein the expression control region drives expression in prokaryotic cell such as a bacterium, e.g. in E coli.

37. The vector according to claim any one of claims 34-36, which is capable of autonomous replication.

38. The vector according to any one of claims 34-37, which is capable of being integrated into the genome of a host cell.

39. The vector according to any one of claims 34-38, which is incapable of being integrated into the genome of a mammalian host cell.

40. The vector according to any one of claims 34-39, which is selected from the group consisting of a virus, such as a attenuated virus, a bacteriophage, a plasmid, a minichromosome, and a cosmid.

41. A cell which is transformed so as to carry the vector according to any one of claims 34-40.

42. The transformed cell according to claim 41, which is capable of replicating the nucleic acid fragment defined in claim 29-i).

43. The transformed cell according to claim 42, which is capable of expressing the nucleic acid fragment defined in claim 29-i).

44. The transformed cell according to any one of claims 41-43, which is selected from a prokaryotic cell and a eukaryotic cell.

45. The transformed cell according to any one of claims 41-43, which is a bacterial cell selected from the group consisting of Escherichia (such as E. coli.), Bacillus (e.g. Bacillus subtilis), Salmonella, and Mycobacterium, preferably non-pathogenic, e.g. M. bovis BCG.

46. The transformed cell according to any one of claims 41-45, which is stably transformed by having the nucleic acid defined in claim 29-i) stably integrated into its genome.

47. The transformed cell according to any one of claims 41-46, which secretes or carries on its surface the polypeptide according to any one of claims 1-28.

48. The transformed cell according to claim 47, wherein the cell is a bacterium and secretion is into the periplasmic space.

49. A cell line derived from a transformed cell according to any one of claims 41-48.

50. A pharmaceutical composition comprising a polypeptide according to any one of claims 1-28, a nucleic acid fragment according to any one of claims 29-33, a vector according to any one of claims 34-40, or a cell according to any one of claims 41-48, and a pharmaceutically acceptable carrier, vehicle or diluent.

51. The pharmaceutical composition according to claim 50, which further comprises an immunological adjuvant.

52. The pharmaceutical composition according to claim 51, wherein the adjuvant is an aluminium based adjuvant.

53. A method for inducing immunity in an animal by administering at least once an immunogenically effective amount of a polypeptide according to any one of claims 1-28, a nucleic acid fragment according to any one of claims 29-33, a vector according to any one of claims 34-340, a cell according to any one of claims 41-48, or a pharmaceutical composition according to any one of claims 50-52 so as to induce adaptive immunity against S. aureus in the animal.

54. The method according to claim 53, wherein, when the polypeptide according to any one of claim 1-28 or a composition comprising said polypeptide is administered, the animal receives between 0.5 and 5,000 .mu.g of the polypeptide according to any one of claims 1-28 per administration.

55. The method according to claim 53 or 54, wherein the animal receives a priming administration and one or more booster administrations.

56. The method according to any one of claims 53-55, wherein the animal is a human being.

57. The method according to any one of claims 53-56, wherein the administration is for the purpose of inducing protective immunity against S. aureus.

58. The method according to claim 57, wherein the protective immunity is effective in reducing the risk of attracting infection with S. aureus or is effective in treating or ameliorating infection with S. aureus.

59. The method according to any one of claims 53-55, wherein the administration is for the purpose of inducing antibodies specific for S. aureus and wherein said antibodies or B-lymphocytes producing said antibodies are subsequently recovered from the animal.

60. The method according to any one of claims 53-55, wherein the administration is for the purpose of inducing antibodies specific for S. aureus and wherein B-lymphocytes producing said antibodies are subsequently recovered from the animal and used for preparation of monoclonal antibodies.

61. A polyclonal antibody in which the antibodies specifically bind to at least one polypeptide according to any one of claims 1-28, and which is essentially free from antibodies binding specifically to other S. aureus polypeptides.

62. An isolated monoclonal antibody or antibody analogue which binds specifically to a polypeptide according to any one of claims 1-28.

63. The isolated monoclonal antibody or antibody analogue according to claim 62, which is a monoclonal antibody selected from a multi-domain antibody such as a murine antibody, a chimeric antibody such as a humanized antibody, a fully human antibody, and single-domain antibody of a llama or a camel, or which is an antibody analogue selected from a fragment of an antibody such as an Fab or an F(ab').sub.2, and an scFV.

64. A pharmaceutical composition comprising an antibody according to any one of claims 61-63 and a pharmaceutically acceptable carrier, vehicle or diluent.

65. A method for prophylaxis, treatment or amelioration of infection with S. aureus, in particular infection with multi-resistant S. aureus, comprising administering a therapeutically effective amount of an antibody according to any one of claims 61-63 or a pharmaceutical composition according to claim 63 to an individual in need thereof.

66. A method for determining, quantitatively or qualitatively, the presence of S. aureus, in particular the presence of multi-resistant S. aureus, in a sample, the method comprising contacting the sample with an antibody according to any one of claims 61-63 and detecting the presence of antibody bound to material in the sample.

67. A method for determining, quantitatively or qualitatively, the presence of antibodies specific for S. aureus, in particular the presence of antibodies specific for multi-resistant S. aureus, in a sample, the method comprising contacting the sample with a polypeptide according to any one of claims 1-28 and detecting the presence of antibody said polypeptide.

68. A method for determining, quantitatively or qualitatively, the presence of a nucleic acid characteristic of S. aureus, in particular the presence of a nucleic acid characteristic of multi-resistant S. aureus, in a sample, the method comprising contacting the sample with a nucleic acid fragment according to any one of claims 29-33 and detecting the presence of nucleic acid in the sample that hybridized to said nucleic acid fragment.

69. The method according to claim 68, which includes at least one step of molecular amplification of the nucleic acid which is to be detected in the sample, for instance a step of PCR amplification.

70. A method for the preparation of the polypeptide according to any one of claims 1-28, comprising culturing a transformed cell according to claim 43 and any one of claims 44-48, insofar as these depend on claim 43 under conditions that facilitate that the transformed cell expresses the nucleic acid fragment according to claim 29-i) and any one of claims 30-33 insofar as these depend on claim 29-i) and subsequently recovering said polypeptide, or preparing said polypeptide by means of solid or liquid phase peptide synthesis.

71. A method for determining whether a substance, such as an antibody, is potentially useful for treating infection with S. aureus, the method comprising contacting the polypeptide according to any one of claims 1-28 with the substance and subsequently establishing whether the substance has at least one of the following characteristics: 1) the ability to bind specifically to said polypeptide, 2) the ability to compeed with said polypeptide for specific binding to a ligand/receptor, 3) the ability to specifically inactivate said polypeptide.

72. A method for determining whether a substance, such as a nucleic acid, is potentially useful for treating infection with S. aureus, the method comprising contacting the substance with the nucleic acid fragment of any one of claims 29-33 and subsequently establishing whether the substance has either the ability to 1) bind specifically to the nucleic acid fragment, or 2) bind specifically to a nucleic acid that hybridizes specifically with the nucleic acid fragment.

73. The polypeptide according to any one of claims 1-28 for use as a pharmaceutical.

74. The polypeptide according to any one of claims 1-28 for use as a pharmaceutical in the treatment, prophylaxis or amelioration of infection with S. aureus.

75. The nucleic acid fragment according to any one of claims 29-33 or the vector according to any one of claims 34-40 for use as a pharmaceutical.

76. The nucleic acid fragment according to any one of claims 29-33 or the vector according to any one of claims 34-40 for use as a pharmaceutical in the treatment, prophylaxis or amelioration of infection with S. aureus.

77. The cell according to any one of claims 41-48 for use as a pharmaceutical.

78. The cell according to any one of claims 41-48 for use as a pharmaceutical in the treatment, prophylaxis or amelioration of infection with S. aureus.

79. The antibody, antibody fragment or antibody analogue according to any one of claims 61-63 for use as a pharmaceutical.

80. The antibody, antibody fragment or antibody analogue according to any one of claims 61-63 for use as a pharmaceutical in the treatment, prophylaxis or amelioration of infection with S. aureus.
Description


FIELD OF THE INVENTION

[0001] The present invention relates to the field of antimicrobial prophylaxis and therapy. In particular the present invention relates to novel proteins and polynucleotides derived from Staphylococcus aureus. The invention further relates to vectors comprising the polynucleotides, transformed host organisms expressing the polynucleotides, antibodies (mono- or polyclonal) specific for the polypeptides as well as diagnostic, prophylactic and therapeutic uses and methods. Finally, also methods of preparation are part of the invention.

BACKGROUND OF THE INVENTION

[0002] Bacterial infections are in most instances successfully treated by administration of antibiotics to patients in need thereof. However, due to careless or thoughtless use of powerful antibiotics, many pathological germs become resistant against antibiotics over time. One threatening example is Staphylococcus aureus. In particular in hospitals this bacterium is of relevance. So-called Methicillin Resistant S. Aureus (MRSA) strains jeopardize patient's survival in hospitals, in particular after surgery.

[0003] Vaccination is considered to be a very effective method of preventing infectious diseases in human and veterinary health care. Vaccination is the administration of immungenically effective amounts of antigenic material (the vaccine) to produce immunity to a disease/disease-causing pathogenic agent. Vaccines have contributed to the eradication of smallpox, the near eradication of polio, and the control of a variety of diseases, including rubella, measles, mumps, chickenpox, typhoid fever.

[0004] Before "the genomic era", vaccines were based on killed or live attenuated, microorganisms, or parts purified from them. Subunit vaccines are considered as a modern upgrade of these types of vaccine, as the subunit vaccines contain one or more protective antigens, which are more or less the weak spot of the pathogen. Hence, in order to develop subunit vaccines, it is critical to identify the proteins, which are important for inducing protection and to eliminate others.

[0005] An antigen is said to be protective if it is able to induce protection from subsequent challenge by a disease-causing infectious agent in an appropriate animal model following immunization.

[0006] The empirical approach to subunit vaccine development, which includes several steps, begins with pathogen cultivation, followed by purification into components, and then testing of antigens for protection. Apart from being time and labour consuming, this approach has several limitations that can lead to failure. It is not possible to develop vaccines using this approach for microorganisms, which cannot easily be cultured and only allows for the identification of the antigens, which can be obtained in sufficient quantities. The empirical approach has a tendency to focus on the most abundant proteins, which in some cases are not immuno-protective. In other cases, the antigen expressed during in vivo infection is not expressed during in vitro cultivation. Furthermore, antigen discovery by use of the empirical approach demands an extreme amount of proteins in order to discover the protective antigens, which are like finding needles in the haystack. This renders it a very expensive approach, and it limits the vaccine development around diseases, which is caused by pathogens with a large genome or disease areas, which perform badly in a cost-effective perspective.

OBJECT OF THE INVENTION

[0007] It is an object of embodiments of the invention to provide S. aureus derived antigenic polypeptides that may serve as constituents in vaccines against S. aureus infections and in diagnosis of S. aureus infections. It is also an object to provide nucleic acids, vectors, transformed cells, vaccine compositions, and other useful means for molecular cloning as well as for therapy and diagnosis with relevance for S. aureus.

SUMMARY OF THE INVENTION

[0008] It has been found by the present inventor(s) that S. aureus, in particular drug resistant S. aureus, expresses a number of hitherto unknown putatively surface exposed proteins which are candidates as vaccine targets as well as candidates as immunizing agents for preparation of antibodies that target S. aureus.

[0009] So, in a first aspect the present invention relates to a polypeptide comprising

a) an amino acid sequence selected from the group consisting of any one of SEQ ID NOs: 1-16 and 49, or b) an amino acid sequence consisting of at least or exactly or at most 5 contiguous amino acid residues from any one of SEQ ID NOs: 1-16 and 49, or c) an amino acid sequence having a sequence identity of at least 60% with the amino acid sequence of a), d) an amino acid sequence having a sequence identity of at least 60% with the amino acid sequence of b), or e) an assembly of amino acids derived from any one of SEQ ID NOs: 1-16 and 49, which has essentially the same 3D conformation as in the protein from which said assembly is derived so as to constitute a B-cell epitope, said polypeptide being antigenic in a mammal.

[0010] In another aspect, the invention relates to an isolated nucleic acid fragment, which comprises

i) a nucleotide sequence encoding a polypeptide of the invention, or ii) a nucleotide sequence consisting of any one of SEQ ID NOs: 17-48, 50, and 51. iii) a nucleotide sequence consisting of at least or exactly or at most 10 consecutive nucleotides in any one of SEQ ID NOs: 17-48, 50, and 51, iv) a nucleotide sequence having a sequence identity of at least 60% with the nucleotide sequence in i) or ii), v) a nucleotide sequence having a sequence identity of at least 60% with the nucleotide sequence in iii), vi) a nucleotide sequence complementary to the nucleotide sequence in i)-v), or vii) a nucleotide sequence which hybridizes under stringent conditions with the nucleotide sequence in i)-vi).

[0011] In a third aspect, the invention relates to a vector comprising the nucleic acid of the invention, such as a cloning vector or an expression vector.

[0012] In fourth aspect, the invention relates to a cell which is transformed so as to carry the vector of the invention.

[0013] In a fifth aspect, the invention relates to a pharmaceutical composition comprising a polypeptide of the invention, a nucleic acid fragment of the invention, a vector of the invention, or a transformed cell of the invention, and a pharmaceutically acceptable carrier, vehicle or diluent.

[0014] In a sixth aspect, the invention relates to a method for inducing immunity in an animal by administering at least once an immunogenically effective amount of a polypeptide of the invention, a nucleic acid fragment of the invention, a vector of the invention, a transformed cell of the invention, or a pharmaceutical composition of the fifth aspect of the invention so as to induce adaptive immunity against S. aureus in the animal.

[0015] In a seventh and eighth aspect, the invention relates to 1) a polyclonal antibody in which the antibodies specifically bind to at least one polypeptide of the invention, and which is essentially free from antibodies binding specifically to other S. aureus polypeptides, and to 2) an isolated monoclonal antibody or antibody analogue which binds specifically to a polypeptide of the invention. In a related ninth aspect, the invention relates to a pharmaceutical composition comprising such a polyclonal or monoclonal antibody and a pharmaceutically acceptable carrier, vehicle or diluent.

[0016] In a 10.sup.th aspect, the invention relates to a method for prophylaxis, treatment or amelioration of infection with S. aureus, comprising administering a therapeutically effective amount of an antibody of the 7.sup.th or 8.sup.th aspect of the invention or a pharmaceutical composition of the eighth aspect to an individual in need thereof.

[0017] In an 11.sup.th aspect, the invention relates to a method for determining, quantitatively or qualitatively, the presence of S. aureus, in particular the presence of multi-resistant S. aureus, in a sample, the method comprising contacting the sample with an antibody of aspects 8 or 9 of the invention and detecting the presence of antibody bound to material in the sample.

[0018] In an 12.sup.th aspect of the invention is provided a method for determining, quantitatively or qualitatively, the presence of antibodies specific for S. aureus, in particular the presence of antibodies specific for multi-resistant S. aureus, in a sample, the method comprising contacting the sample with a polypeptide of the invention and detecting the presence of antibody that specifically bind said polypeptide.

[0019] In a 13.sup.th aspect, the invention relates to a method for determining, quantitatively or qualitatively, the presence of a nucleic acid characteristic of S. aureus, in particular the presence of a nucleic acid characteristic of multi-resistant S. aureus, in a sample, the method comprising contacting the sample with a nucleic acid fragment of the invention and detecting the presence of nucleic acid in the sample that hybridizes to said nucleic acid fragment.

[0020] In a 14.sup.th aspect, the invention relates to a method for the preparation of the polypeptide of the invention, comprising [0021] culturing a transformed cell of the present invention, which is capable of expressing the nucleic acid of the invention, under conditions that facilitate that the transformed cell expresses the nucleic acid fragment of the invention, which encodes a polypeptide of the invention, and subsequently recovering said polypeptide, or [0022] preparing said polypeptide by means of solid or liquid phase peptide synthesis.

[0023] In a 15.sup.th aspect, the invention relates to a method for determining whether a substance, such as an antibody, is potentially useful for treating infection with S. aureus, the method comprising contacting the polypeptide of the invention with the substance and subsequently establishing whether the substance has at least one of the following characteristics:

1) the ability to bind specifically to said polypeptide, 2) the ability to compeed with said polypeptide for specific binding to a ligand/receptor, and 3) the ability to specifically inactivate said polypeptide.

[0024] Finally, in a 16.sup.th aspect, the invention relates to a method for determining whether a substance, such as a nucleic acid, is potentially useful for treating infection with S. aureus, the method comprising contacting the substance with the nucleic acid fragment of claim of the invention and subsequently establishing whether the substance has either the ability to

1) bind specifically to the nucleic acid fragment, or 2) bind specifically to a nucleic acid that hybridizes specifically with the nucleic acid fragment.

LEGENDS TO THE FIGURES

[0025] FIG. 1: Survival plots for mice vaccinated with a polypeptide of the invention and a negative control, respectively. Solid line: negative control. Interrupted line: polypeptide of the invention.

[0026] FIG. 2: Survival plots for mice vaccinated with a polypeptide of the invention and a negative control, respectively. Solid line: negative control. Interrupted line: polypeptide of the invention.

[0027] FIG. 3: Survival plots for mice vaccinated with a polypeptide of the invention and a negative control, respectively. Solid line: negative control. Interrupted line: polypeptide of the invention.

[0028] FIG. 4: Survival plots for mice vaccinated with a polypeptide of the invention and a negative control, respectively. Solid line: negative control. Interrupted line: polypeptide of the invention.

[0029] FIG. 5: Survival plots for mice vaccinated with a polypeptide of the invention and a negative control, respectively. Interrupted line: negative control. Solid line: polypeptide of the invention.

[0030] FIG. 6: Survival plots for mice vaccinated with a polypeptide of the invention and a negative control, respectively. Interrupted line: negative control. Solid line: polypeptide of the invention.

[0031] FIG. 7: Survival plots for mice vaccinated with a polypeptide of the invention and a negative control, respectively. Interrupted line: negative control. Solid line: polypeptide of the invention.

DETAILED DISCLOSURE OF THE INVENTION

Definitions

[0032] The term "polypeptide" is in the present context intended to mean both short peptides of from 2 to 10 amino acid residues, oligopeptides of from 11 to 100 amino acid residues, and polypeptides of more than 100 amino acid residues. Further-more, the term is also intended to include proteins, i.e. functional biomolecules comprising at least one polypeptide; when comprising at least two polypeptides, these may form complexes, be covalently linked, or may be non-covalently linked. The polypeptide(s) in a protein can be glycosylated and/or lipidated and/or comprise prosthetic groups.

[0033] The term "subsequence" means any consecutive stretch of at least 3 amino acids or, when relevant, of at least 3 nucleotides, derived directly from a naturally occurring amino acid sequence or nucleic acid sequence, respectively

[0034] The term "amino acid sequence" s the order in which amino acid residues, connected by peptide bonds, lie in the chain in peptides and proteins.

[0035] The term "adjuvant" has its usual meaning in the art of vaccine technology, i.e. a substance or a composition of matter which is 1) not in itself capable of mounting a specific immune response against the immunogen of the vaccine, but which is 2) nevertheless capable of enhancing the immune response against the immunogen. Or, in other words, vaccination with the adjuvant alone does not provide an immune response against the immunogen, vaccination with the immunogen may or may not give rise to an immune response against the immunogen, but the combined vaccination with immunogen and adjuvant induces an immune response against the immunogen which is stronger than that induced by the immunogen alone.

[0036] "Sequence identity" is in the context of the present invention determined by comparing 2 optimally aligned sequences of equal length (e.g. DNA, RNA or amino acid) according to the following formula: (N.sub.ref-N.sub.dif)100/N.sub.ref, wherein N.sub.ref is the number of residues in one of the 2 sequences and N.sub.dif is the number of residues which are non-identical in the two sequences when they are aligned over their entire lengths and in the same direction. So, two sequences 5'-ATTCGGAACC-3' and 5'-ATACGGGACC-3' will provide the sequence identity 80% (N.sub.ref=10 and N.sub.dif=2).

[0037] An "assembly of amino acids" means two or more amino acids bound together by physical or chemical means.

[0038] The "3D conformation" is the 3 dimensional structure of a biomolecule such as a protein. In monomeric polypeptides/proteins, the 3D conformation is also termed "the tertiary structure" and denotes the relative locations in 3 dimensional space of the amino acid residues forming the polypeptide.

[0039] "An immunogenic carrier" is a molecule or moiety to which an immunogen or a hapten can be coupled in order to enhance or enable the elicitation of an immune response against the immunogen/hapten. Immunogenic carriers are in classical cases relatively large molecules (such as tetanus toxoid, KLH, diphtheria toxoid etc.) which can be fused or conjugated to an immunogen/hapten, which is not sufficiently immunogenic in its own right--typically, the immunogenic carrier is capable of eliciting a strong T-helper lymphocyte response against the combined substance constituted by the immunogen and the immunogenic carrier, and this in turn provides for improved responses against the immungon by B-lymphocytes and cytotoxic lymphocytes. More recently, the large carrier molecules have to a certain extent been substituted by so-called promiscuous T-helper epitopes, i.e. shorter peptides that are recognized by a large fraction of HLA haplotypes in a population, and which elicit T-helper lymphocyte responses.

[0040] A "T-helper lymphocyte response" is an immune response elicited on the basis of a peptide, which is able to bind to an MHC class II molecule (e.g. an HLA class II molecule) in an antigen-presenting cell and which stimulates T-helper lymphocytes in an animal species as a consequence of T-cell receptor recognition of the complex between the peptide and the MHC Class II molecule prese

[0041] An "immunogen" is a substance of matter which is capable of inducing an adaptive immune response in a host, whose immune system is confronted with the immunogen. As such, immunogens are a subset of the larger genus "antigens", which are substances that can be recognized specifically by the immune system (e.g. when bound by antibodies or, alternatively, when fragments of the are antigens bound to MHC molecules are being recognized by T-cell receptors) but which are not necessarily capable of inducing immunity--an antigen is, however, always capable of eliciting immunity, meaning that a host that has an established memory immunity against the antigen will mount a specific immune response against the antigen.

[0042] A "hapten" is a small molecule, which can neither induce or elicit an immune response, but if conjugated to an immunogenic carrier, antibodies or TCRs that recognize the hapten can be induced upon confrontation of the immune system with the hapten carrier conjugate.

[0043] An "adaptive immune response" is an immune response in response to confrontation with an antigen or immunogen, where the immune response is specific for antigenic determinants of the antigen/immunogen--examples of adaptive immune responses are induction of antigen specific antibody production or antigen specific induction/activation of T helper lymphocytes or cytotoxic lymphocytes.

[0044] A "protective, adaptive immune response" is an antigen-specific immune response induced in a subject as a reaction to immunization (artificial or natural) with an antigen, where the immune response is capable of protecting the subject against subsequent challenges with the antigen or a pathology-related agent that includes the antigen. Typically, prophylactic vaccination aims at establishing a protective adaptive immune response against one or several pathogens.

[0045] "Stimulation of the immune system" means that a substance or composition of matter exhibits a general, non-specific immunostimulatory effect. A number of adjuvants and putative adjuvants (such as certain cytokines) share the ability to stimulate the immune system. The result of using an immunostimulating agent is an increased "alertness" of the immune system meaning that simultaneous or subsequent immunization with an immunogen induces a significantly more effective immune response compared to isolated use of the immunogen.

[0046] Hybridization under "stringent conditions" is herein defined as hybridization performed under conditions by which a probe will hybridize to its target sequence, to a detectably greater degree than to other sequences. Stringent conditions are target-sequence-dependent and will differ depending on the structure of the polynucleotide. By controlling the stringency of the hybridization and/or washing conditions, target sequences can be identified which are 100% complementary to a probe (homologous probing). Alternatively, stringency conditions can be adjusted to allow some mismatching in sequences so that lower degrees of similarity are detected (heterologous probing). Specificity is typically the function of post-hybridization washes, the critical factors being the ionic strength and temperature of the final wash solution. Generally, stringent wash temperature conditions are selected to be about 5.degree. C. to about 2.degree. C. lower than the melting point (Tm) for the specific sequence at a defined ionic strength and pH. The melting point, or denaturation, of DNA occurs over a narrow temperature range and represents the disruption of the double helix into its complementary single strands. The process is described by the temperature of the midpoint of transition, Tm, which is also called the melting temperature. Formulas are available in the art for the determination of melting temperatures.

[0047] The term "animal" is in the present context in general intended to denote an animal species (preferably mammalian), such as Homo sapiens, Canis domesticus, etc. and not just one single animal. However, the term also denotes a population of such an animal species, since it is important that the individuals immunized according to the method of the invention substantially all will mount an immune response against the immunogen of the present invention.

[0048] As used herein, the term "antibody" refers to a polypeptide or group of polypeptides composed of at least one antibody combining site. An "antibody combining site" is the three-dimensional binding space with an internal surface shape and charge distribution complementary to the features of an epitope of an antigen, which allows a binding of the antibody with the antigen. "Antibody" includes, for example, vertebrate antibodies, hybrid antibodies, chimeric antibodies, humanised antibodies, altered antibodies, univalent antibodies, Fab proteins, and single domain antibodies.

[0049] "Specific binding" denotes binding between two substances which goes beyond binding of either substance to randomly chosen substances and also goes beyond simple association between substances that tend to aggregate because they share the same overall hydrophobicity or hydrophilicity. As such, specific binding usually involves a combination of electrostatic and other interactions between two conformationally complementary areas on the two substances, meaning that the substances can "recognize" each other in a complex mixture.

[0050] The term "vector" is used to refer to a carrier nucleic acid molecule into which a heterologous nucleic acid sequence can be inserted for introduction into a cell where it can be replicated and expressed. The term further denotes certain biological vehicles useful for the same purpose, e.g. viral vectors and phage--both these infectious agents are capable of introducing a heterelogous nucleic acid sequence

[0051] The term "expression vector" refers to a vector containing a nucleic acid sequence coding for at least part of a gene product capable of being transcribed. In some cases, when the transcription product is an mRNA molecule, this is in trun translated into a protein, polypeptide, or peptide.

Specific Embodiments of the Invention

The Polypeptides of the Invention

[0052] In some embodiments the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention constitute at least or exactly or at most 6 contiguous amino acid residues, such as at least or exactly or at most 7, at least or exactly or at most 8, at least or exactly or at most 9, at least or exactly or at most 10, at least or exactly or at most 11, at least or exactly or at most 12, at least or exactly or at most 13, at least or exactly or at most 14, at least or exactly or at most 15, at least or exactly or at most 16, at least or exactly or at most 17, at least or exactly or at most 18, at least or exactly or at most 19, at least or exactly or at most 20, at least or exactly or at most 21, at least or exactly or at most 22, at least or exactly or at most 23, at least or exactly or at most 24, at least or exactly or at most 25, at least or exactly or at most 26, at least or exactly or at most 27 at least or exactly or at most 28, at least or exactly or at most 29, at least or exactly or at most 30, at least or exactly or at most 31, at least or exactly or at most 32, at least or exactly or at most 33, at least or exactly or at most 34, at least or exactly or at most 35, at least or exactly or at most 36, at least or exactly or at most 37, at least or exactly or at most 38, at least or exactly or at most 39, at least or exactly or at most 40, at least or exactly or at most 41, at least or exactly or at most 42, at least or exactly or at most 43, at least or exactly or at most 44, at least or exactly or at most 45, at least or exactly or at most 46, at least or exactly or at most 47, at least or exactly or at most 48, at least or exactly or at most 49, at least or exactly or at most 50, at least or exactly or at most 51, at least or exactly or at most 52, at least or exactly or at most 53, at least or exactly or at most 54, at least or exactly or at most 55, at least or exactly or at most 56, at least or exactly or at most 57, at least or exactly or at most 58, at least or exactly or at most 59, at least or exactly or at most 60, at least or exactly or at most 61, at least or exactly or at most 62, at least or exactly or at most 63, at least or exactly or at most 64, at least or exactly or at most 65, at least or exactly or at most 66, at least or exactly or at most 67, at least or exactly or at most 68, at least or exactly or at most 69, at least or exactly or at most 70, at least or exactly or at most 71, at least or exactly or at most 72, at least or exactly or at most 73, at least or exactly or at most 74, at least or exactly or at most 75, at least or exactly or at most 76, at least or exactly or at most 77, at least or exactly or at most 78, at least or exactly or at most 79, at least or exactly or at most 80, at least or exactly or at most 81, at least or exactly or at most 82, at least or exactly or at most 83, at least or exactly or at most 84, at least or exactly or at most 85, at least or exactly or at most 86, at least or exactly or at most 87, at least or exactly or at most 88, at least or exactly or at most 89, at least or exactly or at most 90, at least or exactly or at most 91, at least or exactly or at most 92, at least or exactly or at most 93, at least or exactly or at most 94, at least or exactly or at most 95, at least or exactly or at most 96, at least or exactly or at most 97, at least or exactly or at most 98, at least or exactly or at most 99, at least or exactly or at most 100, at least or exactly or at most 101, at least or exactly or at most 102, at least or exactly or at most 103, at least or exactly or at most 104, at least or exactly or at most 105, at least or exactly or at most 106, at least or exactly or at most 107, at least or exactly or at most 108, at least or exactly or at most 109, at least or exactly or at most 110, at least or exactly or at most 111, at least or exactly or at most 112, at least or exactly or at most 113, at least or exactly or at most 114, at least or exactly or at most 115, at least or exactly or at most 116, at least or exactly or at most 117, at least or exactly or at most 118, at least or exactly or at most 119, at least or exactly or at most 120, at least or exactly or at most 121, at least or exactly or at most 122, at least or exactly or at most 123, at least or exactly or at most 124, at least or exactly or at most 125, at least or exactly or at most 126, at least or exactly or at most 127, at least or exactly or at most 128, at least or exactly or at most 129, at least or exactly or at most 130, at least or exactly or at most 131, at least or exactly or at most 132, at least or exactly or at most 133, at least or exactly or at most 134, at least or exactly or at most 135, at least or exactly or at most 136, at least or exactly or at most 137, at least or exactly or at most 138, and at least or exactly or at most 139 contiguous amino acid residues.

[0053] The number of contiguous amino acids can be higher, for all of SEQ ID NOs. 2-16 and 49. Another way to phrase this is that for each of SEQ ID NOs: 1-16 and 49, the number of the contiguous amino acid residues is at least or exactly or at most N-n, where N is the length of the sequence ID in question and n is any integer between N-5 and 0; that is, the at least 5 contiguous amino acids can be at least any number between 5 and the length of the reference sequence minus one, in increments of one. Consequently:

[0054] Insofar as embodiment b relates to SEQ ID NO: 2-16 and 49, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 140, at least or exactly or at most 141, at least or exactly or at most 142, at least or exactly or at most 143, at least or exactly or at most 144, at least or exactly or at most 145, at least or exactly or at most 146, at least or exactly or at most 147, at least or exactly or at most 148, at least or exactly or at most 149, at least or exactly or at most 150, at least or exactly or at most 151, at least or exactly or at most 152, at least or exactly or at most 153, at least or exactly or at most 154, at least or exactly or at most 155, at least or exactly or at most 156, at least or exactly or at most 157, at least or exactly or at most 158, at least or exactly or at most 159, at least or exactly or at most 160, at least or exactly or at most 161, at least or exactly or at most 162, at least or exactly or at most 163, at least or exactly or at most 164, at least or exactly or at most 165, at least or exactly or at most 166, at least or exactly or at most 167, at least or exactly or at most 168, at least or exactly or at most 169, at least or exactly or at most 170, at least or exactly or at most 171, at least or exactly or at most 172, at least or exactly or at most 173, at least or exactly or at most 174, at least or exactly or at most 175, at least or exactly or at most 176, at least or exactly or at most 177, at least or exactly or at most 178, at least or exactly or at most 179, at least or exactly or at most 180, at least or exactly or at most 181, at least or exactly or at most 182, at least or exactly or at most 183, at least or exactly or at most 184, at least or exactly or at most 185, at least or exactly or at most 186, at least or exactly or at most 187, at least or exactly or at most 188, at least or exactly or at most 189, at least or exactly or at most 190, at least or exactly or at most 191, or at least or exactly or at most 192 contiguous amino acid residues.

[0055] Insofar as embodiment b relates to SEQ ID NO: 3-16 and 49, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 193, at least or exactly or at most 194, at least or exactly or at most 195, at least or exactly or at most 196, at least or exactly or at most 197, at least or exactly or at most 198, at least or exactly or at most 199, at least or exactly or at most 200, at least or exactly or at most 201, at least or exactly or at most 202, at least or exactly or at most 203, at least or exactly or at most 204, at least or exactly or at most 205, at least or exactly or at most 206, at least or exactly or at most 207, or at least or exactly or at most 208 contiguous amino acid residues.

[0056] Insofar as embodiment b relates to SEQ ID NO: 4-16 and 49, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 209, at least or exactly or at most 210, at least or exactly or at most 211, at least or exactly or at most 212, at least or exactly or at most 213, at least or exactly or at most 214, at least or exactly or at most 215, at least or exactly or at most 216, at least or exactly or at most 217, at least or exactly or at most 218, at least or exactly or at most 219, at least or exactly or at most 220, at least or exactly or at most 221, at least or exactly or at most 222, at least or exactly or at most 223, at least or exactly or at most 224, at least or exactly or at most 225, at least or exactly or at most 226, at least or exactly or at most 227, at least or exactly or at most 228, at least or exactly or at most 229, at least or exactly or at most 230, at least or exactly or at most 231, at least or exactly or at most 232, at least or exactly or at most 233, at least or exactly or at most 234, at least or exactly or at most 235, at least or exactly or at most 236, at least or exactly or at most 237, at least or exactly or at most 238, at least or exactly or at most 239, at least or exactly or at most 240, or at least or exactly or at most 241 contiguous amino acid residues.

[0057] Insofar as embodiment b relates to SEQ ID NO: 5-16 and 49, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 242, at least or exactly or at most 243, at least or exactly or at most 244, at least or exactly or at most 245, at least or exactly or at most 246, at least or exactly or at most 247, at least or exactly or at most 248, at least or exactly or at most 249, at least or exactly or at most 250, at least or exactly or at most 251, at least or exactly or at most 252, at least or exactly or at most 253, at least or exactly or at most 254, at least or exactly or at most 255, at least or exactly or at most 256, at least or exactly or at most 257, at least or exactly or at most 258, at least or exactly or at most 259, at least or exactly or at most 260, at least or exactly or at most 261, at least or exactly or at most 262, at least or exactly or at most 263, at least or exactly or at most 264, at least or exactly or at most 265, at least or exactly or at most 266, at least or exactly or at most 267, at least or exactly or at most 268, at least or exactly or at most 269, at least or exactly or at most 270, at least or exactly or at most 271, at least or exactly or at most 272, at least or exactly or at most 273, at least or exactly or at most 274, at least or exactly or at most 275, at least or exactly or at most 276, at least or exactly or at most 277, at least or exactly or at most 278, at least or exactly or at most 279, at least or exactly or at most 280, at least or exactly or at most 281, at least or exactly or at most 282, at least or exactly or at most 283, at least or exactly or at most 284, at least or exactly or at most 285, at least or exactly or at most 286, at least or exactly or at most 287, at least or exactly or at most 288, at least or exactly or at most 289, at least or exactly or at most 290, at least or exactly or at most 291, at least or exactly or at most 292, at least or exactly or at most 293, at least or exactly or at most 294, at least or exactly or at most 295, at least or exactly or at most 296, at least or exactly or at most 297, at least or exactly or at most 298, at least or exactly or at most 299, at least or exactly or at most 300, at least or exactly or at most 301, at least or exactly or at most 302, at least or exactly or at most 303, at least or exactly or at most 304, at least or exactly or at most 305, at least or exactly or at most 306, at least or exactly or at most 307, at least or exactly or at most 308, at least or exactly or at most 309, at least or exactly or at most 310, at least or exactly or at most 311, at least or exactly or at most 312, at least or exactly or at most 313, at least or exactly or at most 314, at least or exactly or at most 315, at least or exactly or at most 316, at least or exactly or at most 317, at least or exactly or at most 318, at least or exactly or at most 319, at least or exactly or at most 320, at least or exactly or at most 321, at least or exactly or at most 322, at least or exactly or at most 323, at least or exactly or at most 324, at least or exactly or at most 325, or at least or exactly or at most 326 contiguous amino acid residues.

[0058] Insofar as embodiment b relates to SEQ ID NO: 6-16 and 49, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 327, at least or exactly or at most 328, at least or exactly or at most 329, at least or exactly or at most 330, at least or exactly or at most 331, at least or exactly or at most 332, at least or exactly or at most 333, at least or exactly or at most 334, at least or exactly or at most 335, at least or exactly or at most 336, at least or exactly or at most 337, at least or exactly or at most 338, at least or exactly or at most 339, at least or exactly or at most 340, at least or exactly or at most 341, at least or exactly or at most 342, at least or exactly or at most 343, at least or exactly or at most 344, at least or exactly or at most 345, at least or exactly or at most 346, at least or exactly or at most 347, at least or exactly or at most 348, at least or exactly or at most 349, at least or exactly or at most 350, at least or exactly or at most 351, at least or exactly or at most 352, at least or exactly or at most 353, at least or exactly or at most 354, at least or exactly or at most 355, or at least or exactly or at most 356 contiguous amino acid residues.

[0059] Insofar as embodiment b relates to SEQ ID NO: 7-16 and 49, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 357, at least or exactly or at most 358, at least or exactly or at most 359, at least or exactly or at most 360, at least or exactly or at most 361, at least or exactly or at most 362, at least or exactly or at most 363, at least or exactly or at most 364, at least or exactly or at most 365, at least or exactly or at most 366, at least or exactly or at most 367, at least or exactly or at most 368, at least or exactly or at most 369, at least or exactly or at most 370, at least or exactly or at most 371, at least or exactly or at most 372, at least or exactly or at most 373, at least or exactly or at most 374, at least or exactly or at most 375, at least or exactly or at most 376, at least or exactly or at most 377, at least or exactly or at most 378, at least or exactly or at most 379, at least or exactly or at most 380, at least or exactly or at most 381, at least or exactly or at most 382, at least or exactly or at most 383, at least or exactly or at most 384, at least or exactly or at most 385, at least or exactly or at most 386, at least or exactly or at most 387, at least or exactly or at most 388, at least or exactly or at most 389, at least or exactly or at most 390, at least or exactly or at most 391, at least or exactly or at most 392, at least or exactly or at most 393, at least or exactly or at most 394, at least or exactly or at most 395, at least or exactly or at most 396, at least or exactly or at most 397, or at least or exactly or at most 398 contiguous amino acid residues.

[0060] Insofar as embodiment b relates to SEQ ID NO: 8-18 and 49, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 399, at least or exactly or at most 400, at least or exactly or at most 401, at least or exactly or at most 402, at least or exactly or at most 403, at least or exactly or at most 404, at least or exactly or at most 405, at least or exactly or at most 406, or at least or exactly or at most 407 contiguous amino acid residues.

[0061] Insofar as embodiment b relates to SEQ ID NO: 8-18, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 408, at least or exactly or at most 409, at least or exactly or at most 410, at least or exactly or at most 411, at least or exactly or at most 412, at least or exactly or at most 413, at least or exactly or at most 414, at least or exactly or at most 415, at least or exactly or at most 416, at least or exactly or at most 417, at least or exactly or at most 418, at least or exactly or at most 419, at least or exactly or at most 420, at least or exactly or at most 421, at least or exactly or at most 422, at least or exactly or at most 423, at least or exactly or at most 424, at least or exactly or at most 425, at least or exactly or at most 426, at least or exactly or at most 427, at least or exactly or at most 428, at least or exactly or at most 429, at least or exactly or at most 430, at least or exactly or at most 431, at least or exactly or at most 432, at least or exactly or at most 433, at least or exactly or at most 434, at least or exactly or at most 435, at least or exactly or at most 436, at least or exactly or at most 437, at least or exactly or at most 438, at least or exactly or at most 439, at least or exactly or at most 440, at least or exactly or at most 441, at least or exactly or at most 442, at least or exactly or at most 443, at least or exactly or at most 444, at least or exactly or at most 445, at least or exactly or at most 446, at least or exactly or at most 447, at least or exactly or at most 448, at least or exactly or at most 449, at least or exactly or at most 450, at least or exactly or at most 451, at least or exactly or at most 452, at least or exactly or at most 453, at least or exactly or at most 454, at least or exactly or at most 455, at least or exactly or at most 456, at least or exactly or at most 457, at least or exactly or at most 458, at least or exactly or at most 459, at least or exactly or at most 460, at least or exactly or at most 461, at least or exactly or at most 462, at least or exactly or at most 463, at least or exactly or at most 464, at least or exactly or at most 465, at least or exactly or at most 466, at least or exactly or at most 467, at least or exactly or at most 468, at least or exactly or at most 469, at least or exactly or at most 470, at least or exactly or at most 471, at least or exactly or at most 472, at least or exactly or at most 473, at least or exactly or at most 474, at least or exactly or at most 475, at least or exactly or at most 476, at least or exactly or at most 477, at least or exactly or at most 478, at least or exactly or at most 479, at least or exactly or at most 480, at least or exactly or at most 481, at least or exactly or at most 482, at least or exactly or at most 483, at least or exactly or at most 484, at least or exactly or at most 485, at least or exactly or at most 486, at least or exactly or at most 487, at least or exactly or at most 488, at least or exactly or at most 489, at least or exactly or at most 490, at least or exactly or at most 491, at least or exactly or at most 492, at least or exactly or at most 493, or at least or exactly or at most 494 contiguous amino acid residues.

[0062] Insofar as embodiment b relates to SEQ ID NO: 9-18, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 495, at least or exactly or at most 496, at least or exactly or at most 497, at least or exactly or at most 498, at least or exactly or at most 499, at least or exactly or at most 500, at least or exactly or at most 501, at least or exactly or at most 502, at least or exactly or at most 503, at least or exactly or at most 504, at least or exactly or at most 505, at least or exactly or at most 506 contiguous amino acid residues.

[0063] Insofar as embodiment b relates to SEQ ID NO: 10-18, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 507 contiguous amino acid residues or at least or exactly or at most 508 contiguous amino acid residues.

[0064] Insofar as embodiment b relates to SEQ ID NO: 11-18, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 509, at least or exactly or at most 510, at least or exactly or at most 511, at least or exactly or at most 512, at least or exactly or at most 513, or at least or exactly or at most 514 contiguous amino acid residues.

[0065] Insofar as embodiment b relates to SEQ ID NO: 12-18, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 515, at least or exactly or at most 516, at least or exactly or at most 517, at least or exactly or at most 518, at least or exactly or at most 519, at least or exactly or at most 520, at least or exactly or at most 521, at least or exactly or at most 522, at least or exactly or at most 523, at least or exactly or at most 524, at least or exactly or at most 525, at least or exactly or at most 526, at least or exactly or at most 527, at least or exactly or at most 528, at least or exactly or at most 529, at least or exactly or at most 530, at least or exactly or at most 531, at least or exactly or at most 532, at least or exactly or at most 533, at least or exactly or at most 534, at least or exactly or at most 535, at least or exactly or at most 536, at least or exactly or at most 537, at least or exactly or at most 538, at least or exactly or at most 539, at least or exactly or at most 540, at least or exactly or at most 541, at least or exactly or at most 542, at least or exactly or at most 543, at least or exactly or at most 544, at least or exactly or at most 545, at least or exactly or at most 546, at least or exactly or at most 547, at least or exactly or at most 548, at least or exactly or at most 549, at least or exactly or at most 550, at least or exactly or at most 551, at least or exactly or at most 552, at least or exactly or at most 553, at least or exactly or at most 554, at least or exactly or at most 555, at least or exactly or at most 556, at least or exactly or at most 557, at least or exactly or at most 558, at least or exactly or at most 559, at least or exactly or at most 560, at least or exactly or at most 561, at least or exactly or at most 562, or at least or exactly or at most 563 contiguous amino acid residues.

[0066] Insofar as embodiment b relates to SEQ ID NO: 13-18, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 564, at least or exactly or at most 565, at least or exactly or at most 566, at least or exactly or at most 567, at least or exactly or at most 568, at least or exactly or at most 569, at least or exactly or at most 570, at least or exactly or at most 571, at least or exactly or at most 572, at least or exactly or at most 573, at least or exactly or at most 574, at least or exactly or at most 575, at least or exactly or at most 576, at least or exactly or at most 577, at least or exactly or at most 578, at least or exactly or at most 579, at least or exactly or at most 580, at least or exactly or at most 581, at least or exactly or at most 582, at least or exactly or at most 583, at least or exactly or at most 584, at least or exactly or at most 585, at least or exactly or at most 586, at least or exactly or at most 587, at least or exactly or at most 588, at least or exactly or at most 589, at least or exactly or at most 590, at least or exactly or at most 591, at least or exactly or at most 592, at least or exactly or at most 593, at least or exactly or at most 594, at least or exactly or at most 595, at least or exactly or at most 596, at least or exactly or at most 597, at least or exactly or at most 598, at least or exactly or at most 599, at least or exactly or at most 600, at least or exactly or at most 601, at least or exactly or at most 602, at least or exactly or at most 603, at least or exactly or at most 604, at least or exactly or at most 605, at least or exactly or at most 606, at least or exactly or at most 607, at least or exactly or at most 608, at least or exactly or at most 609, at least or exactly or at most 610, at least or exactly or at most 611, at least or exactly or at most 612, at least or exactly or at most 613, at least or exactly or at most 614, at least or exactly or at most 615, at least or exactly or at most 616, at least or exactly or at most 617, or at least or exactly or at most 618 contiguous amino acid residues.

[0067] Insofar as embodiment b relates to SEQ ID NO: 14-18, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 619, at least or exactly or at most 620, at least or exactly or at most 621, at least or exactly or at most 622, at least or exactly or at most 623, at least or exactly or at most 624, at least or exactly or at most 625, at least or exactly or at most 626, at least or exactly or at most 627, at least or exactly or at most 628, at least or exactly or at most 629, at least or exactly or at most 630, at least or exactly or at most 631, at least or exactly or at most 632, at least or exactly or at most 633, at least or exactly or at most 634, at least or exactly or at most 635, at least or exactly or at most 636, at least or exactly or at most 637, at least or exactly or at most 638, at least or exactly or at most 639, at least or exactly or at most 640, at least or exactly or at most 641, at least or exactly or at most 642, at least or exactly or at most 643, at least or exactly or at most 644, at least or exactly or at most 645, at least or exactly or at most 646, at least or exactly or at most 647, at least or exactly or at most 648, at least or exactly or at most 649, at least or exactly or at most 650, at least or exactly or at most 651, at least or exactly or at most 652, at least or exactly or at most 653, at least or exactly or at most 654, at least or exactly or at most 655, at least or exactly or at most 656, at least or exactly or at most 657, at least or exactly or at most 658, at least or exactly or at most 659, at least or exactly or at most 660, at least or exactly or at most 661, at least or exactly or at most 662, at least or exactly or at most 663, at least or exactly or at most 664, at least or exactly or at most 665, at least or exactly or at most 666, at least or exactly or at most 667, at least or exactly or at most 668, at least or exactly or at most 669, at least or exactly or at most 670, at least or exactly or at most 671, at least or exactly or at most 672, at least or exactly or at most 673, at least or exactly or at most 674, at least or exactly or at most 675, at least or exactly or at most 676, at least or exactly or at most 677, at least or exactly or at most 678, at least or exactly or at most 679, or at least or exactly or at most 680 contiguous amino acid residues.

[0068] Insofar as embodiment b relates to SEQ ID NO: 15-18, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 681, at least or exactly or at most 682, at least or exactly or at most 683, at least or exactly or at most 684, at least or exactly or at most 685, at least or exactly or at most 686, at least or exactly or at most 687, at least or exactly or at most 688, at least or exactly or at most 689, at least or exactly or at most 690, at least or exactly or at most 691, at least or exactly or at most 692, at least or exactly or at most 693, at least or exactly or at most 694, at least or exactly or at most 695, at least or exactly or at most 696, at least or exactly or at most 697, at least or exactly or at most 698, at least or exactly or at most 699, at least or exactly or at most 700, at least or exactly or at most 701, at least or exactly or at most 702, at least or exactly or at most 703, at least or exactly or at most 704, at least or exactly or at most 705, at least or exactly or at most 706, at least or exactly or at most 707, at least or exactly or at most 708, at least or exactly or at most 709, at least or exactly or at most 710, at least or exactly or at most 711, at least or exactly or at most 712, at least or exactly or at most 713, at least or exactly or at most 714, at least or exactly or at most 715, at least or exactly or at most 716, at least or exactly or at most 717, at least or exactly or at most 718, at least or exactly or at most 719, at least or exactly or at most 720, at least or exactly or at most 721, at least or exactly or at most 722, at least or exactly or at most 723, at least or exactly or at most 724, at least or exactly or at most 725, at least or exactly or at most 726, at least or exactly or at most 727, at least or exactly or at most 728, at least or exactly or at most 729, at least or exactly or at most 730, at least or exactly or at most 731, at least or exactly or at most 732, at least or exactly or at most 733, at least or exactly or at most 734, at least or exactly or at most 735, at least or exactly or at most 736, at least or exactly or at most 737, at least or exactly or at most 738, at least or exactly or at most 739, at least or exactly or at most 740, at least or exactly or at most 741, at least or exactly or at most 742, at least or exactly or at most 743, at least or exactly or at most 744, at least or exactly or at most 745, at least or exactly or at most 746, at least or exactly or at most 747, at least or exactly or at most 748, at least or exactly or at most 749, at least or exactly or at most 750, at least or exactly or at most 751, at least or exactly or at most 752, at least or exactly or at most 753, at least or exactly or at most 754, at least or exactly or at most 755, at least or exactly or at most 756, at least or exactly or at most 757, at least or exactly or at most 758, at least or exactly or at most 759, at least or exactly or at most 760, at least or exactly or at most 761, at least or exactly or at most 762, at least or exactly or at most 763, at least or exactly or at most 764, at least or exactly or at most 765, at least or exactly or at most 766, at least or exactly or at most 767, at least or exactly or at most 768, at least or exactly or at most 769, at least or exactly or at most 770, at least or exactly or at most 771, at least or exactly or at most 772, at least or exactly or at most 773, at least or exactly or at most 774, at least or exactly or at most 775, at least or exactly or at most 776, at least or exactly or at most 777, at least or exactly or at most 778, at least or exactly or at most 779, at least or exactly or at most 780, at least or exactly or at most 781, at least or exactly or at most 782, at least or exactly or at most 783, at least or exactly or at most 784, at least or exactly or at most 785, at least or exactly or at most 786, at least or exactly or at most 787, at least or exactly or at most 788, at least or exactly or at most 789, at least or exactly or at most 790, at least or exactly or at most 791, at least or exactly or at most 792, at least or exactly or at most 793, at least or exactly or at most 794, at least or exactly or at most 795, at least or exactly or at most 796, at least or exactly or at most 797, at least or exactly or at most 798, at least or exactly or at most 799, at least or exactly or at most 800, at least or exactly or at most 801, at least or exactly or at most 802, at least or exactly or at most 803, at least or exactly or at most 804, or at least or exactly or at most 805 contiguous amino acid residues.

[0069] Insofar as embodiment b relates to SEQ ID NO: 16, the at least 5 contiguous amino acids referred to in option b) in the definition of the first aspect of the invention will preferably constitute at least or exactly or at most 806 contiguous amino acid residues or at least or exactly or at most 807 contiguous amino acid residues.

[0070] In some embodiments, the polypeptide of the invention also has a sequence identity with the amino acid sequence of a) defined above of at least 65%, such as at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99%. Similarly, the polypeptide of the invention in some embodiments also has a sequence identity with the amino acid sequence of b) defined above of at least 60%, such as at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99%.

[0071] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 in any one of SEQ ID NOs: 1-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0072] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188 and 189 in any on of SEQ ID NOs: 2-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0073] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204 and 205 in any one of SEQ ID NOs: 3-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0074] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237 and 238 in any one of SEQ ID NOs: 4-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0075] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322 and 323 in any one of SEQ ID NOs: 5-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0076] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352 and 353 in any one of SEQ ID NOs: 6-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0077] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394 and 395 in any one of SEQ ID NOs: 7-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0078] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490 and 491 in any one of SEQ ID NOs: 8-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0079] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502 and 503 in any one of SEQ ID NOs: 9-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0080] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 504 and 505 in any one of SEQ ID NOs: 10-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0081] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 506, 507, 508, 509, 510 and 511 in any one of SEQ ID NOs: 11-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0082] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560 and 561 in any one of SEQ ID NOs: 12-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0083] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614 and 615 in any one of SEQ ID NOs: 13-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0084] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676 and 677 in SEQ ID NOs: 14-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0085] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801 and 802 in SEQ ID NOs: 15-16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0086] In the embodiments defined by option b) above, the polypeptide of the invention is also one that has at least or exactly or at most 5 contiguous amino acid residues defined for option b) above and also has its N-terminal amino acid residue corresponding to any one of amino acid residues 803 and 804 in SEQ ID NO: 16, if the length of the at least or exactly or at most 5 amino acid residues so permit--if the length of the at least or exactly or at most 5 amino acids is higher than 5, the N-terminal first residue will not be higher numbered than N-L+1, where N is the number of amino acid residues of the reference sequence and L is the number of amino acids defined for option b.

[0087] The polypeptide of the invention is in certain embodiments also fused or conjugated to an immunogenic carrier molecule; or, phrased otherwise, the polypeptide of the invention also includes such an immunogenic carrier molecule in addition to the material derived from SEQ ID NOs. 1-16. The immunogenic carrier molecule is a typically polypeptide that induces T-helper lymphocyte responses in a majority of humans, such as immunogenic carrier proteins selected from the group consisting of keyhole limpet hemocyanino or a fragment thereof, tetanus toxoid or a fragment thereof, diphtheria toxoid or a fragment thereof. Other suitable carrier molecules are discussed infra. One further fusion partner, which is preferably incorporated is a "His tag", i.e. a stretch of amino acids, which is rich or only consists of histidinyl residues so as to facilitate protein purification.

[0088] In preferred embodiments, the polypeptide of the invention detailed above is capable of inducing an adaptive immune response against the polypeptide in a mammal, in particular in a human being. Preferably, the adaptive immune response is a protective adaptive immune response against infection with S. aureus, in particular multi-resistant S. aureus. The polypeptide may in these cases induce a humeral and/or a cellular immune response.

[0089] A particularly preferred polypeptide of the invention is derived from SEQ ID NO: 13 and is otherwise as defined above.

Epitopes

[0090] SEQ ID NOs: 1-16 include antigenic determinants (epitopes) that are as such recognized by antibodies and/or when bound to MHC molecules by T-cell receptors. For the purposes of the present invention, B-cell epitopes (i.e. antibody binding epitopes) are of particular relevance.

[0091] It is relatively uncomplicated to identify linear B-cell epitopes--one very simple approach entails that antibodies raised against S. aureus or S. aureus derived proteins disclosed herein are tested for binding to overlapping oligomeric peptides derived from any one of SEQ ID NO: 1-16. Thereby, the regions of the S. aureus polypeptide which are responsible for or contribute to binding to the antibodies can be identified.

[0092] Alternatively, or additionally, one can produce mutated versions of the polypeptides of the invention, e.g. version where each single non-alanine residue in SEQ ID NOs.: 1-16 are point mutated to alanine--this method also assists in identifying complex assembled B-cell epitopes; this is the case when binding of the same antibody is modified by exchanging amino acids in different areas of the full-length polypeptide.

[0093] Also, in silico methods for B-cell epitope prediction can be employed: useful state-of-the-art systems for .beta.-turn prediction is provided in Petersen B et al. (November 2010), Plos One 5(11): e15079; prediction of linear B-cell epitopes, cf: Larsen J E P et al. (April 2006), Immunome Research, 2:2; prediction of solvent exposed amino acids: Petersen B et al (July 2009), BMC Structural Biology, 9:51.

The Nucleic Acid Fragments of the Invention

[0094] The nucleic acid fragment of the invention referred to above is preferably is a DNA fragment (such as SEQ ID NOs: 17-32 and 50) or an RNA fragment (such as SEQ ID NOs 33-48 and 51).

[0095] The nucleic acid fragment of the invention typically consists of at least or exactly or at most 11, such as at least or exactly or at most 12, at least or exactly or at most 13, at least or exactly or at most 14, at least or exactly or at most 15, at least or exactly or at most 16, at least or exactly or at most 17 at least or exactly or at most 18, at least or exactly or at most 19, at least or exactly or at most 20, at least or exactly or at most 21, at least or exactly or at most 22, at least or exactly or at most 23, at least or exactly or at most 24, at least or exactly or at most 25, at least or exactly or at most 26, at least or exactly or at most 27, at least or exactly or at most 28, at least or exactly or at most 29, at least or exactly or at most 30, at least or exactly or at most 31, at least or exactly or at most 32, at least or exactly or at most 33, at least or exactly or at most 34, at least or exactly or at most 35, at least or exactly or at most 36, at least or exactly or at most 37, at least or exactly or at most 38, at least or exactly or at most 39, at least or exactly or at most 40, at least or exactly or at most 41, at least or exactly or at most 42, at least or exactly or at most 43, at least or exactly or at most 44, at least or exactly or at most 45, at least or exactly or at most 46, at least or exactly or at most 47, at least or exactly or at most 48, at least or exactly or at most 49, at least or exactly or at most 50, at least or exactly or at most 51, at least or exactly or at most 52, at least or exactly or at most 53, at least or exactly or at most 54, at least or exactly or at most 55, at least or exactly or at most 56, at least or exactly or at most 57, at least or exactly or at most 58, at least or exactly or at most 59, at least or exactly or at most 60, at least or exactly or at most 61, at least or exactly or at most 62, at least or exactly or at most 63, at least or exactly or at most 64, at least or exactly or at most 65, at least or exactly or at most 66, at least or exactly or at most 67, at least or exactly or at most 68, at least or exactly or at most 69, at least or exactly or at most 70, at least or exactly or at most 71, at least or exactly or at most 72, at least or exactly or at most 73, at least or exactly or at most 74, at least or exactly or at most 75, at least or exactly or at most 76, at least or exactly or at most 77, at least or exactly or at most 78, at least or exactly or at most 79, at least or exactly or at most 80, at least or exactly or at most 81, at least or exactly or at most 82, at least or exactly or at most 83, at least or exactly or at most 84, at least or exactly or at most 85, at least or exactly or at most 86, at least or exactly or at most 87, at least or exactly or at most 88, at least or exactly or at most 89, at least or exactly or at most 90, at least or exactly or at most 91, at least or exactly or at most 92, at least or exactly or at most 93, at least or exactly or at most 94, at least or exactly or at most 95, at least or exactly or at most 96, at least or exactly or at most 97, at least or exactly or at most 98, at least or exactly or at most 99, at least or exactly or at most 100, at least or exactly or at most 101, at least or exactly or at most 102, at least or exactly or at most 103, at least or exactly or at most 104, at least or exactly or at most 105, at least or exactly or at most 106, at least or exactly or at most 107, at least or exactly or at most 108, at least or exactly or at most 109, at least or exactly or at most 110, at least or exactly or at most 111, at least or exactly or at most 112, at least or exactly or at most 113, at least or exactly or at most 114, at least or exactly or at most 115, at least or exactly or at most 116, at least or exactly or at most 117, at least or exactly or at most 118, at least or exactly or at most 119, at least or exactly or at most 120, at least or exactly or at most 121, at least or exactly or at most 122, at least or exactly or at most 123, at least or exactly or at most 124, at least or exactly or at most 125, at least or exactly or at most 126, at least or exactly or at most 127, at least or exactly or at most 128, at least or exactly or at most 129, at least or exactly or at most 130, at least or exactly or at most 131, at least or exactly or at most 132, at least or exactly or at most 133, at least or exactly or at most 134, at least or exactly or at most 135, at least or exactly or at most 136, at least or exactly or at most 137, at least or exactly or at most 138, at least or exactly or at most 139, at least or exactly or at most 140, at least or exactly or at most 141, at least or exactly or at most 142, at least or exactly or at most 143, at least or exactly or at most 144, at least or exactly or at most 145, at least or exactly or at most 146, at least or exactly or at most 147, at least or exactly or at most 148, at least or exactly or at most 149, at least or exactly or at most 150, at least or exactly or at most 151, at least or exactly or at most 152, at least or exactly or at most 153, at least or exactly or at most 154, at least or exactly or at most 155, at least or exactly or at most 156, at least or exactly or at most 157, at least or exactly or at most 158, at least or exactly or at most 159, at least or exactly or at most 160, at least or exactly or at most 171, at least or exactly or at most 172, at least or exactly or at most 173, at least or exactly or at most 174, at least or exactly or at most 175, at least or exactly or at most 176, at least or exactly or at most 177, at least or exactly or at most 178, at least or exactly or at most 179, at least or exactly or at most 180, at least or exactly or at most 181, at least or exactly or at most 182, at least or exactly or at most 183, at least or exactly or at most 184, at least or exactly or at most 185, at least or exactly or at most 186, at least or exactly or at most 187, at least or exactly or at most 188, at least or exactly or at most 189, at least or exactly or at most 190, at least or exactly or at most 191, at least or exactly or at most 192, at least or exactly or at most 193, at least or exactly or at most 194, at least or exactly or at most 195, at least or exactly or at most 196, at least or exactly or at most 197, at least or exactly or at most 198, at least or exactly or at most 199, at least or exactly or at most 200, at least or exactly or at most 201, at least or exactly or at most 202, at least or exactly or at most 203, at least or exactly or at most 204, at least or exactly or at most 205, at least or exactly or at most 206, at least or exactly or at most 207, at least or exactly or at most 208, at least or exactly or at most 209, at least or exactly or at most 210, at least or exactly or at most 211, at least or exactly or at most 212, at least or exactly or at most 213, at least or exactly or at most 214, at least or exactly or at most 215, at least or exactly or at most 216, at least or exactly or at most 217, at least or exactly or at most 218, at least or exactly or at most 219, at least or exactly or at most 220, at least or exactly or at most 221, at least or exactly or at most 222, at least or exactly or at most 223, at least or exactly or at most 224, at least or exactly or at most 225, at least or exactly or at most 226, at least or exactly or at most 227, at least or exactly or at most 228, at least or exactly or at most 229, at least or exactly or at most 230, at least or exactly or at most 231, at least or exactly or at most 232, at least or exactly or at most 233, at least or exactly or at most 234, at least or exactly or at most 235, at least or exactly or at most 236, at least or exactly or at most 237, at least or exactly or at most 238, at least or exactly or at most 239, at least or exactly or at most 240, at least or exactly or at most 241, at least or exactly or at most 242, at least or exactly or at most 243, at least or exactly or at most 244, at least or exactly or at most 245, at least or exactly or at most 246, at least or exactly or at most 247, at least or exactly or at most 248, at least or exactly or at most 249, at least or exactly or at most 250, at least or exactly or at most 251, at least or exactly or at most 252, at least or exactly or at most 253, at least or exactly or at most 254, at least or exactly or at most 255, at least or exactly or at most 256, at least or exactly or at most 257, at least or exactly or at most 258, at least or exactly or at most 259, at least or exactly or at most 260, at least or exactly or at most 271, at least or exactly or at most 272, at least or exactly or at most 273, at least or exactly or at most 274, at least or exactly or at most 275, at least or exactly or at most 276, at least or exactly or at most 277, at least or exactly or at most 278, at least or exactly or at most 279, at least or exactly or at most 280, at least or exactly or at most 281, at least or exactly or at most 282, at least or exactly or at most 283, at least or exactly or at most 284, at least or exactly or at most 285, at least or exactly or at most 286, at least or exactly or at most 287, at least or exactly or at most 288, at least or exactly or at most 289, at least or exactly or at most 290, at least or exactly or at most 291, at least or exactly or at most 292, at least or exactly or at most 293, at least or exactly or at most 294, at least or exactly or at most 295, at least or exactly or at most 296, at least or exactly or at most 297, at least or exactly or at most 298, at least or exactly or at most 299, at least or exactly or at most 300, at least or exactly or at most 301, at least or exactly or at most 302, at least or exactly or at most 303, at least or exactly or at most 304, at least or exactly or at most 305, at least or exactly or at most 306, at least or exactly or at most 307, at least or exactly or at most 308, at least or exactly or at most 309, at least or exactly or at most 310, at least or exactly or at most 311, at least or exactly or at most 312, at least or exactly or at most 313, at least or exactly or at most 314, at least or exactly or at most 315, at least or exactly or at most 316, at least or exactly or at most 317, at least or exactly or at most 318, at least or exactly or at most 319, at least or exactly or at most 320, at least or exactly or at most 321, at least or exactly or at most 322, at least or exactly or at most 323, at least or exactly or at most 324, at least or exactly or at most 325, at least or exactly or at most 326, at least or exactly or at most 327, at least or exactly or at most 328, at least or exactly or at most 329, at least or exactly or at most 330, at least or exactly or at most 331, at least or exactly or at most 332, at least or exactly or at most 333, at least or exactly or at most 334, at least or exactly or at most 335, at least or exactly or at most 336, at least or exactly or at most 337, at least or exactly or at most 338, at least or exactly or at most 339, at least or exactly or at most 340, at least or exactly or at most 341, at least or exactly or at most 342, at least or exactly or at most 343, at least or exactly or at most 344, at least or exactly or at most 345, at least or exactly or at most 346, at least or exactly or at most 347, at least or exactly or at most 348, at least or exactly or at most 349, at least or exactly or at most 350, at least or exactly or at most 351, at least or exactly or at most 352, at least or exactly or at most 353, at least or exactly or at most 354, at least or exactly or at most 355, at least or exactly or at most 356, at least or exactly or at most 357, at least or exactly or at most 358, at least or exactly or at most 359, at least or exactly or at most 360, at least or exactly or at most 361, at least or exactly or at most 362, at least or exactly or at most 363, at least or exactly or at most 364, at least or exactly or at most 365, at least or exactly or at most 366, at least or exactly or at most 367, at least or exactly or at most 368, at least or exactly or at most 369, at least or exactly or at most 370, at least or exactly or at most 371, at least or exactly or at most 372, at least or exactly or at most 373, at least or exactly or at most 374, at least or exactly or at most 375, at least or exactly or at most 376, at least or exactly or at most 377, at least or exactly or at most 378, at least or exactly or at most 379, at least or exactly or at most 380, at least or exactly or at most 381, at least or exactly or at most 382, at least or exactly or at most 383, at least or exactly or at most 384, at least or exactly or at most 385, at least or exactly or at most 386, at least or exactly or at most 387, at least or exactly or at most 388, at least or exactly or at most 389, at least or exactly or at most 390, at least or exactly or at most 391, at least or exactly or at most 392, at least or exactly or at most 393, at least or exactly or at most 394, at least or exactly or at most 395, at least or exactly or at most 396, at least or exactly or at most 397, at least or exactly or at most 398, at least or exactly or at most 399, at least or exactly or at most 400, at least or exactly or at most 401, at least or exactly or at most 402, at least or exactly or at most 403, at least or exactly or at most 404, at least or exactly or at most 405, at least or exactly or at most 406, at least or exactly or at most 407, at least or exactly or at most 408, at least or exactly or at most 409, at least or exactly or at most 410, at least or exactly or at most 411, at least or exactly or at most 412, at least or exactly or at most 413, at least or exactly or at most 414, at least or exactly or at most 415, at least or exactly or at most 416, at least or exactly or at most 417, at least or exactly or at most 418, at least or exactly or at most 419, at least or exactly or at most 420, at least or exactly or at most 421, at least or exactly or at most 422, and at least or exactly or at most 423 consecutive nucleotides in any one of SEQ ID NOs: 17-48, 50, and 51. Longer fragments are contemplated, i.e. fragments having at least or exactly or at most 200, at least or exactly or at most 300 at least or exactly or at most 400, at least or exactly or at most 500, at least or exactly or at most 600, at least or exactly or at most 700, at least or exactly or at most 800, at least or exactly or at most 900, at least or exactly or at most 1000, at least or exactly or at most 1500, at least or exactly or at most 2000, at least or exactly or at most 2500, at least or exactly or at most 3000, at least or exactly or at most 3500, or at least or exactly or at most 4000 nucleotides from those of SEQ ID NOs: 17-48, 50, and 51 that encompass fragments of such lengths.

[0096] The nucleic acid fragment of the invention discussed above typically has a sequence identity with the nucleotide sequence defined for i) or ii) above, which is at least 65%, such as at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99%.

[0097] The nucleic acid fragment of the invention discussed above may also have a sequence identity with the nucleotide sequence defined for iii) above, which is at least 65%, such as at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99%.

[0098] The nucleic acid fragment of the invention described above comprises in certain embodiments at least or exactly or at most X distinct nucleic acid sequences each encoding a polypeptide of the invention, where each of said X distinct nucleic acid sequences encodes at least or exactly or at most one immunogenic amino acid sequence present in or derived from any one of SEQ ID NOs: 1-16 and wherein said X distinct nucleic acid sequences together encode immunogenic amino acid sequences present in or derived from at least or exactly or at most X of SEQ ID NOs. 1-16, wherein X is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16. In other words, such a nucleic acid fragment encodes several polypeptides of the invention. In some embodiments, the X nucleic acid sequences are expressed as separate encoded proteins and in other embodiments as "pearls on a string", i.e. fused proteins. In some embodiments, immunogenic amino acid sequences from any one of SEQ ID NO: 16 are only present in one of said X nucleic acid sequences.

[0099] It will be understood that the nucleic acid fragments of the invention may be used for both production, carrier and vaccine purposes--the latter will require that the sequences are included in expression vectors that may lead to production of immunogenic proteins in the host animal receiving the vector.

The Vectors of the Invention

[0100] Vectors of the invention fall into several categories discussed infra. One preferred vector of the invention comprises in operable linkage and in the 5'-3' direction, an expression control region comprising an enhancer/promoter for driving expression of the nucleic acid fragment defined for option i) above, optionally a signal peptide coding sequence, a nucleotide sequence defined for option i), and optionally a terminator. Hence, such a vector constitutes an expression vector useful for effecting production in cells of the polypeptide of the invention. Since the polypeptides of the invention are bacterial of origin, recombinant production is conveniently effected in bacterial host cells, so here it is preferred that the expression control region drives expression in prokaryotic cell such as a bacterium, e.g. in E coli. However, if the vector is to drive expression in mammalian cell (as would be the case for a DNA vaccine vector), the expression control region should be adapted to this particular use.

[0101] At any rate, certain vectors of the invention are capable of autonomous replication.

[0102] Also, the vector of the invention may be one that is capable of being integrated into the genome of a host cell--this is particularly useful if the vector is use in the production of stably transformed cells, where the progeny will also include the genetic information introduced via the vector. Alternatively, vectors incapable of being integrated into the genome of a mammalian host cell are useful in e.g. DNA vaccination.

[0103] Typically, the vector of the invention is selected from the group consisting of a virus, such as a attenuated virus (which may in itself be useful as a vaccine agent), a bacteriophage, a plasmid, a minichromosome, and a cosmid.

[0104] Particularly interesting vectors are viral vectors (in particular those useful as vaccine agents). These may be selected from the group consisting of a retrovirus vector, such as a lentivirus vector, an adenovirus vector, an adeno-associated virus vector, and a pox virus vector. Certain pox virus vectors are preferred, in particular vaccinia virus vectors. A particularly preferred vaccinia virus vector is a modified vaccinia Ankara (MVA) vector.

[0105] A more detailed discussion of vectors of the invention is provided in the following:

[0106] Polypeptides of the invention may be encoded by a nucleic acid molecule comprised in a vector. A nucleic acid sequence can be "heterologous," which means that it is in a context foreign to the cell in which the vector is being introduced, which includes a sequence homologous to a sequence in the cell but in a position within the host cell where it is ordinarily not found. Vectors include naked DNAs, RNAs, plasmids, cosmids, viruses (bacteriophage, animal viruses, and plant viruses), and artificial chromosomes (e.g., YACs). One of skill in the art would be well equipped to construct a vector through standard recombinant techniques (for example Sambrook et al, 2001; Ausubel et al, 1996, both incorporated herein by reference). In addition to encoding the polypeptides of this invention, a vector of the present invention may encode polypeptide sequences such as a tag or immunogenicity enhancing peptide (e.g. an immunogenic carrier or a fusion partner that stimulates the immune system, such as a cytokine or active fragment thereof). Useful vectors encoding such fusion proteins include pIN vectors (Inouye et al, 1985), vectors encoding a stretch of histidines, and pGEX vectors, for use in generating glutathione S-transferase (GST) soluble fusion proteins for later purification and separation or cleavage.

[0107] Vectors of the invention may be used in a host cell to produce a polypeptide of the invention that may subsequently be purified for administration to a subject or the vector may be purified for direct administration to a subject for expression of the protein in the subject (as is the case when administering a nucleic acid vaccine).

[0108] Expression vectors can contain a variety of "control sequences," which refer to nucleic acid sequences necessary for the transcription and possibly translation of an operably linked coding sequence in a particular host organism. In addition to control sequences that govern transcription and translation, vectors and expression vectors may contain nucleic acid sequences that serve other functions as well and are described infra.

1. Promoters and Enhancers

[0109] A "promoter" is a control sequence. The promoter is typically a region of a nucleic acid sequence at which initiation and rate of transcription are controlled. It may contain genetic elements at which regulatory proteins and molecules may bind such as RNA polymerase and other transcription factors. The phrases "operatively positioned," "operatively linked," "under control," and "under transcriptional control" mean that a promoter is in a correct functional location and/or orientation in relation to a nucleic acid sequence to control transcriptional initiation and expression of that sequence. A promoter may or may not be used in conjunction with an "enhancer," which refers to a cis-acting regulatory sequence involved in the transcriptional activation of a nucleic acid sequence.

[0110] A promoter may be one naturally associated with a gene or sequence, as may be obtained by isolating the 5' non-coding sequences located upstream of the coding segment or exon. Such a promoter can be referred to as "endogenous." Similarly, an enhancer may be one naturally associated with a nucleic acid sequence, located either downstream or upstream of that sequence. Alternatively, certain advantages will be gained by positioning the coding nucleic acid segment under the control of a recombinant or heterologous promoter, which refers to a promoter that is not normally associated with a nucleic acid sequence in its natural environment. A recombinant or heterologous enhancer refers also to an enhancer not normally associated with a nucleic acid sequence in its natural state. Such promoters or enhancers may include promoters or enhancers of other genes, and promoters or enhancers isolated from any other prokaryotic, viral, or eukaryotic cell, and promoters or enhancers not "naturally occurring," i.e., containing different elements of different transcriptional regulatory regions, and/or mutations that alter expression. In addition to producing nucleic acid sequences of promoters and enhancers synthetically, sequences may be produced using recombinant cloning and/or nucleic acid amplification technology, including PCR.TM., in connection with the compositions disclosed herein (see U.S. Pat. No. 4,683,202, U.S. Pat. No. 5,928,906, each incorporated herein by reference).

[0111] Naturally, it may be important to employ a promoter and/or enhancer that effectively direct(s) the expression of the DNA segment in the cell type or organism chosen for expression. Those of skill in the art of molecular biology generally know the use of promoters, enhancers, and cell type combinations for protein expression (see Sambrook et al, 2001, incorporated herein by reference). The promoters employed may be constitutive, tissue-specific, or inducible and in certain embodiments may direct high level expression of the introduced DNA segment under specified conditions, such as large-scale production of recombinant proteins or peptides.

[0112] Examples of inducible elements, which are regions of a nucleic acid sequence that can be activated in response to a specific stimulus, include but are not limited to Immunoglobulin Heavy Chain (Banerji et al, 1983; Gilles et al, 1983; Grosschedl et al, 1985; Atchinson et al, 1986, 1987; toiler et al, 1987; Weinberger et al, 1984; Kiledjian et al, 1988; Porton et al; 1990), Immunoglobulin Light Chain (Queen et al, 1983; Picard et al, 1984), T Cell Receptor (Luria et al, 1987; Winoto et al, 1989; Redondo et al; 1990), HLA DQ.alpha. and/or DQ.beta. (Sullivan et al, 1987), .beta.-Interferon (Goodbourn et al, 1986; Fujita et al, 1987; Goodbourn et al, 1988), Interleukin-2 (Greene et al, 1989), Interleukin-2 Receptor (Greene et al, 1989; Lin et al, 1990), MHC Class II 5 (Koch et al, 1989), MHC Class II HLA-DR.alpha. (Sherman et al, 1989), .beta.-Actin (Kawamoto et al, 1988; Ng et al; 1989), Muscle Creatine Kinase (MCK) (Jaynes et al, 1988; Horlick et al, 1989; Johnson et al, 1989), Prealbumin (Transthyretin) (Costa et al, 1988), Elastase I (Omitz et al, 1987), Metallothionein (MTII) (Karin et al, 1987; Culotta et al, 1989), Collagenase (Pinkert et al, 1987; Angel et al, 1987), Albumin (Pinkert et al, 1987; Tranche et al, 1989, 1990), .alpha.-Fetoprotein (Godbout et al, 1988; Campere et al, 1989), .gamma.-Globin (Bodine et al, 1987; Perez-Stable et al, 1990), .beta.-Globin (Trudel et al, 1987), c-fos (Cohen et al, 1987), c-HA-ras (Triesman, 1986; Deschamps et al, 1985), Insulin (Edlund et al, 1985), Neural Cell Adhesion Molecule (NCAM) (Hirsh et al, 1990), al-Antitrypain (Larimer et al, 1990), H2B (TH2B) Histone (Hwang et al, 1990), Mouse and/or Type I Collagen (Ripe et al, 1989), Glucose-Regulated Proteins (GRP94 and GRP78) (Chang et al, 1989), Rat Growth Hormone (Larsen et al, 1986), Human Serum Amyloid A (SAA) (Edbrooke et al, 1989), Troponin I (TN I) (Yutzey et al, 1989), Platelet-Derived Growth Factor (PDGF) (Pech et al, 1989), Duchenne Muscular Dystrophy (Klamut et al, 1990), SV40 (Banerji et al, 1981; Moreau et al, 1981; Sleigh et al, 1985; Firak et al, 1986; Herr et al, 1986; Imbra et al, 1986; Kadesch et al, 1986; Wang et al, 1986; Ondek et al, 1987; Kuhl et al, 1987; Schaffner et al, 1988), Polyoma (Swartzendruber et al, 1975; Vasseur et al, 1980; Katinka et al, 1980, 1981; Tyndell et al, 1981; Dandolo et al, 1983; de Villiers et al, 1984; Hen et al, 1986; Satake et al, 1988; Campbell et al, 1988), Retroviruses (Kriegler et al, 1982, 1983; Levinson et al, 1982; Kriegler et al, 1983, 1984a, b, 1988; Bosze et al, 1986; Miksicek et al, 1986; Celander et al, 1987; Thiesen et al, 1988; Celander et al, 1988; Choi et al, 1988; Reisman et al, 1989), Papilloma Virus (Campo et al, 1983; Lusky et al, 1983; Spandidos and Wilkie, 1983; Spalholz et al, 1985; Lusky et al, 1986; Cripe et al, 1987; Gloss et al, 1987; Hirochika et al, 1987; Stephens et al, 1987), Hepatitis B Virus (Bulla et al, 1986; Jameel et al, 1986; Shaul et al, 1987; Spandau et al, 1988; Vannice et al, 1988), Human Immunodeficiency Virus (Muesing et al, 1987; Hauber et al, 1988; Jakobovits et al, 1988; Feng et al, 1988; Takebe et al, 1988; Rosen et al, 1988; Berkhout et al, 1989; Laspia et al, 1989; Sharp et al, 1989; Braddock et al, 1989), Cytomegalovirus (CMV) IE (Weber et al, 1984; Boshart et al, 1985; Foecking et al, 1986), Gibbon Ape Leukemia Virus (Holbrook et al, 1987; Quinn et al, 1989).

[0113] Inducible Elements include, but are not limited to MT II--Phorbol Ester (TFA)/Heavy metals (Palmiter et al, 1982; Haslinger et al, 1985; Searle et al, 1985; Stuart et al, 1985; Imagawa et al, 1987, Karin et al, 1987; Angel et al, 1987b; McNeall et al, 1989); MMTV (mouse mammary tumor virus)--Glucocorticoids (Huang et al, 1981; Lee et al, 1981; Majors et al, 1983; Chandler et al, 1983; Lee et al, 1984; Ponta et al, 1985; Sakai et al, 1988); .beta.-Interferon--poly(rl)x/poly(rc) (Tavernier et al, 1983); Adenovirus 5 E2--EIA (Imperiale et al, 1984); Collagenase--Phorbol Ester (TPA) (Angel et al, 1987a); Stromelysin--Phorbol Ester (TPA) (Angel et al, 1987b); SV40--Phorbol Ester (TPA) (Angel et al, 1987b); Murine MX Gene--Interferon, Newcastle Disease Virus (Hug et al, 1988); GRP78 Gene--A23187 (Resendez et al, 1988); .alpha.-2-Macroglobulin--IL-6 (Kunz et al, 1989); Vimentin--Serum (Rittling et al, 1989); MHC Class I Gene H-2.kappa.b--Interferon (Blanar et al, 1989); HSP70--E1A/SV40 Large T Antigen (Taylor et al, 1989, 1990a, 1990b); Proliferin--Phorbol Ester/TPA (Mordacq et al, 1989); Tumor Necrosis Factor--PMA (Hensel et al, 1989); and Thyroid Stimulating Hormonea Gene--Thyroid Hormone (Chatterjee et al, 1989).

[0114] Also contemplated as useful in the present invention are the dectin-1 and dectin-2 promoters. Additionally any promoter/enhancer combination (as per the Eukaryotic Promoter Data Base EPDB) could also be used to drive expression of structural genes encoding oligosaccharide processing enzymes, protein folding accessory proteins, selectable marker proteins or a heterologous protein of interest.

[0115] The particular promoter that is employed to control the expression of peptide or protein encoding polynucleotide of the invention is not believed to be critical, so long as it is capable of expressing the polynucleotide in a targeted cell, preferably a bacterial cell. Where a human cell is targeted, it is preferable to position the polynucleotide coding region adjacent to and under the control of a promoter that is capable of being expressed in a human cell. Generally speaking, such a promoter might include either a bacterial, human or viral promoter.

[0116] In various embodiments, the human cytomegalovirus (CMV) immediate early gene promoter, the SV40 early promoter, and the Rous sarcoma virus long terminal repeat can be used to obtain high level expression of a related polynucleotide to this invention. The use of other viral or mammalian cellular or bacterial phage promoters, which are well known in the art, to achieve expression of polynucleotides is contemplated as well.

[0117] In embodiments in which a vector is administered to a subject for expression of the protein, it is contemplated that a desirable promoter for use with the vector is one that is not down-regulated by cytokines or one that is strong enough that even if down-regulated, it produces an effective amount of the protein/polypeptide of the current invention in a subject to elicit an immune response. Non-limiting examples of these are CMV IE and RSV LTR. In other embodiments, a promoter that is up-regulated in the presence of cytokines is employed. The MHC I promoter increases expression in the presence of IFN-.gamma..

[0118] Tissue specific promoters can be used, particularly if expression is in cells in which expression of an antigen is desirable, such as dendritic cells or macrophages. The mammalian MHC I and MHC II promoters are examples of such tissue-specific promoters. 2. Initiation Signals and Internal Ribosome Binding Sites (IRES)

[0119] A specific initiation signal also may be required for efficient translation of coding sequences. These signals include the ATG initiation codon or adjacent sequences. Exogenous translational control signals, including the ATG initiation codon, may need to be provided. One of ordinary skill in the art would readily be capable of determining this and providing the necessary signals. It is well known that the initiation codon must be "in-frame" with the reading frame of the desired coding sequence to ensure translation of the entire insert. The exogenous translational control signals and initiation codons can be either natural or synthetic and may be operable in bacteria or mammalian cells. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements.

[0120] In certain embodiments of the invention, the use of internal ribosome entry sites (IRES) elements are used to create multigene, or polycistronic, messages. IRES elements are able to bypass the ribosome scanning model of 5' methylated Cap dependent translation and begin translation at internal sites (Pelletier and Sonenberg, 1988). IRES elements from two members of the picornavirus family (polio and encephalomyocarditis) have been described (Pelletier and Sonenberg, 1988), as well an IRES from a mammalian message (Macejak and Sarnow, 1991). IRES elements can be linked to heterologous open reading frames. Multiple open reading frames can be transcribed together, each separated by an IRES, creating polycistronic messages. By virtue of the IRES element, each open reading frame is accessible to ribosomes for efficient translation. Multiple genes can be efficiently expressed using a single promoter/enhancer to transcribe a single message (see U.S. Pat. Nos. 5,925,565 and 5,935,819, herein incorporated by reference).

2. Multiple Cloning Sites

[0121] Vectors can include a multiple cloning site (MCS), which is a nucleic acid region that contains multiple restriction enzyme sites, any of which can be used in conjunction with standard recombinant technology to digest the vector. (See Carbonelli et al, 1999, Levenson et al, 1998, and Cocea, 1997, incorporated herein by reference.) Frequently, a vector is linearized or fragmented using a restriction enzyme that cuts within the MCS to enable exogenous sequences to be ligated to the vector. Techniques involving restriction enzymes and ligation reactions are well known to those of skill in the art of recombinant technology.

3. Splicing Sites

[0122] Most transcribed eukaryotic RNA molecules will undergo RNA splicing to remove introns from the primary transcripts. If relevant in the context of vectors of the present invention, vectors containing genomic eukaryotic sequences may require donor and/or acceptor splicing sites to ensure proper processing of the transcript for protein expression. (See Chandler et al, 1997, incorporated herein by reference.)

4. Termination Signals

[0123] The vectors or constructs of the present invention will generally comprise at least one termination signal. A "termination signal" or "terminator" is comprised of the DNA sequences involved in specific termination of an RNA transcript by an RNA polymerase. Thus, in certain embodiments a termination signal that ends the production of an RNA transcript is contemplated. A terminator may be necessary in vivo to achieve desirable message levels.

[0124] In eukaryotic systems, the terminator region may also comprise specific DNA sequences that permit site-specific cleavage of the new transcript so as to expose a polyadenylation site. This signals a specialized endogenous polymerase to add a stretch of about 200 A residues (poly A) to the 3' end of the transcript. RNA molecules modified with this polyA tail appear to more stable and are translated more efficiently. Thus, in other embodiments involving eukaryotes, it is preferred that that terminator comprises a signal for the cleavage of the RNA, and it is more preferred that the terminator signal promotes polyadenylation of the message.

[0125] Terminators contemplated for use in the invention include any known terminator of transcription described herein or known to one of ordinary skill in the art, including but not limited to, for example, the bovine growth hormone terminator or viral termination sequences, such as the SV40 terminator. In certain embodiments, the termination signal may be a lack of transcribable or translatable sequence, such as due to a sequence truncation.

5. Polyadenylation Signals

[0126] In expression, particularly eukaryotic expression (as is relevant in nucleic acid vaccination), one will typically include a polyadenylation signal to effect proper polyadenylation of the transcript. The nature of the polyadenylation signal is not believed to be crucial to the successful practice of the invention, and/or any such sequence may be employed. Preferred embodiments include the SV40 polyadenylation signal and/or the bovine growth hormone polyadenylation signal, convenient and/or known to function well in various target cells. Polyadenylation may increase the stability of the transcript or may facilitate cytoplasmic transport.

6. Origins of Replication

[0127] In order to propagate a vector in a host cell, it may contain one or more origins of replication sites (often termed "on"), which is a specific nucleic acid sequence at which replication is initiated. Alternatively an autonomously replicating sequence (ARS) can be employed if the host cell is yeast.

7. Selectable and Screenable Markers

[0128] In certain embodiments of the invention, cells containing a nucleic acid construct of the present invention may be identified in vitro or in vivo by encoding a screenable or selectable marker in the expression vector. When transcribed and translated, a marker confers an identifiable change to the cell permitting easy identification of cells containing the expression vector. Generally, a selectable marker is one that confers a property that allows for selection. A positive selectable marker is one in which the presence of the marker allows for its selection, while a negative selectable marker is one in which its presence prevents its selection. An example of a positive selectable marker is a drug resistance marker.

[0129] Usually the inclusion of a drug selection marker aids in the cloning and identification of transformants, for example, markers that confer resistance to neomycin, puromycin, hygromycin, DHFR, GPT, zeocin or histidinol are useful selectable markers. In addition to markers conferring a phenotype that allows for the discrimination of transformants based on the implementation of conditions, other types of markers including screenable markers such as GFP for colorimetric analysis. Alternatively, screenable enzymes such as herpes simplex virus thymidine kinase (tk) or chloramphenicol acetyltransferase (CAT) may be utilized. One of skill in the art would also know how to employ immunologic markers that can be used in conjunction with FACS analysis. The marker used is not believed to be important, so long as it is capable of being expressed simultaneously with the nucleic acid encoding a protein of the invention. Further examples of selectable and screenable markers are well known to one of skill in the art.

The Transformed Cells of the Invention

[0130] Transformed cells of the invention are useful as organisms for producing the polypeptide of the invention, but also as simple "containers" of nucleic acids and vectors of the invention.

[0131] Certain transformed cells of the invention are capable of replicating the nucleic acid fragment defined for option i) of the second aspect of the invention. Preferred transformed cells of the invention are capable of expressing the nucleic acid fragment defined for option i).

[0132] For recombinant production it is convenient, but not a prerequisite that the transformed cell according is prokaryotic, such as a bacterium, but generally both prokaryotic cells and eukaryotic cells may be used.

[0133] Suitable prokaryotic cells are bacterial cells selected from the group consisting of Escherichia (such as E. coli.), Bacillus [e.g. Bacillus subtilis], Salmonella, and Mycobacterium [preferably non-pathogenic, e.g. M. bovis BCG].

[0134] Eukaryotic cells can be in the form of yeasts (such as Saccharomyces cerevisiae) and protozoans. Alternatively, the transformed eukaryotic cells are derived from a multicellular organism such as a fungus, an insect cell, a plant cell, or a mammalian cell.

[0135] For production purposes, it is advantageous that the transformed cell of the invention is stably transformed by having the nucleic acid defined above for option i) stably integrated into its genome, and in certain embodiments it is also preferred that the transformed cell secretes or carries on its surface the polypeptide of the invention, since this facilitates recovery of the polypeptides produced. A particular version of this embodiment is one where the transformed cell is a bacterium and secretion of the polypeptide of the invention is into the periplasmic space.

[0136] As noted above, stably transformed cells are preferred--these i.a. allows that cell lines comprised of transformed cells as defined herein may be established--such cell lines are particularly preferred aspects of the invention.

[0137] Further details on cells and cell lines are presented in the following:

[0138] Suitable cells for recombinant nucleic acid expression of the nucleic acid fragments of the present invention are prokaryotes and eukaryotes. Examples of prokaryotic cells include E. coli; members of the Staphylococcus genus, such as S. epidermidis; members of the Lactobacillus genus, such as L. plantarum; members of the Lactococcus genus, such as L. lactis; members of the Bacillus genus, such as B. subtilis; members of the Corynebacterium genus such as C. glutamicum; and members of the Pseudomonas genus such as Ps. fluorescens. Examples of eukaryotic cells include mammalian cells; insect cells; yeast cells such as members of the Saccharomyces genus (e.g. S. cerevisiae), members of the Pichia genus (e.g. P. pastoris), members of the Hansenula genus (e.g. H. polymorpha), members of the Kluyveromyces genus (e.g. K. lactis or K. fragilis) and members of the Schizosaccharomyces genus (e.g. S. pombe).

[0139] Techniques for recombinant gene production, introduction into a cell, and recombinant gene expression are well known in the art. Examples of such techniques are provided in references such as Ausubel, Current Protocols in Molecular Biology, John Wiley, 1987-2002, and Sambrook et al., Molecular Cloning, A Laboratory Manual, 2 nd Edition, Cold Spring Harbor Laboratory Press, 1989.

[0140] As used herein, the terms "cell," "cell line," and "cell culture" may be used interchangeably. All of these terms also include their progeny, which is any and all subsequent generations. It is understood that all progeny may not be identical due to deliberate or inadvertent mutations. In the context of expressing a heterologous nucleic acid sequence, "host cell" refers to a prokaryotic or eukaryotic cell, and it includes any transformable organism that is capable of replicating a vector or expressing a heterologous gene encoded by a vector. A host cell can, and has been, used as a recipient for vectors or viruses. A host cell may be "transfected" or "transformed," which refers to a process by which exogenous nucleic acid, such as a recombinant protein-encoding sequence, is transferred or introduced into the host cell. A transformed cell includes the primary subject cell and its progeny.

[0141] Host cells may be derived from prokaryotes or eukaryotes, including bacteria, yeast cells, insect cells, and mammalian cells for replication of the vector or expression of part or all of the nucleic acid sequence(s). Numerous cell lines and cultures are available for use as a host cell, and they can be obtained through the American Type Culture Collection (ATCC), which is an organization that serves as an archive for living cultures and genetic materials (www.atcc.org) or from other depository institutions such as Deutsche Sammlung vor Micrroorganismen and Zellkulturen (DSM). An appropriate host can be determined by one of skill in the art based on the vector backbone and the desired result. A plasmid or cosmid, for example, can be introduced into a prokaryote host cell for replication of many vectors or expression of encoded proteins. Bacterial cells used as host cells for vector replication and/or expression include Staphylococcus strains, DH5a, JMI 09, and KC8, as well as a number of commercially available bacterial hosts such as SURE.RTM. Competent Cells and SOLOP ACK.TM. Gold Cells (STRATAGENE.RTM., La Jolla, Calif.). Alternatively, bacterial cells such as E. coli LE392 could be used as host cells for phage viruses. Appropriate yeast cells include Saccharomyces cerevisiae, Saccharomyces pombe, and Pichia pastoris.

[0142] Examples of eukaryotic host cells for replication and/or expression of a vector include HeLa, NIH3T3, Jurkat, 293, Cos, CHO, Saos, and PC12. Many host cells from various cell types and organisms are available and would be known to one of skill in the art. Similarly, a viral vector may be used in conjunction with either a eukaryotic or prokaryotic host cell, particularly one that is permissive for replication or expression of the vector.

[0143] Some vectors may employ control sequences that allow it to be replicated and/or expressed in both prokaryotic and eukaryotic cells. One of skill in the art would further understand the conditions under which to incubate all of the above described host cells to maintain them and to permit replication of a vector. Also understood and known are techniques and conditions that would allow large-scale production of vectors, as well as production of the nucleic acids encoded by vectors and their cognate polypeptides, proteins, or peptides.

Expression Systems

[0144] Numerous expression systems exist that comprise at least a part or all of the compositions discussed above. Prokaryote- and/or eukaryote-based systems can be employed for use with the present invention to produce nucleic acid sequences, or their cognate polypeptides, proteins and peptides. Many such systems are commercially and widely available.

[0145] The insect cell/baculovirus system can produce a high level of protein expression of a heterologous nucleic acid segment, such as described in U.S. Pat. Nos. 5,871,986, 4,879,236, both herein incorporated by reference, and which can be bought, for example, under the name MAXBAC.RTM. 2.0 from INVITROGEN.RTM. and BACPACK.TM. Baculovirus expression system from CLONTECH.RTM.

[0146] In addition to the disclosed expression systems of the invention, other examples of expression systems include STRATAGENE.RTM.'s COMPLETE CONTROL.TM. Inducible Mammalian Expression System, which involves a synthetic ecdysone-inducible receptor, or its pET Expression System, an E. coli expression system. Another example of an inducible expression system is available from INVITROGEN.RTM., which carries the T-REX.TM. (tetracycline-regulated expression) System, an inducible mammalian expression system that uses the full-length CMV promoter. INVITROGEN.RTM. also provides a yeast expression system called the Pichia methanolica Expression System, which is designed for high-level production of recombinant proteins in the methylotrophic yeast Pichia methanolica. One of skill in the art would know how to express a vector, such as an expression construct, to produce a nucleic acid sequence or its cognate polypeptide, protein, or peptide.

Amplification of Nucleic Acids

[0147] Nucleic acids used as a template for amplification may be isolated from cells, tissues or other samples according to standard methodologies (Sambrook et al, 2001). In certain embodiments, analysis is performed on whole cell or tissue homogenates or biological fluid samples without substantial purification of the template nucleic acid. The nucleic acid may be genomic DNA or fractionated or whole cell RNA. Where RNA is used, it may be desired to first convert the RNA to a complementary DNA.

[0148] The term "primer," as used herein, is meant to encompass any nucleic acid that is capable of priming the synthesis of a nascent nucleic acid in a template-dependent process. Typically, primers are oligonucleotides from ten to twenty and/or thirty base pairs in length, but longer sequences can be employed. Primers may be provided in double-stranded and/or single-stranded form, although the single-stranded form is preferred.

[0149] Pairs of primers designed to selectively hybridize to nucleic acids corresponding to sequences of genes identified herein are contacted with the template nucleic acid under conditions that permit selective hybridization. Depending upon the desired application, high stringency hybridization conditions may be selected that will only allow hybridization to sequences that are completely complementary to the primers. In other embodiments, hybridization may occur under reduced stringency to allow for amplification of nucleic acids containing one or more mismatches with the primer sequences. Once hybridized, the template-primer complex is contacted with one or more enzymes that facilitate template-dependent nucleic acid synthesis. Multiple rounds of amplification, also referred to as "cycles," are conducted until a sufficient amount of amplification product is produced.

[0150] The amplification product may be detected or quantified. In certain applications, the detection may be performed by visual means. Alternatively, the detection may involve indirect identification of the product via chemiluminescence, radioactive scintigraphy of incorporated radiolabel or fluorescent label or even via a system using electrical and/or thermal impulse signals (Bellus, 1994).

[0151] A number of template dependent processes are available to amplify the oligonucleotide sequences present in a given template sample. One of the best known amplification methods is the polymerase chain reaction (referred to as PCR.TM.) which is described in detail in U.S. Pat. Nos. 4,683,195, 4,683,202 and 4,800,159, and in Innis et al., 1988, each of which is incorporated herein by reference in their entirety.

[0152] Alternative methods for amplification of target nucleic acid sequences that may be used in the practice of the present invention are disclosed in U.S. Pat. Nos. 5,843,650, 5,846,709, 5,846,783, 5,849,546, 5,849,497, 5,849,547, 5,858,652, 5,866,366, 5,916,776, 5,922,574, 5,928,905, 5,928,906, 5,932,451, 5,935,825, 5,939,291 and 5,942,391, GB Application No. 2 202 328, and in PCT Application No. PCT/US89/01025, each of which is incorporated herein by reference in its entirety.

Methods of Gene Transfer

[0153] Suitable methods for nucleic acid delivery to effect expression of compositions of the present invention are believed to include virtually any method by which a nucleic acid (e.g., DNA, including viral and nonviral vectors) can be introduced into a cell, a tissue or an organism, as described herein or as would be known to one of ordinary skill in the art. Such methods include, but are not limited to, direct delivery of DNA such as by injection (U.S. Pat. Nos. 5,994,624, 5,981,274, 5,945,100, 5,780,448, 5,736,524, 5,702,932, 5,656,610, 5,589,466 and 5,580,859, each incorporated herein by reference), including microinjection (Harland and Weintraub, 1985; U.S. Pat. No. 5,789,215, incorporated herein by reference); by electroporation (U.S. Pat. No. 5,384,253, incorporated herein by reference); by calcium phosphate precipitation (Graham and Van Der Eb, 1973; Chen and Okayama, 1987; Rippe et al., 1990); by using DEAE dextran followed by polyethylene glycol (Gopal, 1985); by direct sonic loading (Fechheimer et al, 1987); by liposome mediated transfection (Nicolau and Sene, 1982; Fraley et al, 1979; Nicolau et al, 1987; Wong et al, 1980; Kaneda et al, 1989; Kato et al, 1991); by microprojectile bombardment (PCT Application Nos. WO 94/09699 and 95/06128; U.S. Pat. Nos. 5,610,042; 5,322,783 5,563,055, 5,550,318, 5,538,877 and 5,538,880, and each incorporated herein by reference); by agitation with silicon carbide fibers (Kaeppler et al, 1990; U.S. Pat. Nos. 5,302,523 and 5,464,765, each incorporated herein by reference); by Agrobacterium mediated transformation (U.S. Pat. Nos. 5,591,616 and 5,563,055, each incorporated herein by reference); or by PEG mediated transformation of protoplasts (Omirulleh et al, 1993; U.S. Pat. Nos. 4,684,611 and 4,952,500, each incorporated herein by reference); by desiccation/inhibition mediated DNA uptake (Potrykus et al, 1985). Through the application of techniques such as these, organelle(s), cell(s), tissue(s) or organism(s) may be stably or transiently transformed.

The Antibodies of the Invention--and their Production/Isolation

[0154] Antibodies directed against the proteins of the invention are useful for affinity chromatography, immunoassays, and for distinguishing/identifying staphylococcus proteins as well as for passive immunisation and therapy.

[0155] Antibodies to the proteins of the invention, both polyclonal and monoclonal, may be prepared by conventional methods. In general, the protein is first used to immunize a suitable animal, preferably a mouse, rat, rabbit or goat. Rabbits and goats are preferred for the preparation of polyclonal sera due to the volume of serum obtainable, and the availability of labeled anti-rabbit and anti-goat antibodies. Immunization is generally performed by mixing or emulsifying the protein in saline, preferably in an adjuvant such as Freund's complete adjuvant, and injecting the mixture or emulsion parenterally (generally subcutaneously or intramuscularly). A dose of 50-200 .mu.g/injection is typically sufficient. Immunization is generally boosted 2-6 weeks later with one or more injections of the protein in saline, preferably using Freund's incomplete adjuvant. One may alternatively generate antibodies by in vitro immunization using methods known in the art, which for the purposes of this invention is considered equivalent to in vivo immunization. Polyclonal antiserum is obtained by bleeding the immunized animal into a glass or plastic container, incubating the blood at 25 C for one hour, followed by incubating at 4 C for 2-18 hours. The serum is recovered by centrifugation (eg. 1,000 g for 10 minutes). About 20-50 ml per bleed may be obtained from rabbits.

[0156] Monoclonal antibodies are prepared using the standard method of Kohler & Milstein [Nature (1975) 256: 495-96], or a modification thereof. Typically, a mouse or rat is immunized as described above. However, rather than bleeding the animal to extract serum, the spleen (and optionally several large lymph nodes) is removed and dissociated into single cells. If desired, the spleen cells may be screened (after removal of nonspecifically adherent cells) by applying a cell suspension to a plate or well coated with the protein antigen. B-cells expressing membrane-bound immunoglobulin specific for the antigen bind to the plate, and are not rinsed away with the rest of the suspension. Resulting B-cells, or all dissociated spleen cells, are then induced to fuse with myeloma cells to form hybridomas, and are cultured in a selective I aedium (elg. hypexanthine, aminopterin, thymidine medium, "HAT"). The resulting hybridomas are plated by limiting dilution, and are assayed for production of antibodies, which bind specifically to the immunizing antigen (and which do not bind to unrelated antigens). The selected MAb-secreting hybridomas are then cultured either in vitro (eg. in tissue culture bottles or hollow fiber reactors), or in vivo (as ascites in mice).

[0157] If desired, the antibodies (whether polyclonal or monoclonal) may be labeled using conventional techniques. Suitable labels include fluorophores, chromophores, radioactive atoms (particularly 32p and l25I), electron-dense reagents, enzymes, and ligands having specific binding partners. Enzymes are typically detected by their activity. For example, horseradish peroxidase is usually detected by its ability to convert 3,3', 5,5'-tetramethylbenzidine (TMB) to a blue pigment, quantifiable with a spectrophotometer. "Specific binding partner" refers to a protein capable of binding a ligand molecule with high specificity, as for example in the case of an antigen and a monoclonal antibody specific therefor. Other specific binding partners include biotin and avidin or streptavidin, IgG and protein A, and the numerous receptor-ligand couples known in the art. It should be understood that the above description is not meant to categorize the various labels into distinct classes, as the same label may serve in several different modes. For example, 1151 may serve as a radioactive label or as an electron-dense reagent. HRP may serve as enzyme or as antigen for a MAb. Further, one may combine various labels for desired effect. For example, MAbs and avidin also require labels in the practice of this invention: thus, one might label a MAb with biotin, and detect its presence with avidin labeled with, l25I, or with an anti-biotin MAb labeled with HRP. Other permutations and possibilities will be readily apparent to those of ordinary skill in the art, and are considered as equivalents within the scope of the instant invention.

[0158] According to the invention, the isolated monoclonal antibody or antibody analogue is preferably a monoclonal antibody selected from a multi-domain antibody such as a murine antibody, a chimeric antibody such as a humanized antibody, a fully human antibody, and single-domain antibody of a llama or a camel, or which is an antibody analogue selected from a fragment of an antibody such as an Fab or an F(ab').sub.2, an scFV; cf. also the definition of the term "antibody" presented above.

Compositions of the Invention; Vaccines

[0159] Pharmaceutical compositions, in particular vaccines, according to the invention may either be prophylactic (ie. to prevent infection) or therapeutic (ie, to treat disease after infection).

[0160] Such vaccines comprise immunising antigen(s), immunogen(s), polypeptide(s), protein(s) or nucleic acid(s), usually in combination with "pharmaceutically acceptable carriers", which include any carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition.

[0161] In some embodiments of the invention, the pharmaceutical compositions such as vaccines include merely one single antigen, immunogen, polypeptide, protein, nucleic acid or vector of the invention, but in other embodiments, the pharmaceutical compositions comprise "cocktails" of the antigens or of the immunogens or of the polypeptides or of the protein or of the nucleic acids or of the vectors of the invention.

[0162] In particularly interesting embodiments, the pharmaceutical composition is an MVA vector mentioned herein, which encodes and can effect expression of at least 2 nucleic acid fragments of the invention.

[0163] Another interesting embodiment of a pharmaceutical composition comprises RNA as the active principle, i.e. at least one mRNA encoding a polypeptide of the invention.

[0164] An embodiment of a pharmaceutical composition of the invention comprises Y or at least Y or at most Y distinct polypeptides of the invention described above, where each of said Y or at least Y or at most Y distinct polypeptides comprises an immunogenic amino acid sequence present in or derived from any one of SEQ ID NOs: 1-16 and wherein said Y or at least Y or at most Y distinct polypeptides together comprise immunogenic amino acid sequences present in or derived from Y or at least Y or at most Y of SEQ ID NOs. 1-16, wherein Y is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0165] Another embodiment of the pharmaceutical composition of the invention comprises Z or at least Z or at most Z distinct nucleic acid molecules (such as DNA and RNA) each encoding a polypeptide of the invention, where each of said Z or at least Z or at most Z distinct nucleic acid molecules encodes an immunogenic amino acid sequence present in or derived from any one of SEQ ID NOs: 1-16 and wherein said at Z or least Z distinct nucleic acid molecules together encode immunogenic amino acid sequences present in or derived from Z or at least Z or at most Z of SEQ ID NOs. 1-16, wherein Z is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0166] Suitable carriers are typically large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, lipid aggregates (such as oil droplets or liposomes), and inactive virus particles.

[0167] Such carriers are well known to those of ordinary skill in the art. Additionally, these carriers may function as immunostimulating agents ("adjuvants"). Furthermore, the antigen or immunogen may be conjugated to a bacterial toxoid, such as a toxoid from diphtheria, tetanus, cholera, H. pylori, etc. pathogen, cf. the description of immunogenic carriers supra.

[0168] The pharmaceutical compositions of the invention thus typically contain an immunological adjuvant, which is commonly an aluminium based adjuvant or one of the other adjuvants described in the following:

[0169] Preferred adjuvants to enhance effectiveness of the composition include, but are not limited to: (1) aluminum salts (alum), such as aluminum hydroxide, aluminum phosphate, aluminum sulfate, etc; (2) oil-in-water emulsion formulations (with or without other specific immunostimulating agents such as muramyl peptides (see below) or bacterial cell wall components), such as for example (a) MF59 (WO 90/14837; Chapter 10 in Vaccine design: the subunit and adjuvant approach, eds. Powell & Newman, Plenum Press 1995), containing 5% Squalene, 0.5% Tween 80, and 0.5% Span 85 (optionally containing various amounts of MTP-PE (see below), although not required) formulated into submicron particles using a microfluidizer such as Model 110Y microfluidizer (Microfluidics, Newton, Mass.), (b) SAF, containing 10% Squalane, 0.4% Tween 80, 5% pluronic-blocked polymer L121, and thr-MDP (see below) either microfluidized into a submicron emulsion or vortexed to generate a larger particle size emulsion, and (c) Ribi adjuvant system (RAS), (Ribi Immunochem, Hamilton, Mont.) containing 2% Squalene, 0.2% Tween 80, and one or more bacterial cell wall components from the group consisting of monophosphoryl lipid A (MPL), trehalose dimycolate (TDM), and cell wall skeleton (CWS), preferably MPL+CWS (Detox.TM.); (3) saponin adjuvants such as Stimulon.TM. (Cambridge Bioscience, Worcester, Mass.) may be used or particles generated therefrom such as ISCOMs (immunostimulating complexes); (4) Complete Freund's Adjuvant (CFA) and Incomplete Freund's Adjuvant (IFA); (5) cytokines, such as interleukins (eg. IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, etc.), interferons (eg. gamma interferon), macrophage colony stimulating factor (M-CSF), tumor necrosis factor (TNF), etc.; and (6) other substances that act as immunostimulating agents to enhance the effectiveness of the composition. Alum and MF59.TM. adjuvants are preferred.

[0170] As mentioned above, muramyl peptides include, but are not limited to, N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-normuramyl-L-alanyl-D-isoglutamine (nor-MDP), N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2''-2'-dipalmitoyl-sn-- glycero-3-hydroxyphosphoryloxy)-ethylamine (MTP-PE), etc.

[0171] The immunogenic compositions (eg. the immunising antigen or immunogen or polypeptide or protein or nucleic acid, pharmaceutically acceptable carrier, and adjuvant) typically will contain diluents, such as water, saline, glycerol, ethanol, etc. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such vehicles.

[0172] Typically, the immunogenic compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared. The preparation also may be emulsified or encapsulated in liposomes for enhanced adjuvant effect, as discussed above under pharmaceutically acceptable carriers.

[0173] Immunogenic compositions used as vaccines comprise an immunologically effective amount of the antigenic or immunogenic polypeptides, as well as any other of the above-mentioned components, as needed. By "immunollogically effective amount", it is meant that the administration of that amount to an individual, either in a single dose or as part of a series, is effective for treatment or prevention. This amount varies depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated (eg. nonhuma primate, primate, etc.), the capacity of the individual's immune system to synthesize antibodies or generally mount an immune response, the degree of protection desired, the formulation of the vaccine, the treating doctor's assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials. However, for the purposes of protein vaccination, the amount administered per immunization is typically in the range between 0.5 .mu.g and 500 mg (however, often not higher than 5,000 .mu.g), and very often in the range between 10 and 200 .mu.g.

[0174] The immunogenic compositions are conventionally administered parenterally, eg, by injection, either subcutaneously, intramuscularly, or transdermally/transcutaneously (eg. W098/20734). Additional formulations suitable for other modes of administration include oral and pulmonary formulations, suppositories, and transdermal applications. In the case of nucleic acid vaccination, also the intravenous or intraarterial routes may be applicable.

[0175] Dosage treatment may be a single dose schedule or a multiple dose schedule. The vaccine may be administered in conjunction with other immunoregulatory agents.

[0176] As an alternative to protein-based vaccines, DNA vaccination (also termed nucleic acid vaccination or gene vaccination) may be used [eg. Robinson & Torres (1997) Seminars in Imlllunol 9: 271-283; Donnelly et al. (1997) Avnu Rev Innnunol 15: 617-648; later herein].

[0177] A further aspect of the invention is as mentioned above the recognition that combination vaccines can be provided, wherein 2 or more antigens disclosed herein are combined to enhance the immune response by the vaccinated animal, including to optimize initial immune response and duration of immunity. For the purposes of this aspect of the invention, multiple antigenic fragments derived from the same, longer protein can also be used, such as the use of a combination of different lengths of polypeptide sequence fragments from one protein.

[0178] Thus, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 1 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0179] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 2 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 3, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0180] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 3 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0181] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 4 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0182] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 5 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0183] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 6 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0184] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 7 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0185] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 8 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0186] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 9 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0187] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 10 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0188] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 11 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0189] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 12 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0190] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 13 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0191] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 14 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0192] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 15 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

[0193] Also, embodiments of the invention relate to a composition (or the use as a vaccine thereof) comprising 2 distinct (i.e. non-identical) proteinaceous immunogens disclosed herein wherein the first of said immunogens is SEQ ID NO: 16 or a variant or fragment thereof disclosed herein in combination with a proteinaceous immunogen selected from any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 or in combination with a variant or fragment disclosed herein of any one of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16.

Treatment Methods of the Invention

[0194] The method of the sixth aspect of the invention generally relates to induction of immunity and as such also entails method that relate to treatment, prophylaxis and amelioration of disease.

[0195] When immunization methods entail that a polypeptide of the invention or a composition comprising such a polypeptide is administered the animal (e.g. the human) typically receives between 0.5 and 5,000 .mu.g of the polypeptide of the invention per administration.

[0196] In preferred embodiments of the sixth aspect, the immunization scheme includes that the animal (e.g. the human) receives a priming administration and one or more booster administrations.

[0197] Preferred embodiments of the 6.sup.th aspect of the invention comprise that the administration is for the purpose of inducing protective immunity against S. aureus. In this embodiment it is particularly preferred that the protective immunity is effective in reducing the risk of attracting infection with S. aureus or is effective in treating or ameliorating infection with S. aureus.

[0198] As mentioned herein, the preferred vaccines of the invention induce humoral immunity, so it is preferred that the administration is for the purpose of inducing antibodies specific for S. aureus and wherein said antibodies or B-lymphocytes producing said antibodies are subsequently recovered from the animal.

[0199] But, as also mentioned the method of the 6.sup.th aspect may also be useful in antibody production, so in other embodiments the administration is for the purpose of inducing antibodies specific for S. aureus and wherein B-lymphocytes producing said antibodies are subsequently recovered from the animal and used for preparation of monoclonal antibodies.

[0200] Pharmaceutical compositions can as mentioned above comprise polypeptides, antibodies, or nucleic acids of the invention. The pharmaceutical compositions will comprise a therapeutically effective amount thereof.

[0201] The term "therapeutically effective amount" or "prophylactically effective amount" as used herein refers to an amount of a therapeutic agent to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect. The effect can be detected by, for example, chemical markers or antigen levels. Therapeutic effects also include reduction in physical symptoms, such as decreased body temperature. The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition, and the therapeutics or combination of therapeutics selected for administration. Thus, it is not useful to specify an exact effective amount in advance. Reference is however made to the ranges for dosages of immunologically effective amounts of polypeptides, cf. above.

[0202] However, the effective amount for a given situation can be determined by routine experimentation and is within the judgement of the clinician.

[0203] For purposes of the present invention, an effective dose will be from about 0.01 mg/kg to 50 mg/kg or 0.05 mg/kg to about 10 mg/kg of the DNA constructs in the individual to which it is administered.

[0204] A pharmaceutical composition can also contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to a carrier for administration of a therapeutic agent, such as antibodies or a polypeptide, genes, and other therapeutic agents. The term refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. Suitable carriers may be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Such carriers are well known to those of ordinary skill in the art.

[0205] Pharmaceutically acceptable salts can be used therein, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. A thorough discussion of pharmaceutically acceptable excipients is available in Remington's Pharmaceutical Sciences (Mack Pub. Co., N. J. 1991).

[0206] Pharmaceutically acceptable carriers in therapeutic compositions may contain liquids such as water, saline, glycerol and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such vehicles. Typically, the therapeutic compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared. Liposomes are included within the definition of a pharmaceutically acceptable carrier.

[0207] As is apparent from the claims, the invention also relates to related embodiments to the treatment and prophylaxis disclosed herein: the invention also includes embodiments where [0208] the polypeptide of the invention is for use as a pharmaceutical, in particular for use as a pharmaceutical in the treatment, prophylaxis or amelioration of infection with S. aureus; [0209] the nucleic acid fragment of the invention or the vector of the invention is for use as a pharmaceutical, in particular for use as a pharmaceutical in the treatment, prophylaxis or amelioration of infection with S. aureus; [0210] the transformed cell of the invention is for use as a pharmaceutical, in particular for use as a pharmaceutical in the treatment, prophylaxis or amelioration of infection with S. aureus. [0211] the antibody, antibody fragment or antibody analogue of the invention is for use as a pharmaceutical, in particular for use as a pharmaceutical in the treatment, prophylaxis or amelioration of infection with S. aureus.

Example

Testing S. aureus Derived Vaccines in Mice Challenged with MRSA

[0212] Expression and Purification of S. aureus Genes 1. Gene fragments that encode the selected S. aureus polypeptides of the invention are prepared synthetically and are introduced into the pQE-1 vector (Qiagen) from Genscript. The fragments are inserted by blunt ended ligation into the PVU II site in the 5'-end, immediately following the vector's coding region for the 6 histidinyl residues. In the 3'-end, all inserted gene fragments include a stop codon. 2. The vectors from 1 are transfected into the E. Coli M15[pREP4] strain, which contains an expression as well as a repressor plasmid facilitating proper expression. 3. The vectors from 1 are further inserted into the E. coli XL1 Blue for long-time storage. 4. The transfected and selected clones are tested for expression in small scale whereby optimum conditions for expression in terms of the amount of IPTG, the density of cells and the time of expression induction are determined. 5. From the information obtained in 4, large scale cultures are established; subsequently the expression products are harvested and purified on a Ni-NTA column. 6. Purity and yield of the large-scale expression is investigated by means of SDS-PAGE and spectrophotometry, whereafter the proteins are aliquoted for use in immunization experiments and other experiments. Immunization and S. aureus Challenge Infection in Mice 1. 2 months old NMRI mice were used. 2. Groups of at least 8 mice were used for immunization. The mice were immunized 3 times (at day 0, 14, and 28) prior to challenge infection. A control group was treated according to an identical protocol with the exception that an irrelevant protein antigen or phosphate buffered saline was used for immunization.

1st Immunization:

[0213] 25 .mu.g protein (per mice) was mixed with 100 .mu.l aluminum hydroxide (Alhydrogel 2.0%, Brenntag) per 125 ug protein and incubated with end-over-end rotation for 15 min. Freund's incomplete adjuvant (sigma) was added in the volume 1:1 and the mixture was vortexed thoroughly for 1 hour. This mixture was injected subcutaneously.

2nd and 3rd Immunization:

[0214] The mice were booser injected intraperitoneally with 2 weeks interval, using the same amount of protein mixed with aluminum hydroxide and physiological saline solution.

3. 14 days after the last immunization, a number of bacteria (2.times.10.sup.9 cells) corresponding to a predetermined LD.sub.90 in the control group of mice was administered intraperitoneally to all mice.

[0215] The cells were handled cold and kept on ice until use. The stock solution of MRSA cells were thawed on ice and then the appropriate amount of cells was diluted in sterile physiological saline (total volume per mouse 500 .mu.l).

[0216] The survival was surveilled twice daily in the first 48 hours after challenge and once daily in the subsequent 7 days. The mice were sacrificed if they showed signs of suffering. The mice were monitored with respect to loss of weight and body temperature using an implanted chip. The organs of the mice were used for determination of CFU counts for SAR1402 (SEQ ID NO: 5), SAR 2723 (SEQ ID NO: 13) and SAR2753 (SEQ ID NO: 14).

[0217] The results from 7 polypeptide vaccinations are presented in the Figures.

[0218] FIG. 1 shows the survival curves for 8 mice immunized with full-length SAR1402 (SEQ ID NO: 5) and 8 mice immunized with negative control. Survival in the vaccinated group at day 7 was 7/8 mice, whereas only 1/8 mice in the control group survived. The increased survival in the vaccinated group is statistically highly significant (P=0.001 according to a Log-rank Mantel-Cox test).

[0219] FIG. 2 shows the survival curves for 8 mice immunized with amino acids 20-515 of SAR2496 (SEQ ID NO: 11) and 8 mice immunized with negative control. Survival in the vaccinated group at day 7 was 6/8 mice, whereas only 1/8 mice in the control group survived. The increased survival in the vaccinated group is statistically highly significant (P=0.005 according to a Log-rank Mantel-Cox test).

[0220] FIG. 3 shows the survival curves for 8 mice immunized with amino acids 28-619 of SAR2723 (SEQ ID NO: 13) and 8 mice immunized with negative control. Survival in the vaccinated group at day 7 was 4/8 mice, whereas only 1/8 mice in the control group survived. The increased survival in the vaccinated group is statistically highly significant (P=0.0145 according to a Log-rank Mantel-Cox test).

[0221] FIG. 4 shows the survival curves for 8 mice immunized with amino acids 36-681 of SAR2753 (SEQ ID NO: 14) and 8 mice immunized with negative control. Survival in the vaccinated group at day 7 was 4/8 mice, whereas only 1/8 mice in the control group survived. The increased survival in the vaccinated group is statistically highly significant (P=0.0032 according to a Log-rank Mantel-Cox test).

[0222] FIG. 5 shows the survival curves for 20 mice immunized with amino acids 28-619 of SAR2723 (SEQ ID NO: 13) and 20 mice immunized with negative control (phosphate buffered saline, PBS). Survival in the vaccinated group at day 7 was 15/20 mice, whereas only 6/20 mice in the control group survived. The increased survival in the vaccinated group is statistically highly significant (P=0.0053 according to a Log-rank Mantel-Cox test).

[0223] FIG. 6 shows the survival curves for 20 mice immunized with a homologue of SAR2716 (USA300HOU_2637_28_439 shown in SEQ ID NO: 49) and 20 mice immunized with negative control (PBS). Survival in the vaccinated group at day 7 was 15/20 mice, whereas only 6/20 mice in the control group survived. The increased survival in the vaccinated group is statistically highly significant (P=0.0063 according to a Log-rank Mantel-Cox test). USA300HOU_2637_28_439 has a sequence identity with SEQ ID NO: 10, residues 28-439, of 93%.

[0224] FIG. 7 shows the survival curves for 19 mice immunized with amino acids 25-564 of SAR1795 (SEQ ID NO: 12) and 20 mice immunized with negative control (PBS). Survival in the vaccinated group at day 7 was 15/19 mice, whereas only 6/20 mice in the control group survived. The increased survival in the vaccinated group is statistically highly significant (P=0.0049 according to a Log-rank Mantel-Cox test).

Sequence Information

[0225] The sequence listing included sets forth the sequences of polypeptides and nucleic acids of the present invention. For easy reference, the sequences are presented in the following:

[0226] The polypeptides of the present invention have the following amino acid sequences:

TABLE-US-00001 SEQ IN NO: 1 MAKGNLFKAILGIGGAVAAVLVTRKDSRDKLKAEYNKYKQDPQSYKDN AKDKATQLGTIANETIKEVKTNPKEYANRLKNNPKAFFEEEKSKFTEY DNKTDESIEKGKFDDEGGAAPNNNLRIVTEEDLKKNKNALSDKE SEQ IN NO: 2 MKKLVSIVGATLLLAGCGSQNLAPLEEKTTDLREDNHQLKLDIQELNQ QISDSKSKIKGLEKDKENSKKTASNNTKIKLMNVTSTYYDKVAKALKS YNDIEKDVSKNKGDKNVQSKLNQISNDIQSAHTSYKDAIDGLSLSDDD KKTSKNIDKLNSDLNHAFDDIKNGYQNKDKKQLTKGQQALSKLNLNAK S SEQ IN NO: 3 MKKLVTGLLALSLFLAACGQDSDQQKDSNKEKDDKAKTEQQDKKTNDS SKDKKDNKDDSKDVNKDNKDNSANDNQQQSNSNATNNDQNQTNNNQSN SGQTTNNQKSSYVAPYYGQNAAPVARQIYPFNGNKSQALQQLPNFQTA LNAANNEANKFGNGHKVYNDYSIEEHNGNYKYVFSFKDPNVNGKYSIV TVDYTGQAMVTDPNYQQ SEQ IN NO: 4 MKKVMGILLASTLILGACGHHQDSAKKESTSHKKKENDNEELNEELKE FKSKKNMDIKIKGDTIVSDKFEAKIKEPFIINEKDEKKKYIAFKMEIT AKKDDKDLNPSSISHDYINITQDDKNTVNKLRDGYLLSDKNYKDWTEH NQDQIKKGKTAQAMFIYELRGDGNINLNVHKYSEDKTVDSKSFKFSKL KTEDFSHRAETREEVEKKEKEFEEEYKKEQEREKEKEKQKDDDHSGLD EV SEQ IN NO: 5 MKKWQFVGTTALGATLLLGACGGGNGGSGNSDLKGEAKGDGSSTVAPI VEKLNEKWAQDHSDAKISAGQAGTGAGFQKFIAGDIDFADASRPIKDE EKQKLQDKNIKYKEFKIAQDGVTVAVNKENDFVDELDKQQLKAIYSGK AKTWKDVNSKWPDKKINAVSPNSSHGTYDFFENEVMNKEDIKAEKNAD TNAIVSSVTKNKEGIGYFGYNFYVQNKDKLKEVKIKDENGKATEPTKK TIQDNSYALSRPLFIYVNEKALKDNKVMSEFIKFVLEDKGKAAEEGGY VAAPEKTYKSQLDDLKAFIDKNQKSDDKKSDDKKSEDKK SEQ IN NO: 6 MKGKFLKVSSLFVATLTTATLVSSPAANALSSKAMDNHPQQTQTDKQQ TPKIQKGGNLKPLEQRERANVILPNNDRHQITDTTNGHYAPVTYIQVE APTGTFIASGVVVGKDTLLTNKHIVDATHGDPHALKAFASAINQDNYP NGGFTAEQITKYSGEGDLAIVKFSPNEQNKHIGEVVKPATMSNNAETQ VNQNITVTGYPGDKPVATMWESKGKITYLKGEAMQYDLSTTGGNSGSP VFNEKNEVIGIHWGGVPNQFNGAVFINENVRNFLKQNIEDINFANDDH PNNPDNPDNPNNPDNPNNPDNPNNPDNPDNPNNPDNPNNPDNPNNPDQ PNNPNNPDNGDNNNSDNPDAA SEQ IN NO: 7 MKRTLVLLITAIFILAACGNHKDDQAGKDNQKHNNSSNQVKEIATDKN VQGDNYRTLLPFKESQARGLLQDNMANSYNGGDFEDGLLNLSKEVFPT DKYLYQDGQFLDKKTINAYLNLKYTKREIDKMSEKDKKDKKANENLGL NPSHEGETDPEKIAEKSPAYLSNILEQDFYGGGDTKGKNIKGMTIGLA MNSVYYYKKEKDGPTFSKKLDDSEVKKQGKQMASEILSRLRENDDLKD IPIHFAIYKQSSEDSITPGEFITQATAEKSQTKLNEWHNINEKSALLP SSTAADYDENLNNNFKQFNDNLQSYFSNFTQAVGKVKFVDKKPQRLVV DLPIDYYGQAETIGITQYVTEQANKYFDKIDNYEIRIKDGNQPRALIS KTKDDKEPQVHIYSN SEQ IN NO: 8 MRENFKLRKMKVGLVSVAITMLYIMTNGQAEASEANEKPSTNQESKVV SQTEQNSKETKTVESNKNFVKLDTIKPGAQKITGTTLPNHYVLLTVDG KSADSVENGGLGFVEANDKGEFEYPLNNRKIVHNQEIEVSSSSPDLGE DEEDEEVEEASTDKAGVEEESTEAKVTYTTPRYEKAYEIPKEQLKEKD GHHQVFIEPITEGSGIIKGHTSVKGKVALSINNKFINFEESVKGGVSK EDTKASSDGIWMPIDDKGYFNFDFKTKRFDNLELKEGNDISLTFAPDD EEDALKPLIFKTKVTSLEDIDKAETKYDHTKLNKVKVLDNVKEDLHVD EIYGSLYHTDKGKGILDKEGTKVIKGKTKFANAVVKVDSELGEAQLFP DLQVNEKGEFSFDSHGAGFRLQNGEKLNFTVVDPITGDLLSNEFVSKE IDIEETPEQKADREFDEKLENTPAYYKLYGDKIVGFDTNDFPITWFYP LGEKKVERTTPKLEK SEQ IN NO: 9 MSKKLKIIIPIIIVLLLIGGIAWGVYAFFANTPKNTYLKSEQQTAKMY KDYFNDRFENEVKFQEKMKDNSFLSSLELSADASDEIVKGLGIPKSVV NASKIKMSYGHDPKKEKSMINLEPTIADSALGKFQLAADKDKHYFESP LFKGKYSVNNSDLLSTYSKLTGEDEETAKENGITNQQLNLNTLFSNAQ AQQSDYSKIAEKYSELIVDKLDDDNFDKGKKEEIKVNGEKYKVRPVTL TLSRADTKKITLAVLEEAKKDKDLKKLMEEQGTTKDFEKDIKKAIDDV KETKKDEFAKIQSKIYTEKHTIVKREITITDKENNKTKIKGTNTLEDD KLKLDYALDFDQDKYTYAEAKYTIKGVSSKEKDNKYSDKYEFGKKTEY DESKIKLDNQEKVDGTKRQDKGKITVALDKYSDENEFTFENNIDSDVK NNTQKSTLNIGIKYAEEPINFILKSSTKLKADIDFDDSGAKDFNSLSS KDREKLEKEIEKNGGKMFESILKKASK SEQ IN NO: 10 MRKFSRYAFTSMATVTLLSSLTPAALASDTNHKPATSDINFEITQKSD AVKALKELPKSENVKNHYQDYSVTDVKTDKKGFTHYTLQPSVDGVHAP DKEVKVHADKSGKVVLINGDTDAKKVKPTNKVTLSKDEAADKAFNAVK IDKNKAKNLQDDVIKENKVEIDGDSNKYIYNIELITVTPEISHWKVKI DADTGAVVEKTNLVKEAAATGTGKGVLGDTKDININSIDGGFSLEDLT HQGKLSAYNFNDQTGQATLITNEDENFVKDDQRAGVDANYYAKQTYDY YKNTFGRESYDNHGSPIVSLTHVNHYGGQDNRNNAAWIGDKMIYGDGD GRTFTNLSGANDVVAHELTHGVTQETANLEYKDQSGALNESFSDVFGY FVDDEDFLMGEDVYTPGKEGDALRSMSNPEQFGQPSHMKDYVYTEKDN GGVHTNSGIPNKAAYNVIQAIGKSKSEQIYYRALTEYLTSNSNFKDCK DALYQAAKDLYDEQTAEQVYEAWNEVGVE SEQ IN NO: 11 MKKKLGMLLLVPAVTLSLAACGNDDGKDKDGKVTIKTTVYPLQSFAEQ IGGKHVKVSSIYPAGTDLHSYEPTQKDILSASKSDLFMYTGDNLDPVA KKVASTIKDKDKKLSLEDKLDKAKLLTDQHEHGEEHEHEGHDHGKEEH HHHGGYDPHVWLDPKINQTFAKEIKDELVKKDPKHKDDYEKNYKKLND DLKKIDNDMKQVTKDKQGNAVFISHESIGYLADRYGFVQKGIQNMNAE DPSQKELTKIVKEIRDSNAKYILYEDNVANKVTETIRKETDAKPLKFY NMESLNKEQQKKDNITYQSLMKSNIENIGKALDSGVKVKDDKAESKHD KAISDGYFKDEQVKDRELSDYAGEWQSVYPYLKDGTLDEVMEHKAEND PKKSAKDLKAYYDKGYKTDITNIDIKGNEITFTKDGTKHTGKYEYNGK KTLKYPKGNRGVRFMFKLVDGNDKDLPKFIQFSDHNIAPKKAEHFHIF MGNDNDALLKEMDNWPTYYPSKLNKDQIKEEMLAH SEQ IN NO: 12 MVLYIILAIIVIILIAVGVLFYLRSNKRQIIEKAIERKNEIETLPFDQ NLAQLSKLNLKGETKTKYDAMKKDNVESTNKYLAPVEEKIHNAEALLD KFSFNASQCEIDDANELMDSYEQSYQQQLEDVNEIIALYKDNDELYDK CKVDYREMKRDVLANRHQFGEAASLLETEIEKFEPRLEQYEVLKADGN YVQAHNHIAALNEQMKQLRSYMEEIPELIRETQKELPGQFQDLKYGCR DLKVEGYDLDHVKVDSTLQSLKTELSFVEPLISRLELEEANDKLANIN DKLDDMYDLIENEVKAKNDVEETKDIITDNLFKAKDMNYTLQTEIEYV RENYYINESDAQSVRQFENEIQSLISVYDDILKEMSKSAVRYSEVQDN LQYLEDHVTVINDKQEKLQNHLIQLREDEAEAEDNLLRVQSKKEEVYR RLLASNLTSVPERFIIMKNEIDHEVRDVNEQFSERPIHVKQLKDKVSK IVIQMNTFEDEANDVLVNAVYAEKLIQYGNRYRKDYSNVDKSLNEAER LFKNNRYKRAIEIAEQALESVEPGVTKHIEEEVIKQ SEQ IN NO: 13 MPKNKILIYLLSTTLVLPTLVSPTAYADTPQKDTTAKTTSHDSKKSTD DETSKDTTSKDIDKADNNNTSNQDNNDKKVKTIDDSTSDSNNIIDFIY KNLPQTNINQLLTKNKYDDNYSLTTLIQNLFNLNSDISDYEQPRNGEK STNDSNKNSDNSIKNDTDTQSSKQDKADNQKAPKSNNTKPSTSNKQPN SPKPTQPNQSNSQPASDDKVNQKSSSKDNQSMSDSALDSILDQYSEDA KKTQKDYASQSKKDKNEKSNTKNPQLPTQDELKHKSKPAQSFNNDVNQ KDTRATSLFETDPSISNNDDSGQFNVVDSKDTRQFVKSIAKDAHRIGQ DNDIYASVMIAQAILESDSGRSALAKSPNHNLFGIKGAFEGNSVPFNT LEADGNQLYSINAGFRKYPSTKESLKDYSDLIKNGIDGNRTIYKPTWK SEADSYKDATSHLSKTYATDPNYAKKLNSIIKHYQLTQFDDERMPDLD KYERSIKDYDDSSDEFKPFREVSDNMPYPHGQCTWYVYNRMKQFGTSI SGDLGDAHNWNNRAQYRDYQVSHTPKRHAAVVFEAGQFGADQHYGHVA FVEKVNSDGSIVISESNVKGLGIISHRTINAAAAEELSYITGK SEQ IN NO: 14 MMKSQNKYSIRKFSVGASSILIATLLFLSGGQAQAAEKQVNMGNSQED TVTAQSIGDQQTRENANYQRENGVDEQQHTENLTKNLHNDKTISEENH RKTDDLNKDQLKDDKKSSLNNKNIQRDTTKNNNANPRDVNQGLEQAIN DGKQSKVASQQQSKEADNSQDLNANNNLPSQSRTKVSPSLNKSDQTSQ REIVNETEIEKVQPQQKNQANDKITDHNFNNEQEVKPQKDEKTLSVSD LKNNQKSPVEPTKDNDKKNGLNLLKSSAVATLPNKGTKELTAKAKGDQ

TNKVAKQGQYKNQDPIVLVHGFNGFTDDINPSVLAHYWGGNKMNIRQD LEENGYKAYEASISAFGSNYDRAVELYYYIKGGRVDYGAAHAAKYGHE RYGKTYEGIYKDWKPGQKVHLVGHSMGGQTIRQLEELLRNGSREEIEY QKKHSGEISPLFKGNNDNMISSITTLGTPHNGTHASDLAGNEALVRQI VFDIGKMFGNKNSRVDFGLAQWGLKQKPNESYIDYVKRVKQSNLWKSK DNGFYDLTREGATDLNRKTSLNPNIVYKTYTGEATHKALNSDRQKADL NMFFPFVITGNLIGKATEKEWRENDGLVSVISSQHPFNQAYTNATDKI QKGIWQVTPTKHDWDHVDFVGQDSSDTVRTREELQDFWHHLADDLVKT EKVTDTKQA SEQ IN NO: 15 MTNKMKKWQKLSTITLLMTGVIALNNGEFRNVDKHQIAVADTNVQTPD YEKLKKTWLDVNYGYDQYDENNQDMKKKFDAKEKEAKKLLDDMKTDTN RTYLWSGAENLETNSSHMTKTYRNIEKIAESMQHKNTVLKTVENKLKI KEALDWMHKNVYGKNPSQKVEDLTKNRKGQTTPKNNSLNWWDYEIGTP RALTNTLLLMDDMLTKDEMKNYSKPISTYAPSSDKILSSVGESEDAKG GNLVDISKVKLLESVIEEDVDMLKKSIDSFNKVFTYVQDSATGKGRNG FYKDGSYIDHQDVPYTGAYGVVLLEGISQMMPMIKESPFKTTQDNATL SNWIDEGFMPLIYKGEMMDLSRGRAISRENETSHTASATVMKSLLRLN DTMDDSTKTRYKQIVKTSVNSDSSYNQNNYLNSYSDIAKMKKLMNDST ISKNDLTQQLKIYNDMDRVTYHNKDLDFAFGLSMTSKNIARYENINGE NLKGWHTGAGMSYLYNSDVKHYRDNFWATADMTCLPGTTTLNDMPSTN TKNDKSFVGGTKLNNKYASIGMDFENQDKTLTAKKSYFILNDKIVFLG TGIKSTDSSKNPVTSVENRKANGYKLFKDDIEITTSDVNAQETHSVFL ESNDTKKNIGYHFLDKPKITVKKESHTGKWSEINKSQKKDDKKDEYYE VTQTHNTSDSKYAYVLYPGLSKSDFKSKNNNVSIVKQDEDFHVIKDND GVFAGVNYSDNTKSFDINGITVELKEKGMFVIKKKDDKAYKCSFYNPE TTNTASNIESKIFIKGYTITNKSVINSNDAGVNFELTK SEQ IN NO: 16 MTYRMKKWQKLSTITLLMAGVITLNGGEFRSIDKHQIAVADTNVQTTD YEKLRNIWLDVNYGYDKYDENNPDMKKKFEATENEAEKLLKEMKTESD RKYLWESSKDLDTKSADMTRTYRNIEKISEAMKHKNTKLKTDENKTKV KDALEWLHKNAYGKEPDKKVADLTSNFKNKTSRNTNLNWWDYEIGTPR ALTNTLILLQEDFTDEEKKKYTAPIKTFAPDSDKILSSVGKSEPAKGG NLVDISKVKLLESIIEEDKDMMKKSIDSFNTVFTYAQNSATGKERNGF YKDGSYIDHQDVPYTGAYGVVLLEGISQMMPMIKETPFNDSNQNDTTL KSWIDDGFMPLIYKGEMMDLSRGRAISRENETSHSASATVMKSLLRLS DTMDKSTKAKYKKIVKTSVESDSSYKQTDYLSSYSDISKMKSLMEDST ISTNGLTQQLKIYNDMDRVTYHNKGLDFAFGLSMTSKNVARYESINGE NLKGWHTGAGMSYLYNSDVKHYRDNFWATADMKRLAGTTTLDNEEPKS TDVKKSSKTFVGGTKFDDQHASIGMDFENQDKTLTAKKSYFILNDKIV FLGTGIKSTDSSKNPVTTIENRKANDYKLYKDDTQTTNSDNQETNSLF LESTNSTQNNIGYHFLNESKITVKKESHTGKWSDINKSQKDIQKTDEY YEVTQKHSNTDSKYAYVLYPGLSKDVFKSKASKVTVVKQEDDFHVVKD NESVWAGINYSDSAKTFEINNTKVEVKAKGMFILTKKDDNTYECSFYN PESTNSVSDIESKISMTGYSIINKNTSTSNESGVRFELTK SEQ ID NO: 49: IDSKNKPANSDIKFEVTQKSDAVKALKELPKSENVKNIYQDYAVTDVK TDKKGFTHYTLQPSVDGVHAPDKEVKVHADKSGKVVLINGDTDAKKVK PTNKVTLSKDDAADKAFKAVKIDKNKAKNLKDKVIKENKVEIDGDSNK YVYNVELITVTPEISHWKVKIDAQTGEILEKMNLVKEAAETGKGKGVL GDTKDININSIDGGFSLEDLTHQGKLSAFSFNDQTGQATLITNEDENF VKDEQRAGVDANYYAKQTYDYYKDTFGRESYDNQGSPIVSLTHVNNYG GQDNRNNAAWIGDKMIYGDGDGRTFTSLSGANDVVAHELTHGVTQETA NLEYKDQSGALNESFSDVFGYFVDDEDFLMGEDVYTPGKEGDALRSMS NPEQFGQPAHMKDYVFTEKDNGGVHTNS

[0227] The nucleic acid fragments of the present invention have the following sequences:

TABLE-US-00002 SEQ IN NO: 17 ATGGCAAAAGGTAATTTATTTAAAGCGATTTTAGGTATAGGTGGCGCTGTAGCAGCTGTACTTGTTACA CGTAAAGATAGTCGTGACAAGCTGAAAGCAGAATATAATAAATACAAACAAGATCCTCAAAGCTATAA AGATAATGCTAAGGATAAAGCGACGCAATTAGGAACAATTGCAAATGAAACAATTAAAGAAGTAAAAA CAAATCCGAAAGAATATGCTAATAGATTAAAAAATAATCCAAAAGCATTTTTCGAAGAAGAAAAATCAA AATTTACCGAATATGACAATAAGACTGACGAAAGTATTGAAAAAGGTAAATTTGATGATGAAGGTGGC GCAGCACCAAATAATAATTTACGTATCGTCACTGAAGAAGATTTAAAAAAGAATAAAAATGCATTGTCT GATAAAGAATAA SEQ IN NO: 18 ATGAAAAAATTGGTTTCAATTGTTGGCGCAACATTATTGTTAGCTGGATGTGGATCACAAAATTTAGCA CCATTAGAAGAAAAAACAACAGATTTAAGAGAAGATAATCATCAACTCAAACTAGATATTCAAGAACTT AATCAACAAATTAGTGATTCTAAATCTAAAATTAAAGGGCTTGAAAAGGATAAAGAAAATAGTAAAAAA ACTGCATCTAATAATACGAAAATTAAATTGATGAATGTTACATCAACATACTACGACAAAGTTGCTAAA GCTTTGAAATCCTATAACGATATTGAAAAGGATGTAAGTAAAAACAAAGGCGATAAGAATGTTCAATCG AAATTAAATCAAATTTCTAATGATATTCAAAGTGCTCACACTTCATACAAAGATGCTATCGATGGTTTAT CACTTAGTGATGATGATAAAAAAACGTCTAAAAATATCGATAAATTAAACTCTGATTTGAATCATGCATT TGATGATATTAAAAATGGCTATCAAAATAAAGATAAAAAACAACTTACAAAAGGACAACAAGCGTTGTC AAAATTAAACTTAAATGCAAAATCATGA SEQ IN NO: 19 ATGAAAAAATTAGTTACAGGGTTATTAGCATTATCATTATTTTTAGCTGCATGTGGTCAAGATAGTGAC CAACAAAAAGACAGTAATAAAGAAAAAGATGATAAAGCGAAAACTGAACAACAAGATAAAAAAACAAA TGATTCATCTAAAGATAAGAAAGACAATAAAGATGATAGTAAAGACGTAAACAAAGATAATAAAGATAA TAGTGCAAACGATAACCAGCAACAATCTAATTCAAATGCAACAAACAATGACCAAAATCAAACGAATAA TAACCAGTCAAACAGTGGACAAACGACTAACAATCAAAAATCAAGTTACGTTGCACCATATTATGGACA AAACGCAGCGCCAGTGGCTCGTCAAATTTATCCATTTAATGGTAATAAATCACAAGCATTACAACAATT GCCTAATTTCCAAACAGCTTTAAATGCAGCTAACAACGAAGCAAATAAATTTGGTAATGGTCATAAAGT TTATAATGATTATTCAATTGAAGAACATAATGGTAACTATAAGTATGTTTTTAGTTTTAAAGACCCAAAC GTAAATGGAAAATATTCAATTGTAACGGTTGATTATACTGGACAAGCAATGGTTACTGATCCAAACTAC CAACAATAA SEQ IN NO: 20 ATGAAAAAAGTAATGGGGATATTATTAGCAAGTACACTTATCTTAGGTGCTTGTGGACATCATCAAGAT AGTGCAAAAAAAGAGAGCACTAGTCACAAAAAGAAAGAAAATGACAATGAAGAATTAAATGAAGAACT TAAAGAATTTAAAAGCAAAAAAAATATGGATATAAAAATTAAAGGCGATACTATTGTTAGTGACAAATT TGAAGCTAAAATAAAAGAACCGTTTATCATCAATGAAAAAGATGAGAAAAAGAAATATATCGCTTTTAA AATGGAAATTACTGCTAAAAAAGACGATAAAGATTTAAATCCATCTTCTATTTCTCATGACTATATTAAT ATCACTCAAGATGATAAAAATACAGTAAATAAATTAAGAGATGGTTATCTTTTAAGTGATAAAAATTATA AAGATTGGACAGAACATAACCAAGATCAAATTAAAAAAGGCAAAACTGCACAAGCCATGTTTATCTATG AGTTAAGAGGTGATGGAAACATTAATTTAAATGTCCATAAATACTCAGAAGATAAAACAGTTGATTCTA AATCATTCAAATTTAGTAAACTTAAAACCGAAGATTTTTCTCATAGAGCGGAAACAAGGGAAGAAGTAG AAAAGAAAGAAAAAGAATTTGAAGAAGAGTACAAAAAAGAACAAGAACGAGAGAAAGAAAAAGAAAA GCAAAAAGATGACGACCACAGTGGTTTAGATGAAGTATAA SEQ IN NO: 21 ATGAAAAAATGGCAATTTGTTGGTACTACAGCTTTAGGTGCAACACTATTATTAGGTGCTTGTGGTGGC GGTAATGGTGGCAGTGGTAATAGTGATTTAAAAGGGGAAGCTAAAGGGGATGGCTCATCAACAGTAG CACCAATTGTGGAGAAATTAAATGAAAAATGGGCTCAAGATCACTCGGATGCTAAAATCTCAGCAGGA CAAGCTGGTACAGGTGCTGGTTTCCAAAAATTCATTGCAGGAGATATCGACTTCGCTGATGCTTCTAG ACCAATTAAAGATGAAGAGAAGCAAAAATTACAAGATAAGAATATCAAATACAAAGAATTCAAAATTGC GCAAGATGGTGTAACGGTTGCTGTAAATAAAGAAAATGATTTTGTAGATGAATTAGACAAACAGCAAT TAAAAGCAATTTATTCTGGAAAAGCTAAAACATGGAAAGATGTTAATAGTAAATGGCCAGATAAAAAAA TAAATGCTGTATCACCAAACTCAAGTCATGGTACTTATGACTTCTTTGAAAATGAAGTAATGAATAAAG AAGATATTAAAGCAGAAAAAAATGCTGATACAAATGCTATCGTTTCTTCTGTAACGAAAAACAAAGAGG GAATCGGATACTTTGGATATAACTTCTACGTACAAAATAAAGATAAATTAAAAGAAGTTAAAATCAAAG ATGAAAATGGTAAAGCAACAGAGCCTACGAAAAAAACAATTCAAGATAACTCTTATGCATTAAGTAGAC CATTATTCATTTATGTAAATGAAAAAGCATTGAAAGATAATAAAGTAATGTCAGAATTTATCAAATTCGT CTTAGAAGATAAAGGTAAAGCAGCTGAAGAAGGTGGATATGTAGCAGCACCAGAGAAAACATACAAAT CACAATTAGATGATTTAAAAGCATTTATTGATAAAAATCAAAAATCAGACGACAAGAAATCTGATGATA AAAAGTCTGAAGACAAGAAATAA SEQ IN NO: 22 ATGAAAGGTAAATTTTTAAAAGTTAGTTCTTTATTCGTTGCAACTTTGACAACAGCGACACTTGTGAGTT CTCCAGCAGCAAATGCGTTATCTTCAAAAGCTATGGACAATCATCCACAACAAACGCAGACAGACAAA CAGCAAACACCTAAGATTCAAAAAGGCGGTAACCTTAAACCATTAGAACAACGTGAACGCGCTAATGT TATATTACCAAATAACGATCGTCACCAAATCACAGATACAACGAATGGTCATTATGCACCTGTTACTTA TATTCAAGTTGAAGCACCTACTGGTACATTTATTGCTTCTGGTGTAGTTGTAGGTAAAGATACACTTTT AACAAATAAACACATCGTAGATGCTACGCACGGTGATCCTCATGCTTTAAAAGCATTCGCTTCTGCAAT TAACCAAGACAATTATCCTAATGGTGGTTTCACTGCTGAACAAATCACTAAATATTCAGGCGAAGGTGA TTTAGCAATCGTTAAATTCTCCCCTAATGAGCAAAACAAACATATTGGCGAAGTAGTTAAACCAGCAAC AATGAGTAATAATGCTGAAACACAAGTTAACCAAAATATTACTGTAACAGGATATCCTGGTGATAAACC TGTCGCAACAATGTGGGAAAGTAAAGGAAAAATAACGTACTTAAAAGGTGAAGCAATGCAATATGATT TAAGTACAACTGGTGGTAACTCAGGTTCACCTGTATTTAATGAAAAAAATGAAGTCATTGGCATTCATT GGGGTGGCGTTCCAAATCAATTTAACGGTGCAGTATTTATTAATGAAAATGTACGCAACTTCTTAAAAC AAAATATTGAAGATATCAATTTCGCAAATGATGACCACCCTAACAACCCTGATAATCCAGACAATCCAA ATAATCCGGACAATCCTAACAACCCTGATAACCCTAACAACCCTGATAATCCAGACAATCCTAATAATC CTGATAACCCTAACAACCCGGACAATCCAAATAACCCTGACCAACCTAACAACCCAAATAACCCGGAC AATGGCGATAACAATAATTCAGACAACCCTGACGCTGCATAA SEQ IN NO: 23 ATGAAGCGTACATTAGTATTATTGATTACAGCTATCTTTATACTCGCTGCTTGTGGTAACCATAAGGAT GACCAGGCTGGAAAAGATAATCAAAAACATAACAATAGTTCAAATCAAGTAAAAGAAATTGCTACGGA TAAAAATGTACAAGGTGATAACTATCGTACATTGTTACCATTTAAAGAAAGCCAGGCAAGAGGACTTTT ACAAGATAACATGGCAAATAGTTATAATGGCGGCGACTTTGAAGATGGTTTATTGAACTTAAGTAAAG AAGTGTTTCCAACAGACAAATATTTGTATCAAGATGGTCAATTTTTGGACAAGAAAACAATTAATGCCT ATTTAAATCTTAAGTATACAAAACGTGAAATCGATAAAATGTCTGAAAAAGATAAAAAAGACAAGAAAG CGAATGAAAATTTAGGACTTAATCCATCACACGAAGGTGAAACAGATCCTGAAAAGATTGCAGAAAAA TCACCAGCCTATTTATCTAACATTTTAGAGCAAGATTTTTATGGTGGTGGAGATACAAAAGGTAAGAAT ATTAAAGGTATGACGATTGGTTTAGCTATGAATAGTGTTTATTACTATAAAAAAGAAAAAGATGGACCG ACTTTTAGTAAAAAACTAGATGATAGCGAAGTTAAAAAGCAAGGTAAACAAATGGCTAGTGAGATATTA TCAAGGTTACGTGAAAATGATGATTTAAAAGATATACCAATTCATTTTGCAATTTATAAGCAATCAAGTG AAGATTCAATCACACCAGGTGAATTTATCACTCAAGCGACTGCAGAAAAGAGTCAAACAAAGCTTAAT GAATGGCATAATATCAATGAAAAATCAGCTTTATTACCTTCTTCAACAGCAGCAGATTATGATGAAAAT TTAAATAATAATTTCAAGCAATTTAATGATAATTTGCAATCATATTTTTCTAATTTCACACAAGCAGTAG GAAAAGTTAAATTTGTTGATAAAAAGCCACAACGATTAGTAGTAGATTTACCAATCGATTACTATGGAC AAGCTGAAACAATTGGTATTACACAGTACGTTACTGAACAAGCGAATAAATATTTCGATAAAATCGATA ACTATGAAATTCGGATTAAAGATGGTAACCAACCACGTGCTTTAATTAGTAAGACAAAAGATGACAAAG AACCGCAAGTTCATATTTACAGTAATTAA SEQ IN NO: 24 ATGAGGGAAAATTTTAAGTTACGTAAAATGAAAGTCGGGTTAGTATCTGTTGCAATTACAATGTTATAT ATCATGACAAACGGACAAGCAGAAGCATCAGAGGCTAATGAGAAGCCAAGTACAAATCAAGAATCAAA AGTTGTTTCACAGACTGAACAAAATTCAAAAGAAACAAAAACAGTAGAATCTAATAAGAACTTTGTTAA ATTAGATACTATTAAACCTGGAGCTCAAAAGATAACGGGAACTACTTTACCAAATCACTATGTTTTATTA ACAGTTGATGGGAAAAGTGCGGATTCAGTAGAAAATGGCGGTTTGGGTTTTGTTGAAGCAAATGACAA AGGAGAATTTGAGTACCCTTTAAATAATCGTAAAATTGTTCATAATCAAGAAATTGAGGTTTCGTCGTC AAGCCCTGATTTAGGTGAAGATGAAGAAGATGAAGAGGTGGAAGAAGCTTCAACTGATAAAGCTGGC GTTGAGGAAGAAAGTACAGAAGCTAAAGTTACTTACACAACACCGCGATATGAAAAAGCGTATGAAAT ACCGAAAGAACAACTAAAAGAAAAAGATGGACATCACCAAGTTTTTATCGAACCTATTACTGAAGGATC AGGTATTATTAAAGGGCATACGTCTGTAAAAGGTAAAGTTGCTTTATCTATTAATAATAAATTTATTAAT TTTGAAGAGAGCGTTAAGGGCGGAGTTAGTAAAGAAGACACTAAAGCTAGTTCAGATGGTATCTGGAT GCCTATTGATGACAAAGGATACTTTAACTTTGACTTCAAAACGAAACGTTTCGATAATTTAGAGTTAAA AGAAGGTAATGACATTTCACTAACATTTGCACCTGATGATGAAGAAGATGCATTAAAACCTTTAATTTT CAAAACTAAAGTAACGAGCTTAGAAGATATCGATAAAGCAGAAACTAAATATGACCATACTAAACTCAA CAAAGTGAAAGTTTTAGATAATGTTAAAGAAGATTTACATGTTGATGAAATATATGGAAGCTTATATCA TACAGACAAAGGTAAAGGTATTCTTGATAAAGAAGGTACTAAAGTAATTAAAGGAAAGACTAAATTCG CGAATGCAGTAGTGAAGGTAGACTCTGAACTAGGTGAAGCACAATTATTCCCTGATTTACAAGTAAAT GAAAAAGGTGAATTTAGCTTTGACTCACATGGTGCTGGTTTTAGATTACAAAATGGAGAAAAATTAAAC TTCACAGTGGTTGATCCTATTACAGGTGACTTGTTAAGTAATGAGTTTGTTTCTAAAGAGATTGATATT GAAGAAACACCTGAACAAAAAGCGGATCGTGAGTTTGACGAAAAACTTGAAAATACGCCTGCTTACTA CAAGTTATACGGCGATAAAATAGTTGGATTCGATACTAACGATTTCCCGATTACTTGGTTCTATCCATT GGGTGAAAAGAAAGTTGAACGTACAACACCTAAATTAGAAAAATAA SEQ IN NO: 25 ATGTCTAAAAAGTTAAAAATTATAATTCCTATTATTATTGTCTTATTATTAATAGGTGGAATCGCATGGG GAGTTTATGCATTTTTTGCAAACACACCGAAAAATACATACTTAAAAAGTGAACAACAAACTGCAAAAA TGTATAAAGATTATTTTAATGACCGTTTTGAAAACGAAGTGAAGTTCCAAGAAAAGATGAAAGATAATT CATTTTTATCTTCATTAGAATTAAGCGCAGATGCATCTGATGAAATTGTTAAAGGGCTTGGTATTCCTAA ATCTGTTGTTAATGCTTCGAAAATTAAAATGTCATATGGACATGATCCTAAAAAAGAGAAATCAATGAT TAATCTTGAACCAACAATAGCAGACTCTGCATTAGGGAAATTCCAGTTAGCTGCAGATAAAGATAAGC ATTATTTCGAATCACCATTATTTAAAGGGAAATATAGTGTTAATAATTCTGATTTATTATCAACTTATTCA AAACTTACAGGTGAAGATGAAGAAACAGCAAAAGAAAATGGTATTACAAACCAACAACTAAATTTAAAT ACTCTTTTCAGTAATGCTCAAGCACAACAAAGTGACTACAGCAAAATTGCCGAAAAATATTCCGAACTT ATTGTCGACAAATTAGATGACGATAATTTTGATAAAGGTAAAAAAGAAGAAATTAAGGTTAATGGTGAA AAGTACAAAGTTAGACCTGTCACGTTAACACTTAGCAGAGCTGACACTAAAAAAATTACATTAGCTGTA TTAGAAGAAGCTAAAAAGGATAAAGACCTTAAAAAATTAATGGAAGAACAAGGTACTACAAAAGACTTT GAAAAAGACATTAAAAAAGCAATTGACGATGTCAAAGAAACTAAAAAGGATGAATTTGCTAAAATTCAA

TCTAAAATTTATACCGAAAAACATACGATTGTAAAACGAGAAATTACTATTACAGACAAAGAAAATAAT AAAACTAAAATCAAAGGTACTAATACTTTAGAAGACGATAAGTTAAAACTAGATTACGCACTTGATTTC GATCAAGATAAATACACGTATGCTGAAGCGAAATATACAATTAAAGGCGTATCTTCTAAGGAAAAAGA CAATAAATACAGTGATAAATACGAATTTGGTAAAAAGACAGAATATGATGAATCAAAAATCAAATTAGA TAACCAAGAAAAAGTAGATGGCACAAAACGTCAAGATAAAGGTAAAATCACTGTCGCGTTAGATAAAT ATAGCGACGAAAATGAATTCACTTTTGAAAATAATATAGATTCTGACGTAAAAAATAACACTCAGAAAT CTACGTTAAATATCGGCATCAAATATGCTGAAGAACCAATTAATTTCATTTTAAAATCTAGCACAAAATT GAAAGCAGATATTGATTTTGATGATAGTGGTGCGAAAGATTTCAATAGTCTATCTTCAAAAGACCGTGA AAAACTTGAAAAAGAAATCGAAAAAAATGGCGGCAAAATGTTTGAATCAATTTTAAAAAAGGCATCTAA ATAA SEQ IN NO: 26 GTGAGGAAATTTTCAAGATATGCATTTACAAGTATGGCAACAGTAACGTTGCTGAGCTCTTTGACACCT GCAGCACTAGCGAGTGATACGAATCACAAACCAGCAACTTCAGATATTAATTTTGAAATCACGCAAAA GAGTGATGCAGTTAAAGCATTAAAAGAGTTACCTAAATCTGAAAATGTGAAAAATCATTATCAAGATTA CTCTGTTACAGATGTAAAAACAGATAAGAAAGGATTCACGCATTACACGTTACAACCGAGTGTGGATG GTGTGCATGCGCCTGACAAAGAAGTGAAAGTGCATGCGGACAAATCGGGTAAAGTCGTTTTAATCAAC GGTGATACTGATGCGAAGAAAGTAAAGCCGACAAATAAAGTGACATTAAGCAAGGATGAAGCGGCTG ACAAAGCATTTAACGCAGTTAAGATTGATAAAAATAAAGCTAAAAACCTCCAAGATGACGTTATCAAAG AAAATAAAGTCGAAATCGATGGTGACAGTAATAAATACATTTACAATATTGAATTAATTACAGTAACAC CAGAAATTTCACATTGGAAAGTTAAAATTGATGCAGACACAGGAGCAGTTGTTGAAAAAACGAACTTA GTTAAAGAAGCAGCAGCAACTGGCACAGGTAAAGGTGTGCTTGGAGATACAAAAGATATCAATATCAA TAGTATTGATGGTGGATTTAGTTTAGAGGATTTGACGCATCAAGGTAAATTATCAGCATACAATTTTAA CGATCAAACAGGTCAAGCGACATTAATTACTAATGAAGATGAAAACTTCGTCAAAGATGATCAACGTG CTGGTGTAGATGCGAATTATTATGCTAAACAAACATATGATTACTACAAAAATACATTTGGTCGTGAGT CTTACGATAACCATGGTAGTCCAATAGTCTCATTAACACATGTAAATCATTATGGTGGACAAGATAACA GAAATAACGCTGCATGGATTGGAGACAAAATGATTTATGGTGATGGCGATGGCCGCACGTTTACAAAT TTATCAGGTGCAAATGACGTAGTAGCACATGAGTTAACACATGGCGTGACACAAGAAACGGCGAATTT AGAGTATAAAGATCAATCTGGTGCGTTAAATGAAAGCTTTTCAGATGTTTTTGGATACTTTGTAGATGA TGAGGATTTCTTGATGGGTGAAGATGTTTACACACCAGGAAAAGAGGGAGATGCTTTACGAAGCATGT CAAACCCAGAACAATTTGGTCAACCATCTCATATGAAAGACTATGTATACACTGAAAAAGATAACGGTG GTGTGCATACGAATTCTGGCATTCCAAATAAAGCAGCTTATAACGTAATTCAAGCAATAGGGAAATCTA AATCAGAACAAATTTACTACCGAGCATTAACGGAATACTTAACAAGTAATTCAAACTTCAAAGATTGTA AAGATGCATTATACCAAGCGGCTAAAGATTTATATGACGAGCAAACAGCTGAACAAGTATATGAAGCA TGGAACGAAGTTGGCGTCGAGTAA SEQ IN NO: 27 ATGAAAAAGAAATTAGGTATGTTACTTCTTGTACCAGCCGTAACTTTATCATTAGCCGCATGTGGGAAT GATGATGGAAAAGATAAAGATGGCAAGGTAACAATTAAAACGACAGTTTATCCATTGCAATCATTTGCA GAGCAAATTGGTGGAAAACACGTGAAGGTATCATCAATCTATCCAGCAGGGACAGATTTACATAGCTA TGAACCAACACAAAAAGATATATTAAGTGCAAGCAAGTCAGACTTGTTTATGTATACAGGGGATAATTT AGATCCGGTTGCTAAGAAAGTTGCATCTACTATTAAAGATAAAGATAAAAAACTGTCTTTAGAAGATAA ATTAGATAAAGCAAAGCTTTTAACTGATCAACACGAACATGGTGAAGAGCATGAACATGAGGGACATG ATCATGGGAAAGAAGAACATCATCATCATGGCGGATATGATCCACACGTATGGTTAGATCCTAAAATT AACCAAACTTTCGCTAAAGAAATTAAAGATGAATTAGTGAAGAAAGATCCAAAACATAAAGATGACTAT GAGAAAAACTACAAAAAATTAAACGACGATCTTAAGAAAATTGATAACGATATGAAGCAAGTTACTAAA GATAAGCAAGGTAATGCAGTATTCATTTCACATGAATCAATTGGATACTTAGCTGATCGTTATGGTTTT GTTCAAAAAGGTATTCAAAACATGAATGCTGAAGATCCATCACAAAAAGAATTGACTAAAATTGTTAAA GAAATTAGAGATAGCAATGCTAAATATATTCTTTACGAAGATAATGTTGCGAATAAAGTGACTGAAACA ATTCGTAAAGAAACAGATGCGAAGCCTTTAAAATTCTACAACATGGAGTCTTTAAATAAAGAACAACAG AAAAAAGATAATATTACCTATCAATCATTAATGAAATCGAATATTGAAAATATCGGTAAAGCTTTAGACA GTGGTGTTAAAGTGAAAGACGACAAAGCTGAAAGTAAACACGACAAAGCAATTTCTGATGGGTATTTT AAAGATGAGCAAGTTAAAGACCGTGAATTAAGCGATTATGCTGGTGAATGGCAATCTGTTTACCCTTA CTTAAAAGACGGTACGCTTGATGAAGTGATGGAACATAAAGCTGAAAATGATCCGAAGAAATCTGCTA AAGATTTAAAAGCTTATTATGACAAAGGATATAAAACTGATATTACTAACATTGATATAAAAGGAAATG AAATTACATTTACTAAAGATGGTACGAAACACACTGGTAAATATGAATACAATGGTAAGAAAACATTGA AATATCCTAAAGGTAACCGTGGCGTGAGATTTATGTTTAAATTGGTCGATGGTAATGATAAAGACTTAC CGAAATTCATCCAATTTAGCGATCACAACATTGCACCTAAAAAGGCAGAACACTTCCATATCTTTATGG GTAATGATAATGACGCGTTATTAAAAGAAATGGATAACTGGCCAACATATTATCCTTCAAAATTAAATA AAGACCAAATCAAAGAAGAAATGTTAGCGCATTAA SEQ IN NO: 28 ATGGTGTTATATATCATTTTGGCAATAATTGTGATTATATTGATTGCTGTAGGTGTATTATTCTATTTAC GTTCAAATAAAAGACAAATAATAGAAAAAGCAATCGAACGTAAAAATGAAATTGAAACGTTACCTTTTG ATCAAAACCTTGCACAATTATCTAAGTTGAATTTAAAAGGTGAAACAAAAACGAAATACGATGCAATGA AAAAGGACAACGTAGAAAGTACAAATAAGTATCTAGCTCCTGTGGAAGAAAAAATCCATAATGCTGAG GCTTTATTAGATAAATTTAGTTTCAACGCATCTCAATGTGAAATTGATGATGCAAATGAGTTGATGGAT AGTTACGAACAAAGCTATCAGCAACAATTAGAAGATGTAAATGAAATTATTGCGTTATACAAAGATAAT GATGAATTATATGACAAATGTAAGGTTGATTATCGTGAAATGAAACGTGATGTTTTAGCAAATCGTCAT CAATTTGGTGAGGCAGCAAGTCTTCTTGAAACTGAAATTGAAAAATTCGAGCCAAGGTTAGAGCAATA TGAAGTACTAAAAGCTGATGGTAATTATGTACAAGCGCACAACCATATAGCTGCCTTGAATGAACAAAT GAAACAGCTAAGATCTTATATGGAAGAAATACCAGAATTAATTAGAGAAACTCAAAAAGAATTACCTGG TCAATTCCAAGATTTAAAATATGGTTGCCGTGATCTTAAAGTTGAAGGGTATGATCTGGATCACGTAAA AGTAGACAGTACATTACAAAGCTTAAAAACAGAGCTTAGTTTCGTTGAACCATTAATTAGTCGCTTAGA ATTAGAAGAAGCTAATGATAAACTAGCTAATATCAATGATAAGTTAGATGACATGTATGATTTAATTGA ACATGAAGTTAAAGCTAAAAATGATGTCGAAGAAACAAAAGATATCATTACGGATAACTTATTCAAAGC AAAAGACATGAATTATACATTGCAAACAGAAATTGAATATGTACGTGAAAACTACTATATAAATGAATC TGATGCTCAGAGTGTTCGTCAATTTGAAAATGAAATTCAAAGTTTAATTTCTGTATATGATGATATTTTA AAAGAAATGTCTAAATCTGCTGTACGATATAGCGAGGTTCAGGATAATTTACAATATTTAGAAGATCAT GTCACAGTTATTAATGACAAACAAGAAAAGCTACAAAATCATCTGATTCAATTGCGTGAAGATGAAGCA GAAGCAGAAGACAATCTGTTACGAGTACAATCGAAGAAAGAAGAAGTGTATCGTCGATTACTTGCTTC TAACTTAACAAGCGTTCCTGAAAGGTTTATCATCATGAAAAATGAAATTGATCATGAAGTTCGTGATGT TAACGAACAATTTAGTGAACGTCCAATACACGTTAAACAGTTAAAAGATAAAGTGTCTAAAATTGTGAT TCAAATGAATACATTTGAAGATGAAGCAAATGATGTTCTTGTTAATGCTGTTTATGCAGAGAAATTAAT TCAATATGGAAATAGATATCGTAAGGACTATAGCAATGTTGATAAGAGCTTAAATGAAGCTGAACGATT ATTTAAAAATAATCGCTATAAGCGTGCGATTGAAATTGCAGAGCAAGCTCTTGAAAGTGTTGAGCCAG GTGTCACTAAACATATTGAAGAAGAAGTTATTAAGCAATAG SEQ IN NO: 29 ATGCCTAAAAATAAAATTTTAATTTATTTGCTATCAACTACGCTCGTATTACCTACTTTAGTTTCACCTAC CGCTTATGCTGACACACCTCAAAAAGATACTACAGCTAAGACAACATCTCATGATTCCAAAAAATCTAC TGATGATGAAACTTCTAAGGATACTACAAGTAAAGATATTGATAAAGCAGACAACAATAATACTAGTAA CCAAGACAATAACGACAAAAAAGTTAAAACTATAGACGACAGCACTTCAGACTCTAACAATATCATTGA TTTTATTTATAAGAATTTACCACAAACCAATATAAACCAATTGCTAACCAAAAATAAATACGATGATAAT TACTCATTAACAACTTTAATCCAAAACTTATTCAATTTAAATTCGGATATTTCTGATTACGAACAACCTC GTAATGGTGAAAAGTCAACAAATGATTCGAATAAAAACAGTGATAATAGCATCAAAAATGATACGGAT ACGCAATCATCTAAACAAGATAAAGCAGACAATCAAAAAGCACCTAAATCAAACAATACAAAACCAAGT ACATCTAATAAGCAACCAAATTCGCCAAAGCCAACACAACCAAATCAATCAAATAGTCAACCAGCAAGT GACGATAAAGTAAATCAAAAATCTTCATCGAAAGATAATCAATCAATGTCAGATTCGGCTTTAGATTCT ATTTTGGATCAATACAGTGAAGATGCAAAGAAAACACAAAAAGATTACGCATCTCAATCTAAAAAAGAC AAAAATGAAAAATCTAATACAAAGAATCCACAGTTACCAACACAAGATGAATTGAAACATAAATCTAAA CCTGCTCAATCATTCAATAACGATGTTAATCAAAAGGATACACGTGCAACATCACTATTCGAAACAGAT CCTAGTATATCTAACAATGATGATAGTGGACAATTTAACGTTGTTGACTCAAAAGATACACGTCAATTT GTCAAATCAATTGCTAAAGATGCACACCGCATTGGTCAAGATAACGATATTTATGCGTCTGTCATGATT GCCCAAGCAATCTTAGAATCTGACTCAGGTCGTAGTGCTTTAGCTAAGTCACCAAACCATAATTTATTC GGTATCAAAGGTGCTTTTGAAGGGAATTCTGTTCCTTTTAACACATTAGAAGCTGATGGTAATCAATTG TATAGTATTAATGCTGGATTCCGAAAATATCCAAGCACGAAAGAATCACTAAAAGATTACTCTGACCTT ATTAAAAATGGTATTGATGGCAATCGAACAATTTATAAACCAACATGGAAATCGGAAGCCGATTCTTAT AAAGATGCAACATCACACTTATCTAAAACATATGCTACAGATCCAAACTATGCTAAGAAATTAAACAGT ATTATTAAACACTATCAATTAACTCAGTTTGACGATGAACGTATGCCAGATTTAGATAAATATGAACGTT CTATCAAGGATTATGATGATTCATCAGATGAATTCAAACCTTTCCGCGAGGTATCTGATAATATGCCAT ATCCACATGGCCAATGTACTTGGTACGTATATAACCGTATGAAACAATTTGGTACATCTATCTCAGGTG ATTTAGGTGATGCACATAATTGGAATAATCGAGCTCAATACCGTGATTATCAAGTAAGTCATACACCAA AACGTCATGCTGCTGTTGTATTTGAGGCTGGACAATTTGGTGCAGATCAACATTACGGTCATGTAGCA TTTGTTGAAAAAGTTAACAGTGATGGTTCTATCGTTATTTCAGAATCCAATGTTAAAGGATTAGGTATC ATTTCTCATAGAACTATCAATGCAGCTGCCGCTGAAGAATTATCATATATTACAGGTAAATAA SEQ IN NO: 30 ATGATGAAAAGTCAAAATAAGTATAGTATTCGTAAATTTAGTGTAGGTGCATCTTCCATTTTAATAGCTA CATTACTATTTTTAAGTGGTGGACAAGCACAAGCAGCTGAGAAGCAAGTGAATATGGGAAATTCACAG GAGGATACAGTTACAGCACAATCTATTGGGGATCAACAAACTAGGGAAAATGCTAATTATCAACGTGA AAACGGTGTTGACGAACAGCAACATACTGAAAATTTAACTAAGAACTTGCATAATGATAAAACAATATC AGAAGAAAATCATCGTAAAACAGATGATTTGAATAAAGATCAACTAAAGGATGATAAAAAATCATCGCT TAATAATAAAAATATTCAACGTGATACAACAAAAAATAACAATGCTAATCCTAGGGATGTAAATCAAGG GTTAGAACAGGCTATTAATGATGGCAAACAAAGTAAAGTGGCGTCACAGCAACAGTCAAAAGAGGCA GATAATAGTCAAGACTTAAACGCTAATAACAATCTACCTTCACAAAGTCGAACAAAGGTATCACCATCA TTAAATAAGTCAGATCAAACAAGTCAACGAGAAATTGTTAATGAGACAGAAATAGAGAAAGTACAACC GCAACAAAAGAATCAAGCGAATGATAAAATTACTGACCACAATTTTAACAATGAACAAGAAGTGAAAC CTCAAAAAGACGAAAAAACACTATCAGTTTCAGATTTAAAAAACAATCAAAAATCACCAGTTGAACCAA CAAAGGACAATGACAAGAAAAATGGATTAAATTTATTAAAAAGTAGTGCAGTAGCAACGTTACCAAAC AAAGGGACAAAGGAACTTACTGCAAAAGCGAAAGGTGATCAAACGAATAAAGTTGCCAAACAAGGGC AGTATAAAAATCAAGATCCTATAGTTTTAGTGCATGGTTTCAATGGGTTTACAGATGATATTAATCCTTC AGTGTTAGCTCATTATTGGGGCGGTAATAAAATGAACATTCGCCAAGATTTAGAAGAAAATGGTTACA

AAGCTTATGAAGCAAGTATAAGTGCTTTTGGAAGTAACTATGACCGCGCAGTTGAACTTTATTATTATA TCAAAGGCGGTCGTGTAGATTATGGTGCAGCACATGCAGCAAAATATGGACATGAACGTTATGGAAAA ACATACGAAGGAATTTACAAAGACTGGAAACCAGGACAGAAGGTACACCTTGTTGGACATAGTATGGG TGGTCAAACGATACGTCAACTAGAAGAATTACTGCGTAATGGTAGTCGTGAAGAAATAGAGTATCAAA AGAAACATAGTGGCGAAATTTCTCCACTATTCAAAGGTAATAATGACAATATGATTTCATCAATTACTAC TTTAGGAACGCCACATAATGGAACGCATGCTTCAGATTTAGCTGGTAATGAAGCTTTAGTGAGACAAA TTGTATTTGATATCGGTAAAATGTTTGGTAATAAAAATTCAAGAGTAGACTTCGGGTTGGCTCAATGGG GTCTAAAACAGAAGCCAAATGAATCATATATTGATTATGTCAAACGCGTTAAACAATCTAATTTATGGA AATCAAAAGATAATGGATTTTACGATCTGACGCGTGAGGGTGCAACAGATTTAAATCGTAAAACGTCG TTGAACCCTAACATTGTGTATAAAACATACACTGGTGAAGCAACGCACAAAGCATTAAATAGCGATAG ACAAAAAGCAGACTTAAATATGTTTTTCCCATTTGTGATTACTGGTAACTTAATCGGTAAAGCTACTGA AAAAGAATGGCGAGAAAACGATGGTTTAGTATCCGTTATTTCTTCTCAACATCCATTTAATCAAGCTTA TACAAATGCGACGGATAAAATTCAAAAAGGCATTTGGCAAGTAACGCCTACAAAACATGATTGGGATC ATGTTGATTTTGTCGGACAAGATAGTTCTGATACAGTGCGCACAAGAGAAGAATTACAAGATTTTTGG CATCATTTAGCAGACGATTTAGTGAAAACTGAAAAGGTGACTGATACTAAGCAAGCATAA SEQ IN NO: 31 ATGACAAATAAAATGAAGAAATGGCAAAAATTATCCACCATTACGTTATTAATGACCGGAGTGATTGCT TTAAATAATGGTGAATTTAGAAATGTTGATAAACATCAAATCGCTGTGGCTGATACGAATGTTCAAACG CCAGATTATGAAAAATTGAAGAAGACGTGGCTCGACGTTAACTACGGTTATGATCAGTATGATGAGAA TAATCAAGATATGAAGAAGAAGTTTGATGCTAAAGAAAAAGAAGCCAAGAAGTTACTTGATGACATGA AAACTGATACGAATAGAACATATTTGTGGTCAGGAGCTGAAAACCTTGAAACTAATTCTTCTCACATGA CAAAAACCTATCGTAATATCGAGAAAATCGCAGAATCAATGCAACATAAGAATACGGTATTAAAAACAG TTGAAAACAAGTTGAAAATAAAAGAAGCCCTAGATTGGATGCACAAAAATGTTTATGGCAAGAATCCTT CTCAAAAAGTCGAGGATTTAACTAAAAATCGTAAGGGGCAAACTACACCCAAGAATAACTCATTGAATT GGTGGGATTATGAAATTGGTACGCCAAGAGCATTAACAAATACACTACTTCTAATGGATGATATGCTCA CTAAAGATGAAATGAAAAATTATTCAAAACCTATTAGTACATATGCACCATCCAGTGACAAAATTTTATC TTCTGTTGGTGAATCAGAAGATGCTAAAGGTGGAAATTTAGTGGACATTTCTAAAGTAAAACTTTTAGA AAGTGTTATTGAAGAAGATGTAGATATGTTGAAAAAGTCTATAGATTCTTTTAATAAAGTGTTCACTTAT GTTCAAGATTCTGCCACTGGTAAAGGTCGCAATGGATTCTATAAAGATGGCTCTTACATTGATCATCAA GATGTCCCTTACACTGGTGCTTATGGTGTTGTACTATTAGAGGGTATTTCTCAAATGATGCCGATGATA AAAGAATCTCCTTTTAAAACTACACAAGATAATGCTACATTAAGCAATTGGATTGACGAAGGGTTTATG CCATTAATCTATAAAGGTGAAATGATGGATTTATCACGAGGTAGAGCTATCAGTCGTGAAAATGAAAC GAGTCATACAGCGTCAGCGACTGTAATGAAATCATTGTTGAGATTGAATGATACCATGGATGATTCAA CAAAAACTAGATATAAGCAAATCGTTAAAACTTCTGTTAATTCTGATTCAAGTTACAACCAAAATAATTA TTTAAATTCATATTCAGACATAGCTAAAATGAAAAAGTTAATGAATGATAGTACTATTTCTAAAAACGAT TTAACACAGCAACTTAAAATATATAATGACATGGATCGTGTCACCTATCACAATAAAGACCTGGACTTT GCATTTGGTTTAAGTATGACATCGAAAAACATCGCACGATACGAAAATATCAACGGAGAGAACTTAAA AGGTTGGCACACCGGTGCAGGCATGTCTTATTTATATAACAGCGATGTCAAACACTATCGCGATAACT TCTGGGCAACAGCCGATATGACTTGTCTTCCAGGCACTACTACTTTAAATGATATGCCATCTACTAATA CTAAGAATGATAAATCTTTTGTTGGCGGGACAAAATTAAATAATAAATACGCAAGCATCGGTATGGATT TTGAAAATCAGGACAAAACTTTAACTGCCAAAAAATCATATTTCATATTAAACGATAAAATTGTCTTCTT AGGAACTGGCATTAAAAGTACTGATTCATCAAAGAATCCAGTTACAAGTGTTGAAAATCGCAAAGCAA ATGGGTATAAATTATTTAAAGATGATATTGAAATTACCACTTCAGATGTTAATGCTCAGGAAACCCATT CAGTCTTTTTAGAGTCCAACGATACTAAAAAGAACATTGGTTATCATTTCTTAGACAAGCCAAAAATAA CTGTAAAAAAAGAAAGTCATACTGGTAAGTGGAGTGAAATTAATAAAAGTCAAAAAAAAGATGACAAA AAAGATGAGTATTATGAAGTAACTCAAACACATAATACATCTGACAGTAAATATGCATATGTTTTGTATC CTGGTTTATCAAAAAGTGATTTTAAATCGAAGAATAATAATGTAAGTATTGTTAAACAAGATGAAGATTT TCATGTGATAAAAGATAATGATGGCGTATTTGCTGGGGTTAATTATAGTGATAATACTAAATCTTTTGA TATAAACGGAATTACTGTTGAATTAAAAGAAAAAGGCATGTTTGTAATTAAAAAGAAAGATGATAAAGC ATATAAATGTAGCTTCTATAATCCTGAAACTACAAATACCGCTTCAAATATAGAATCAAAAATTTTTATT AAAGGTTACACCATAACTAATAAAAGTGTCATAAACTCTAATGATGCTGGTGTAAACTTTGAATTAACT AAATAA SEQ IN NO: 32 ATGACATATAGAATGAAGAAATGGCAAAAATTGTCCACCATTACGTTATTAATGGCTGGTGTGATTACT TTGAATGGTGGTGAATTCAGAAGTATTGATAAACATCAAATCGCTGTGGCTGATACGAATGTTCAAAC GACAGATTATGAAAAGTTGAGGAACATATGGCTGGACGTTAACTATGGTTATGATAAGTATGATGAGA ATAATCCAGATATGAAGAAGAAGTTTGAGGCTACGGAGAATGAGGCAGAGAAATTACTCAAGGAAAT GAAAACTGAAAGTGATAGGAAATACTTGTGGGAAAGCTCAAAAGATTTAGATACGAAGTCTGCGGATA TGACTCGTACCTATCGTAATATTGAGAAAATCTCAGAAGCGATGAAACATAAAAATACTAAATTAAAAA CAGATGAAAACAAGACAAAAGTAAAAGATGCACTTGAGTGGCTGCATAAAAATGCATATGGAAAAGAA CCAGATAAAAAAGTTGCTGATTTGACCTCAAACTTTAAAAATAAAACTTCTAGAAATACCAACTTAAATT GGTGGGATTATGAAATTGGAACACCTAGAGCATTAACAAATACGCTTATACTCTTACAAGAAGATTTCA CTGATGAAGAAAAGAAAAAATATACAGCTCCTATTAAAACTTTCGCCCCAGATAGTGACAAAATATTAT CTTCTGTAGGAAAATCTGAACCTGCTAAAGGCGGAAATTTAGTAGACATTTCTAAAGTAAAACTTTTAG AAAGTATTATCGAAGAAGACAAAGATATGATGAAAAAGTCTATAGATTCATTTAATACAGTCTTCACTT ACGCGCAAAATTCTGCCACTGGAAAAGAACGTAATGGATTCTATAAAGATGGCTCTTACATTGATCATC AAGACGTCCCATACACTGGTGCTTATGGCGTTGTACTATTAGAGGGTATTTCTCAAATGATGCCGATG ATAAAAGAAACACCTTTTAATGATAGTAACCAAAATGATACAACCTTAAAATCATGGATTGACGACGGA TTTATGCCACTCATTTATAAAGGTGAAATGATGGATTTATCAAGAGGTAGAGCTATCAGTCGTGAAAAT GAAACGAGTCACTCAGCATCTGCAACAGTAATGAAATCATTGTTGAGATTGAGTGATACCATGGATAA GTCTACAAAAGCTAAATATAAAAAGATTGTCAAGACTTCAGTAGAGTCAGATTCAAGTTATAAACAAAC CGATTATTTAAGCTCTTATTCGGATATAAGCAAAATGAAGTCTTTAATGGAAGACAGCACTATTTCTACT AACGGTTTAACACAACAACTTAAAATATATAATGACATGGATCGTGTCACCTATCACAATAAAGGCTTA GACTTTGCATTTGGTTTAAGTATGACGTCGAAAAACGTCGCACGTTACGAAAGTATCAACGGAGAGAA CTTAAAAGGTTGGCACACTGGTGCTGGAATGTCTTATTTATACAATAGCGATGTGAAACACTACCGTG ATAACTTCTGGGCGACAGCTGATATGAAACGTTTAGCAGGTACTACAACTTTAGATAATGAAGAACCTA AAAGTACGGATGTTAAAAAGTCTAGTAAAACTTTTGTAGGAGGAACAAAATTCGATGACCAACATGCTA GTATCGGAATGGATTTTGAAAATCAGGACAAAACTTTAACTGCCAAAAAATCATATTTCATATTAAACG ATAAAATTGTCTTCTTAGGAACTGGCATTAAAAGTACTGATTCATCAAAGAATCCAGTTACAACGATTG AAAATCGCAAAGCGAATGATTATAAATTATATAAAGATGATACGCAAACAACCAATTCCGATAATCAGG AAACCAATTCCCTCTTTTTAGAGTCAACGAATAGCACTCAAAACAATATAGGTTATCATTTTTTAAACGA ATCGAAAATAACTGTAAAAAAAGAAAGTCATACTGGTAAGTGGAGTGATATAAATAAAAGCCAAAAGG ATATACAAAAAACTGATGAGTATTATGAAGTAACTCAAAAGCATTCTAATACAGATAGTAAATATGCAT ATGTGTTGTATCCAGGCTTATCTAAAGATGTCTTTAAATCCAAAGCAAGCAAAGTAACTGTCGTTAAGC AAGAAGATGACTTCCACGTTGTGAAAGATAATGAATCGGTTTGGGCTGGTATCAATTATAGTGATAGC GCTAAAACTTTTGAAATTAATAACACTAAAGTCGAAGTTAAAGCCAAAGGAATGTTTATTCTTACAAAG AAAGATGATAACACTTATGAATGTAGCTTCTATAATCCCGAATCTACAAATTCCGTTTCAGATATTGAAT CTAAAATTTCAATGACTGGATACTCTATTATAAACAAAAATACGTCGACTTCTAATGAATCCGGCGTAC GCTTTGAATTAACTAAATAA SEQ IN NO: 33 AUGGCAAAAGGUAAUUUAUUUAAAGCGAUUUUAGGUAUAGGUGGCGCUGUAGCAGCUGUACUUGU UACACGUAAAGAUAGUCGUGACAAGCUGAAAGCAGAAUAUAAUAAAUACAAACAAGAUCCUCAAAG CUAUAAAGAUAAUGCUAAGGAUAAAGCGACGCAAUUAGGAACAAUUGCAAAUGAAACAAUUAAAGA AGUAAAAACAAAUCCGAAAGAAUAUGCUAAUAGAUUAAAAAAUAAUCCAAAAGCAUUUUUCGAAGAA GAAAAAUCAAAAUUUACCGAAUAUGACAAUAAGACUGACGAAAGUAUUGAAAAAGGUAAAUUUGAU GAUGAAGGUGGCGCAGCACCAAAUAAUAAUUUACGUAUCGUCACUGAAGAAGAUUUAAAAAAGAAU AAAAAUGCAUUGUCUGAUAAAGAAUAA SEQ IN NO: 34 AUGAAAAAAUUGGUUUCAAUUGUUGGCGCAACAUUAUUGUUAGCUGGAUGUGGAUCACAAAAUUU AGCACCAUUAGAAGAAAAAACAACAGAUUUAAGAGAAGAUAAUCAUCAACUCAAACUAGAUAUUCAA GAACUUAAUCAACAAAUUAGUGAUUCUAAAUCUAAAAUUAAAGGGCUUGAAAAGGAUAAAGAAAAU AGUAAAAAAACUGCAUCUAAUAAUACGAAAAUUAAAUUGAUGAAUGUUACAUCAACAUACUACGACA AAGUUGCUAAAGCUUUGAAAUCCUAUAACGAUAUUGAAAAGGAUGUAAGUAAAAACAAAGGCGAUA AGAAUGUUCAAUCGAAAUUAAAUCAAAUUUCUAAUGAUAUUCAAAGUGCUCACACUUCAUACAAAG AUGCUAUCGAUGGUUUAUCACUUAGUGAUGAUGAUAAAAAAACGUCUAAAAAUAUCGAUAAAUUAA ACUCUGAUUUGAAUCAUGCAUUUGAUGAUAUUAAAAAUGGCUAUCAAAAUAAAGAUAAAAAACAAC UUACAAAAGGACAACAAGCGUUGUCAAAAUUAAACUUAAAUGCAAAAUCAUGA SEQ IN NO: 35 AUGAAAAAAUUAGUUACAGGGUUAUUAGCAUUAUCAUUAUUUUUAGCUGCAUGUGGUCAAGAUAG UGACCAACAAAAAGACAGUAAUAAAGAAAAAGAUGAUAAAGCGAAAACUGAACAACAAGAUAAAAAA ACAAAUGAUUCAUCUAAAGAUAAGAAAGACAAUAAAGAUGAUAGUAAAGACGUAAACAAAGAUAAUA AAGAUAAUAGUGCAAACGAUAACCAGCAACAAUCUAAUUCAAAUGCAACAAACAAUGACCAAAAUCA AACGAAUAAUAACCAGUCAAACAGUGGACAAACGACUAACAAUCAAAAAUCAAGUUACGUUGCACCA UAUUAUGGACAAAACGCAGCGCCAGUGGCUCGUCAAAUUUAUCCAUUUAAUGGUAAUAAAUCACAA GCAUUACAACAAUUGCCUAAUUUCCAAACAGCUUUAAAUGCAGCUAACAACGAAGCAAAUAAAUUU GGUAAUGGUCAUAAAGUUUAUAAUGAUUAUUCAAUUGAAGAACAUAAUGGUAACUAUAAGUAUGUU UUUAGUUUUAAAGACCCAAACGUAAAUGGAAAAUAUUCAAUUGUAACGGUUGAUUAUACUGGACAA GCAAUGGUUACUGAUCCAAACUACCAACAAUAA SEQ IN NO: 36 AUGAAAAAAGUAAUGGGGAUAUUAUUAGCAAGUACACUUAUCUUAGGUGCUUGUGGACAUCAUCA AGAUAGUGCAAAAAAAGAGAGCACUAGUCACAAAAAGAAAGAAAAUGACAAUGAAGAAUUAAAUGA AGAACUUAAAGAAUUUAAAAGCAAAAAAAAUAUGGAUAUAAAAAUUAAAGGCGAUACUAUUGUUAG UGACAAAUUUGAAGCUAAAAUAAAAGAACCGUUUAUCAUCAAUGAAAAAGAUGAGAAAAAGAAAUA UAUCGCUUUUAAAAUGGAAAUUACUGCUAAAAAAGACGAUAAAGAUUUAAAUCCAUCUUCUAUUUC UCAUGACUAUAUUAAUAUCACUCAAGAUGAUAAAAAUACAGUAAAUAAAUUAAGAGAUGGUUAUCU UUUAAGUGAUAAAAAUUAUAAAGAUUGGACAGAACAUAACCAAGAUCAAAUUAAAAAAGGCAAAAC UGCACAAGCCAUGUUUAUCUAUGAGUUAAGAGGUGAUGGAAACAUUAAUUUAAAUGUCCAUAAAUA CUCAGAAGAUAAAACAGUUGAUUCUAAAUCAUUCAAAUUUAGUAAACUUAAAACCGAAGAUUUUUC

UCAUAGAGCGGAAACAAGGGAAGAAGUAGAAAAGAAAGAAAAAGAAUUUGAAGAAGAGUACAAAAA AGAACAAGAACGAGAGAAAGAAAAAGAAAAGCAAAAAGAUGACGACCACAGUGGUUUAGAUGAAGU AUAA SEQ IN NO: 37 AUGAAAAAAUGGCAAUUUGUUGGUACUACAGCUUUAGGUGCAACACUAUUAUUAGGUGCUUGUGG UGGCGGUAAUGGUGGCAGUGGUAAUAGUGAUUUAAAAGGGGAAGCUAAAGGGGAUGGCUCAUCA ACAGUAGCACCAAUUGUGGAGAAAUUAAAUGAAAAAUGGGCUCAAGAUCACUCGGAUGCUAAAAUC UCAGCAGGACAAGCUGGUACAGGUGCUGGUUUCCAAAAAUUCAUUGCAGGAGAUAUCGACUUCGC UGAUGCUUCUAGACCAAUUAAAGAUGAAGAGAAGCAAAAAUUACAAGAUAAGAAUAUCAAAUACAA AGAAUUCAAAAUUGCGCAAGAUGGUGUAACGGUUGCUGUAAAUAAAGAAAAUGAUUUUGUAGAUG AAUUAGACAAACAGCAAUUAAAAGCAAUUUAUUCUGGAAAAGCUAAAACAUGGAAAGAUGUUAAUA GUAAAUGGCCAGAUAAAAAAAUAAAUGCUGUAUCACCAAACUCAAGUCAUGGUACUUAUGACUUCU UUGAAAAUGAAGUAAUGAAUAAAGAAGAUAUUAAAGCAGAAAAAAAUGCUGAUACAAAUGCUAUCG UUUCUUCUGUAACGAAAAACAAAGAGGGAAUCGGAUACUUUGGAUAUAACUUCUACGUACAAAAUA AAGAUAAAUUAAAAGAAGUUAAAAUCAAAGAUGAAAAUGGUAAAGCAACAGAGCCUACGAAAAAAAC AAUUCAAGAUAACUCUUAUGCAUUAAGUAGACCAUUAUUCAUUUAUGUAAAUGAAAAAGCAUUGAA AGAUAAUAAAGUAAUGUCAGAAUUUAUCAAAUUCGUCUUAGAAGAUAAAGGUAAAGCAGCUGAAGA AGGUGGAUAUGUAGCAGCACCAGAGAAAACAUACAAAUCACAAUUAGAUGAUUUAAAAGCAUUUAU UGAUAAAAAUCAAAAAUCAGACGACAAGAAAUCUGAUGAUAAAAAGUCUGAAGACAAGAAAUAA SEQ IN NO: 38 AUGAAAGGUAAAUUUUUAAAAGUUAGUUCUUUAUUCGUUGCAACUUUGACAACAGCGACACUUGU GAGUUCUCCAGCAGCAAAUGCGUUAUCUUCAAAAGCUAUGGACAAUCAUCCACAACAAACGCAGAC AGACAAACAGCAAACACCUAAGAUUCAAAAAGGCGGUAACCUUAAACCAUUAGAACAACGUGAACG CGCUAAUGUUAUAUUACCAAAUAACGAUCGUCACCAAAUCACAGAUACAACGAAUGGUCAUUAUGC ACCUGUUACUUAUAUUCAAGUUGAAGCACCUACUGGUACAUUUAUUGCUUCUGGUGUAGUUGUAG GUAAAGAUACACUUUUAACAAAUAAACACAUCGUAGAUGCUACGCACGGUGAUCCUCAUGCUUUAA AAGCAUUCGCUUCUGCAAUUAACCAAGACAAUUAUCCUAAUGGUGGUUUCACUGCUGAACAAAUCA CUAAAUAUUCAGGCGAAGGUGAUUUAGCAAUCGUUAAAUUCUCCCCUAAUGAGCAAAACAAACAUA UUGGCGAAGUAGUUAAACCAGCAACAAUGAGUAAUAAUGCUGAAACACAAGUUAACCAAAAUAUUA CUGUAACAGGAUAUCCUGGUGAUAAACCUGUCGCAACAAUGUGGGAAAGUAAAGGAAAAAUAACGU ACUUAAAAGGUGAAGCAAUGCAAUAUGAUUUAAGUACAACUGGUGGUAACUCAGGUUCACCUGUA UUUAAUGAAAAAAAUGAAGUCAUUGGCAUUCAUUGGGGUGGCGUUCCAAAUCAAUUUAACGGUGC AGUAUUUAUUAAUGAAAAUGUACGCAACUUCUUAAAACAAAAUAUUGAAGAUAUCAAUUUCGCAAA UGAUGACCACCCUAACAACCCUGAUAAUCCAGACAAUCCAAAUAAUCCGGACAAUCCUAACAACCCU GAUAACCCUAACAACCCUGAUAAUCCAGACAAUCCUAAUAAUCCUGAUAACCCUAACAACCCGGACA AUCCAAAUAACCCUGACCAACCUAACAACCCAAAUAACCCGGACAAUGGCGAUAACAAUAAUUCAGA CAACCCUGACGCUGCAUAA SEQ IN NO: 39 AUGAAGCGUACAUUAGUAUUAUUGAUUACAGCUAUCUUUAUACUCGCUGCUUGUGGUAACCAUAA GGAUGACCAGGCUGGAAAAGAUAAUCAAAAACAUAACAAUAGUUCAAAUCAAGUAAAAGAAAUUGC UACGGAUAAAAAUGUACAAGGUGAUAACUAUCGUACAUUGUUACCAUUUAAAGAAAGCCAGGCAAG AGGACUUUUACAAGAUAACAUGGCAAAUAGUUAUAAUGGCGGCGACUUUGAAGAUGGUUUAUUGA ACUUAAGUAAAGAAGUGUUUCCAACAGACAAAUAUUUGUAUCAAGAUGGUCAAUUUUUGGACAAGA AAACAAUUAAUGCCUAUUUAAAUCUUAAGUAUACAAAACGUGAAAUCGAUAAAAUGUCUGAAAAAG AUAAAAAAGACAAGAAAGCGAAUGAAAAUUUAGGACUUAAUCCAUCACACGAAGGUGAAACAGAUC CUGAAAAGAUUGCAGAAAAAUCACCAGCCUAUUUAUCUAACAUUUUAGAGCAAGAUUUUUAUGGUG GUGGAGAUACAAAAGGUAAGAAUAUUAAAGGUAUGACGAUUGGUUUAGCUAUGAAUAGUGUUUAU UACUAUAAAAAAGAAAAAGAUGGACCGACUUUUAGUAAAAAACUAGAUGAUAGCGAAGUUAAAAAG CAAGGUAAACAAAUGGCUAGUGAGAUAUUAUCAAGGUUACGUGAAAAUGAUGAUUUAAAAGAUAUA CCAAUUCAUUUUGCAAUUUAUAAGCAAUCAAGUGAAGAUUCAAUCACACCAGGUGAAUUUAUCACU CAAGCGACUGCAGAAAAGAGUCAAACAAAGCUUAAUGAAUGGCAUAAUAUCAAUGAAAAAUCAGCU UUAUUACCUUCUUCAACAGCAGCAGAUUAUGAUGAAAAUUUAAAUAAUAAUUUCAAGCAAUUUAAU GAUAAUUUGCAAUCAUAUUUUUCUAAUUUCACACAAGCAGUAGGAAAAGUUAAAUUUGUUGAUAAA AAGCCACAACGAUUAGUAGUAGAUUUACCAAUCGAUUACUAUGGACAAGCUGAAACAAUUGGUAUU ACACAGUACGUUACUGAACAAGCGAAUAAAUAUUUCGAUAAAAUCGAUAACUAUGAAAUUCGGAUU AAAGAUGGUAACCAACCACGUGCUUUAAUUAGUAAGACAAAAGAUGACAAAGAACCGCAAGUUCAU AUUUACAGUAAUUAA SEQ IN NO: 40 AUGAGGGAAAAUUUUAAGUUACGUAAAAUGAAAGUCGGGUUAGUAUCUGUUGCAAUUACAAUGUU AUAUAUCAUGACAAACGGACAAGCAGAAGCAUCAGAGGCUAAUGAGAAGCCAAGUACAAAUCAAGA AUCAAAAGUUGUUUCACAGACUGAACAAAAUUCAAAAGAAACAAAAACAGUAGAAUCUAAUAAGAAC UUUGUUAAAUUAGAUACUAUUAAACCUGGAGCUCAAAAGAUAACGGGAACUACUUUACCAAAUCAC UAUGUUUUAUUAACAGUUGAUGGGAAAAGUGCGGAUUCAGUAGAAAAUGGCGGUUUGGGUUUUG UUGAAGCAAAUGACAAAGGAGAAUUUGAGUACCCUUUAAAUAAUCGUAAAAUUGUUCAUAAUCAAG AAAUUGAGGUUUCGUCGUCAAGCCCUGAUUUAGGUGAAGAUGAAGAAGAUGAAGAGGUGGAAGAA GCUUCAACUGAUAAAGCUGGCGUUGAGGAAGAAAGUACAGAAGCUAAAGUUACUUACACAACACCG CGAUAUGAAAAAGCGUAUGAAAUACCGAAAGAACAACUAAAAGAAAAAGAUGGACAUCACCAAGUU UUUAUCGAACCUAUUACUGAAGGAUCAGGUAUUAUUAAAGGGCAUACGUCUGUAAAAGGUAAAGU UGCUUUAUCUAUUAAUAAUAAAUUUAUUAAUUUUGAAGAGAGCGUUAAGGGCGGAGUUAGUAAAG AAGACACUAAAGCUAGUUCAGAUGGUAUCUGGAUGCCUAUUGAUGACAAAGGAUACUUUAACUUU GACUUCAAAACGAAACGUUUCGAUAAUUUAGAGUUAAAAGAAGGUAAUGACAUUUCACUAACAUUU GCACCUGAUGAUGAAGAAGAUGCAUUAAAACCUUUAAUUUUCAAAACUAAAGUAACGAGCUUAGAA GAUAUCGAUAAAGCAGAAACUAAAUAUGACCAUACUAAACUCAACAAAGUGAAAGUUUUAGAUAAU GUUAAAGAAGAUUUACAUGUUGAUGAAAUAUAUGGAAGCUUAUAUCAUACAGACAAAGGUAAAGGU AUUCUUGAUAAAGAAGGUACUAAAGUAAUUAAAGGAAAGACUAAAUUCGCGAAUGCAGUAGUGAAG GUAGACUCUGAACUAGGUGAAGCACAAUUAUUCCCUGAUUUACAAGUAAAUGAAAAAGGUGAAUUU AGCUUUGACUCACAUGGUGCUGGUUUUAGAUUACAAAAUGGAGAAAAAUUAAACUUCACAGUGGU UGAUCCUAUUACAGGUGACUUGUUAAGUAAUGAGUUUGUUUCUAAAGAGAUUGAUAUUGAAGAAA CACCUGAACAAAAAGCGGAUCGUGAGUUUGACGAAAAACUUGAAAAUACGCCUGCUUACUACAAGU UAUACGGCGAUAAAAUAGUUGGAUUCGAUACUAACGAUUUCCCGAUUACUUGGUUCUAUCCAUUG GGUGAAAAGAAAGUUGAACGUACAACACCUAAAUUAGAAAAAUAA SEQ IN NO: 41 AUGUCUAAAAAGUUAAAAAUUAUAAUUCCUAUUAUUAUUGUCUUAUUAUUAAUAGGUGGAAUCGCA UGGGGAGUUUAUGCAUUUUUUGCAAACACACCGAAAAAUACAUACUUAAAAAGUGAACAACAAACU GCAAAAAUGUAUAAAGAUUAUUUUAAUGACCGUUUUGAAAACGAAGUGAAGUUCCAAGAAAAGAUG AAAGAUAAUUCAUUUUUAUCUUCAUUAGAAUUAAGCGCAGAUGCAUCUGAUGAAAUUGUUAAAGGG CUUGGUAUUCCUAAAUCUGUUGUUAAUGCUUCGAAAAUUAAAAUGUCAUAUGGACAUGAUCCUAAA AAAGAGAAAUCAAUGAUUAAUCUUGAACCAACAAUAGCAGACUCUGCAUUAGGGAAAUUCCAGUUA GCUGCAGAUAAAGAUAAGCAUUAUUUCGAAUCACCAUUAUUUAAAGGGAAAUAUAGUGUUAAUAAU UCUGAUUUAUUAUCAACUUAUUCAAAACUUACAGGUGAAGAUGAAGAAACAGCAAAAGAAAAUGGU AUUACAAACCAACAACUAAAUUUAAAUACUCUUUUCAGUAAUGCUCAAGCACAACAAAGUGACUACA GCAAAAUUGCCGAAAAAUAUUCCGAACUUAUUGUCGACAAAUUAGAUGACGAUAAUUUUGAUAAAG GUAAAAAAGAAGAAAUUAAGGUUAAUGGUGAAAAGUACAAAGUUAGACCUGUCACGUUAACACUUA GCAGAGCUGACACUAAAAAAAUUACAUUAGCUGUAUUAGAAGAAGCUAAAAAGGAUAAAGACCUUA AAAAAUUAAUGGAAGAACAAGGUACUACAAAAGACUUUGAAAAAGACAUUAAAAAAGCAAUUGACG AUGUCAAAGAAACUAAAAAGGAUGAAUUUGCUAAAAUUCAAUCUAAAAUUUAUACCGAAAAACAUAC GAUUGUAAAACGAGAAAUUACUAUUACAGACAAAGAAAAUAAUAAAACUAAAAUCAAAGGUACUAAU ACUUUAGAAGACGAUAAGUUAAAACUAGAUUACGCACUUGAUUUCGAUCAAGAUAAAUACACGUAU GCUGAAGCGAAAUAUACAAUUAAAGGCGUAUCUUCUAAGGAAAAAGACAAUAAAUACAGUGAUAAA UACGAAUUUGGUAAAAAGACAGAAUAUGAUGAAUCAAAAAUCAAAUUAGAUAACCAAGAAAAAGUA GAUGGCACAAAACGUCAAGAUAAAGGUAAAAUCACUGUCGCGUUAGAUAAAUAUAGCGACGAAAAU GAAUUCACUUUUGAAAAUAAUAUAGAUUCUGACGUAAAAAAUAACACUCAGAAAUCUACGUUAAAU AUCGGCAUCAAAUAUGCUGAAGAACCAAUUAAUUUCAUUUUAAAAUCUAGCACAAAAUUGAAAGCA GAUAUUGAUUUUGAUGAUAGUGGUGCGAAAGAUUUCAAUAGUCUAUCUUCAAAAGACCGUGAAAA ACUUGAAAAAGAAAUCGAAAAAAAUGGCGGCAAAAUGUUUGAAUCAAUUUUAAAAAAGGCAUCUAA AUAA SEQ IN NO: 42 GUGAGGAAAUUUUCAAGAUAUGCAUUUACAAGUAUGGCAACAGUAACGUUGCUGAGCUCUUUGAC ACCUGCAGCACUAGCGAGUGAUACGAAUCACAAACCAGCAACUUCAGAUAUUAAUUUUGAAAUCAC GCAAAAGAGUGAUGCAGUUAAAGCAUUAAAAGAGUUACCUAAAUCUGAAAAUGUGAAAAAUCAUUA UCAAGAUUACUCUGUUACAGAUGUAAAAACAGAUAAGAAAGGAUUCACGCAUUACACGUUACAACC GAGUGUGGAUGGUGUGCAUGCGCCUGACAAAGAAGUGAAAGUGCAUGCGGACAAAUCGGGUAAAG UCGUUUUAAUCAACGGUGAUACUGAUGCGAAGAAAGUAAAGCCGACAAAUAAAGUGACAUUAAGCA AGGAUGAAGCGGCUGACAAAGCAUUUAACGCAGUUAAGAUUGAUAAAAAUAAAGCUAAAAACCUCC AAGAUGACGUUAUCAAAGAAAAUAAAGUCGAAAUCGAUGGUGACAGUAAUAAAUACAUUUACAAUA UUGAAUUAAUUACAGUAACACCAGAAAUUUCACAUUGGAAAGUUAAAAUUGAUGCAGACACAGGAG CAGUUGUUGAAAAAACGAACUUAGUUAAAGAAGCAGCAGCAACUGGCACAGGUAAAGGUGUGCUU GGAGAUACAAAAGAUAUCAAUAUCAAUAGUAUUGAUGGUGGAUUUAGUUUAGAGGAUUUGACGCA UCAAGGUAAAUUAUCAGCAUACAAUUUUAACGAUCAAACAGGUCAAGCGACAUUAAUUACUAAUGA AGAUGAAAACUUCGUCAAAGAUGAUCAACGUGCUGGUGUAGAUGCGAAUUAUUAUGCUAAACAAAC AUAUGAUUACUACAAAAAUACAUUUGGUCGUGAGUCUUACGAUAACCAUGGUAGUCCAAUAGUCUC AUUAACACAUGUAAAUCAUUAUGGUGGACAAGAUAACAGAAAUAACGCUGCAUGGAUUGGAGACAA AAUGAUUUAUGGUGAUGGCGAUGGCCGCACGUUUACAAAUUUAUCAGGUGCAAAUGACGUAGUAG CACAUGAGUUAACACAUGGCGUGACACAAGAAACGGCGAAUUUAGAGUAUAAAGAUCAAUCUGGUG CGUUAAAUGAAAGCUUUUCAGAUGUUUUUGGAUACUUUGUAGAUGAUGAGGAUUUCUUGAUGGGU GAAGAUGUUUACACACCAGGAAAAGAGGGAGAUGCUUUACGAAGCAUGUCAAACCCAGAACAAUUU GGUCAACCAUCUCAUAUGAAAGACUAUGUAUACACUGAAAAAGAUAACGGUGGUGUGCAUACGAAU UCUGGCAUUCCAAAUAAAGCAGCUUAUAACGUAAUUCAAGCAAUAGGGAAAUCUAAAUCAGAACAA AUUUACUACCGAGCAUUAACGGAAUACUUAACAAGUAAUUCAAACUUCAAAGAUUGUAAAGAUGCA

UUAUACCAAGCGGCUAAAGAUUUAUAUGACGAGCAAACAGCUGAACAAGUAUAUGAAGCAUGGAAC GAAGUUGGCGUCGAGUAA SEQ IN NO: 43 AUGAAAAAGAAAUUAGGUAUGUUACUUCUUGUACCAGCCGUAACUUUAUCAUUAGCCGCAUGUGG GAAUGAUGAUGGAAAAGAUAAAGAUGGCAAGGUAACAAUUAAAACGACAGUUUAUCCAUUGCAAUC AUUUGCAGAGCAAAUUGGUGGAAAACACGUGAAGGUAUCAUCAAUCUAUCCAGCAGGGACAGAUU UACAUAGCUAUGAACCAACACAAAAAGAUAUAUUAAGUGCAAGCAAGUCAGACUUGUUUAUGUAUA CAGGGGAUAAUUUAGAUCCGGUUGCUAAGAAAGUUGCAUCUACUAUUAAAGAUAAAGAUAAAAAAC UGUCUUUAGAAGAUAAAUUAGAUAAAGCAAAGCUUUUAACUGAUCAACACGAACAUGGUGAAGAGC AUGAACAUGAGGGACAUGAUCAUGGGAAAGAAGAACAUCAUCAUCAUGGCGGAUAUGAUCCACACG UAUGGUUAGAUCCUAAAAUUAACCAAACUUUCGCUAAAGAAAUUAAAGAUGAAUUAGUGAAGAAAG AUCCAAAACAUAAAGAUGACUAUGAGAAAAACUACAAAAAAUUAAACGACGAUCUUAAGAAAAUUGA UAACGAUAUGAAGCAAGUUACUAAAGAUAAGCAAGGUAAUGCAGUAUUCAUUUCACAUGAAUCAAU UGGAUACUUAGCUGAUCGUUAUGGUUUUGUUCAAAAAGGUAUUCAAAACAUGAAUGCUGAAGAUC CAUCACAAAAAGAAUUGACUAAAAUUGUUAAAGAAAUUAGAGAUAGCAAUGCUAAAUAUAUUCUUU ACGAAGAUAAUGUUGCGAAUAAAGUGACUGAAACAAUUCGUAAAGAAACAGAUGCGAAGCCUUUAA AAUUCUACAACAUGGAGUCUUUAAAUAAAGAACAACAGAAAAAAGAUAAUAUUACCUAUCAAUCAUU AAUGAAAUCGAAUAUUGAAAAUAUCGGUAAAGCUUUAGACAGUGGUGUUAAAGUGAAAGACGACAA AGCUGAAAGUAAACACGACAAAGCAAUUUCUGAUGGGUAUUUUAAAGAUGAGCAAGUUAAAGACCG UGAAUUAAGCGAUUAUGCUGGUGAAUGGCAAUCUGUUUACCCUUACUUAAAAGACGGUACGCUUG AUGAAGUGAUGGAACAUAAAGCUGAAAAUGAUCCGAAGAAAUCUGCUAAAGAUUUAAAAGCUUAUU AUGACAAAGGAUAUAAAACUGAUAUUACUAACAUUGAUAUAAAAGGAAAUGAAAUUACAUUUACUA AAGAUGGUACGAAACACACUGGUAAAUAUGAAUACAAUGGUAAGAAAACAUUGAAAUAUCCUAAAG GUAACCGUGGCGUGAGAUUUAUGUUUAAAUUGGUCGAUGGUAAUGAUAAAGACUUACCGAAAUUC AUCCAAUUUAGCGAUCACAACAUUGCACCUAAAAAGGCAGAACACUUCCAUAUCUUUAUGGGUAAU GAUAAUGACGCGUUAUUAAAAGAAAUGGAUAACUGGCCAACAUAUUAUCCUUCAAAAUUAAAUAAA GACCAAAUCAAAGAAGAAAUGUUAGCGCAUUAA SEQ IN NO: 44 AUGGUGUUAUAUAUCAUUUUGGCAAUAAUUGUGAUUAUAUUGAUUGCUGUAGGUGUAUUAUUCUA UUUACGUUCAAAUAAAAGACAAAUAAUAGAAAAAGCAAUCGAACGUAAAAAUGAAAUUGAAACGUU ACCUUUUGAUCAAAACCUUGCACAAUUAUCUAAGUUGAAUUUAAAAGGUGAAACAAAAACGAAAUA CGAUGCAAUGAAAAAGGACAACGUAGAAAGUACAAAUAAGUAUCUAGCUCCUGUGGAAGAAAAAAU CCAUAAUGCUGAGGCUUUAUUAGAUAAAUUUAGUUUCAACGCAUCUCAAUGUGAAAUUGAUGAUG CAAAUGAGUUGAUGGAUAGUUACGAACAAAGCUAUCAGCAACAAUUAGAAGAUGUAAAUGAAAUUA UUGCGUUAUACAAAGAUAAUGAUGAAUUAUAUGACAAAUGUAAGGUUGAUUAUCGUGAAAUGAAAC GUGAUGUUUUAGCAAAUCGUCAUCAAUUUGGUGAGGCAGCAAGUCUUCUUGAAACUGAAAUUGAA AAAUUCGAGCCAAGGUUAGAGCAAUAUGAAGUACUAAAAGCUGAUGGUAAUUAUGUACAAGCGCAC AACCAUAUAGCUGCCUUGAAUGAACAAAUGAAACAGCUAAGAUCUUAUAUGGAAGAAAUACCAGAA UUAAUUAGAGAAACUCAAAAAGAAUUACCUGGUCAAUUCCAAGAUUUAAAAUAUGGUUGCCGUGAU CUUAAAGUUGAAGGGUAUGAUCUGGAUCACGUAAAAGUAGACAGUACAUUACAAAGCUUAAAAACA GAGCUUAGUUUCGUUGAACCAUUAAUUAGUCGCUUAGAAUUAGAAGAAGCUAAUGAUAAACUAGC UAAUAUCAAUGAUAAGUUAGAUGACAUGUAUGAUUUAAUUGAACAUGAAGUUAAAGCUAAAAAUGA UGUCGAAGAAACAAAAGAUAUCAUUACGGAUAACUUAUUCAAAGCAAAAGACAUGAAUUAUACAUU GCAAACAGAAAUUGAAUAUGUACGUGAAAACUACUAUAUAAAUGAAUCUGAUGCUCAGAGUGUUCG UCAAUUUGAAAAUGAAAUUCAAAGUUUAAUUUCUGUAUAUGAUGAUAUUUUAAAAGAAAUGUCUAA AUCUGCUGUACGAUAUAGCGAGGUUCAGGAUAAUUUACAAUAUUUAGAAGAUCAUGUCACAGUUA UUAAUGACAAACAAGAAAAGCUACAAAAUCAUCUGAUUCAAUUGCGUGAAGAUGAAGCAGAAGCAG AAGACAAUCUGUUACGAGUACAAUCGAAGAAAGAAGAAGUGUAUCGUCGAUUACUUGCUUCUAACU UAACAAGCGUUCCUGAAAGGUUUAUCAUCAUGAAAAAUGAAAUUGAUCAUGAAGUUCGUGAUGUU AACGAACAAUUUAGUGAACGUCCAAUACACGUUAAACAGUUAAAAGAUAAAGUGUCUAAAAUUGUG AUUCAAAUGAAUACAUUUGAAGAUGAAGCAAAUGAUGUUCUUGUUAAUGCUGUUUAUGCAGAGAA AUUAAUUCAAUAUGGAAAUAGAUAUCGUAAGGACUAUAGCAAUGUUGAUAAGAGCUUAAAUGAAGC UGAACGAUUAUUUAAAAAUAAUCGCUAUAAGCGUGCGAUUGAAAUUGCAGAGCAAGCUCUUGAAAG UGUUGAGCCAGGUGUCACUAAACAUAUUGAAGAAGAAGUUAUUAAGCAAUAG SEQ IN NO: 45 AUGCCUAAAAAUAAAAUUUUAAUUUAUUUGCUAUCAACUACGCUCGUAUUACCUACUUUAGUUUCA CCUACCGCUUAUGCUGACACACCUCAAAAAGAUACUACAGCUAAGACAACAUCUCAUGAUUCCAAAA AAUCUACUGAUGAUGAAACUUCUAAGGAUACUACAAGUAAAGAUAUUGAUAAAGCAGACAACAAUA AUACUAGUAACCAAGACAAUAACGACAAAAAAGUUAAAACUAUAGACGACAGCACUUCAGACUCUAA CAAUAUCAUUGAUUUUAUUUAUAAGAAUUUACCACAAACCAAUAUAAACCAAUUGCUAACCAAAAAU AAAUACGAUGAUAAUUACUCAUUAACAACUUUAAUCCAAAACUUAUUCAAUUUAAAUUCGGAUAUU UCUGAUUACGAACAACCUCGUAAUGGUGAAAAGUCAACAAAUGAUUCGAAUAAAAACAGUGAUAAU AGCAUCAAAAAUGAUACGGAUACGCAAUCAUCUAAACAAGAUAAAGCAGACAAUCAAAAAGCACCUA AAUCAAACAAUACAAAACCAAGUACAUCUAAUAAGCAACCAAAUUCGCCAAAGCCAACACAACCAAA UCAAUCAAAUAGUCAACCAGCAAGUGACGAUAAAGUAAAUCAAAAAUCUUCAUCGAAAGAUAAUCAA UCAAUGUCAGAUUCGGCUUUAGAUUCUAUUUUGGAUCAAUACAGUGAAGAUGCAAAGAAAACACAA AAAGAUUACGCAUCUCAAUCUAAAAAAGACAAAAAUGAAAAAUCUAAUACAAAGAAUCCACAGUUAC CAACACAAGAUGAAUUGAAACAUAAAUCUAAACCUGCUCAAUCAUUCAAUAACGAUGUUAAUCAAAA GGAUACACGUGCAACAUCACUAUUCGAAACAGAUCCUAGUAUAUCUAACAAUGAUGAUAGUGGACA AUUUAACGUUGUUGACUCAAAAGAUACACGUCAAUUUGUCAAAUCAAUUGCUAAAGAUGCACACCG CAUUGGUCAAGAUAACGAUAUUUAUGCGUCUGUCAUGAUUGCCCAAGCAAUCUUAGAAUCUGACUC AGGUCGUAGUGCUUUAGCUAAGUCACCAAACCAUAAUUUAUUCGGUAUCAAAGGUGCUUUUGAAG GGAAUUCUGUUCCUUUUAACACAUUAGAAGCUGAUGGUAAUCAAUUGUAUAGUAUUAAUGCUGGA UUCCGAAAAUAUCCAAGCACGAAAGAAUCACUAAAAGAUUACUCUGACCUUAUUAAAAAUGGUAUU GAUGGCAAUCGAACAAUUUAUAAACCAACAUGGAAAUCGGAAGCCGAUUCUUAUAAAGAUGCAACA UCACACUUAUCUAAAACAUAUGCUACAGAUCCAAACUAUGCUAAGAAAUUAAACAGUAUUAUUAAAC ACUAUCAAUUAACUCAGUUUGACGAUGAACGUAUGCCAGAUUUAGAUAAAUAUGAACGUUCUAUCA AGGAUUAUGAUGAUUCAUCAGAUGAAUUCAAACCUUUCCGCGAGGUAUCUGAUAAUAUGCCAUAUC CACAUGGCCAAUGUACUUGGUACGUAUAUAACCGUAUGAAACAAUUUGGUACAUCUAUCUCAGGU GAUUUAGGUGAUGCACAUAAUUGGAAUAAUCGAGCUCAAUACCGUGAUUAUCAAGUAAGUCAUACA CCAAAACGUCAUGCUGCUGUUGUAUUUGAGGCUGGACAAUUUGGUGCAGAUCAACAUUACGGUCA UGUAGCAUUUGUUGAAAAAGUUAACAGUGAUGGUUCUAUCGUUAUUUCAGAAUCCAAUGUUAAAG GAUUAGGUAUCAUUUCUCAUAGAACUAUCAAUGCAGCUGCCGCUGAAGAAUUAUCAUAUAUUACAG GUAAAUAA SEQ IN NO: 46 AUGAUGAAAAGUCAAAAUAAGUAUAGUAUUCGUAAAUUUAGUGUAGGUGCAUCUUCCAUUUUAAUA GCUACAUUACUAUUUUUAAGUGGUGGACAAGCACAAGCAGCUGAGAAGCAAGUGAAUAUGGGAAA UUCACAGGAGGAUACAGUUACAGCACAAUCUAUUGGGGAUCAACAAACUAGGGAAAAUGCUAAUUA UCAACGUGAAAACGGUGUUGACGAACAGCAACAUACUGAAAAUUUAACUAAGAACUUGCAUAAUGA UAAAACAAUAUCAGAAGAAAAUCAUCGUAAAACAGAUGAUUUGAAUAAAGAUCAACUAAAGGAUGA UAAAAAAUCAUCGCUUAAUAAUAAAAAUAUUCAACGUGAUACAACAAAAAAUAACAAUGCUAAUCCU AGGGAUGUAAAUCAAGGGUUAGAACAGGCUAUUAAUGAUGGCAAACAAAGUAAAGUGGCGUCACA GCAACAGUCAAAAGAGGCAGAUAAUAGUCAAGACUUAAACGCUAAUAACAAUCUACCUUCACAAAG UCGAACAAAGGUAUCACCAUCAUUAAAUAAGUCAGAUCAAACAAGUCAACGAGAAAUUGUUAAUGA GACAGAAAUAGAGAAAGUACAACCGCAACAAAAGAAUCAAGCGAAUGAUAAAAUUACUGACCACAAU UUUAACAAUGAACAAGAAGUGAAACCUCAAAAAGACGAAAAAACACUAUCAGUUUCAGAUUUAAAAA ACAAUCAAAAAUCACCAGUUGAACCAACAAAGGACAAUGACAAGAAAAAUGGAUUAAAUUUAUUAAA AAGUAGUGCAGUAGCAACGUUACCAAACAAAGGGACAAAGGAACUUACUGCAAAAGCGAAAGGUGA UCAAACGAAUAAAGUUGCCAAACAAGGGCAGUAUAAAAAUCAAGAUCCUAUAGUUUUAGUGCAUGG UUUCAAUGGGUUUACAGAUGAUAUUAAUCCUUCAGUGUUAGCUCAUUAUUGGGGCGGUAAUAAAA UGAACAUUCGCCAAGAUUUAGAAGAAAAUGGUUACAAAGCUUAUGAAGCAAGUAUAAGUGCUUUUG GAAGUAACUAUGACCGCGCAGUUGAACUUUAUUAUUAUAUCAAAGGCGGUCGUGUAGAUUAUGGU GCAGCACAUGCAGCAAAAUAUGGACAUGAACGUUAUGGAAAAACAUACGAAGGAAUUUACAAAGAC UGGAAACCAGGACAGAAGGUACACCUUGUUGGACAUAGUAUGGGUGGUCAAACGAUACGUCAACU AGAAGAAUUACUGCGUAAUGGUAGUCGUGAAGAAAUAGAGUAUCAAAAGAAACAUAGUGGCGAAA UUUCUCCACUAUUCAAAGGUAAUAAUGACAAUAUGAUUUCAUCAAUUACUACUUUAGGAACGCCAC AUAAUGGAACGCAUGCUUCAGAUUUAGCUGGUAAUGAAGCUUUAGUGAGACAAAUUGUAUUUGAU AUCGGUAAAAUGUUUGGUAAUAAAAAUUCAAGAGUAGACUUCGGGUUGGCUCAAUGGGGUCUAAA ACAGAAGCCAAAUGAAUCAUAUAUUGAUUAUGUCAAACGCGUUAAACAAUCUAAUUUAUGGAAAUC AAAAGAUAAUGGAUUUUACGAUCUGACGCGUGAGGGUGCAACAGAUUUAAAUCGUAAAACGUCGU UGAACCCUAACAUUGUGUAUAAAACAUACACUGGUGAAGCAACGCACAAAGCAUUAAAUAGCGAUA GACAAAAAGCAGACUUAAAUAUGUUUUUCCCAUUUGUGAUUACUGGUAACUUAAUCGGUAAAGCUA CUGAAAAAGAAUGGCGAGAAAACGAUGGUUUAGUAUCCGUUAUUUCUUCUCAACAUCCAUUUAAUC AAGCUUAUACAAAUGCGACGGAUAAAAUUCAAAAAGGCAUUUGGCAAGUAACGCCUACAAAACAUG AUUGGGAUCAUGUUGAUUUUGUCGGACAAGAUAGUUCUGAUACAGUGCGCACAAGAGAAGAAUUA CAAGAUUUUUGGCAUCAUUUAGCAGACGAUUUAGUGAAAACUGAAAAGGUGACUGAUACUAAGCAA GCAUAA SEQ IN NO: 47 AUGACAAAUAAAAUGAAGAAAUGGCAAAAAUUAUCCACCAUUACGUUAUUAAUGACCGGAGUGAUU GCUUUAAAUAAUGGUGAAUUUAGAAAUGUUGAUAAACAUCAAAUCGCUGUGGCUGAUACGAAUGU UCAAACGCCAGAUUAUGAAAAAUUGAAGAAGACGUGGCUCGACGUUAACUACGGUUAUGAUCAGUA UGAUGAGAAUAAUCAAGAUAUGAAGAAGAAGUUUGAUGCUAAAGAAAAAGAAGCCAAGAAGUUACU UGAUGACAUGAAAACUGAUACGAAUAGAACAUAUUUGUGGUCAGGAGCUGAAAACCUUGAAACUAA UUCUUCUCACAUGACAAAAACCUAUCGUAAUAUCGAGAAAAUCGCAGAAUCAAUGCAACAUAAGAA UACGGUAUUAAAAACAGUUGAAAACAAGUUGAAAAUAAAAGAAGCCCUAGAUUGGAUGCACAAAAA UGUUUAUGGCAAGAAUCCUUCUCAAAAAGUCGAGGAUUUAACUAAAAAUCGUAAGGGGCAAACUAC ACCCAAGAAUAACUCAUUGAAUUGGUGGGAUUAUGAAAUUGGUACGCCAAGAGCAUUAACAAAUAC ACUACUUCUAAUGGAUGAUAUGCUCACUAAAGAUGAAAUGAAAAAUUAUUCAAAACCUAUUAGUAC

AUAUGCACCAUCCAGUGACAAAAUUUUAUCUUCUGUUGGUGAAUCAGAAGAUGCUAAAGGUGGAA AUUUAGUGGACAUUUCUAAAGUAAAACUUUUAGAAAGUGUUAUUGAAGAAGAUGUAGAUAUGUUG AAAAAGUCUAUAGAUUCUUUUAAUAAAGUGUUCACUUAUGUUCAAGAUUCUGCCACUGGUAAAGGU CGCAAUGGAUUCUAUAAAGAUGGCUCUUACAUUGAUCAUCAAGAUGUCCCUUACACUGGUGCUUA UGGUGUUGUACUAUUAGAGGGUAUUUCUCAAAUGAUGCCGAUGAUAAAAGAAUCUCCUUUUAAAA CUACACAAGAUAAUGCUACAUUAAGCAAUUGGAUUGACGAAGGGUUUAUGCCAUUAAUCUAUAAAG GUGAAAUGAUGGAUUUAUCACGAGGUAGAGCUAUCAGUCGUGAAAAUGAAACGAGUCAUACAGCG UCAGCGACUGUAAUGAAAUCAUUGUUGAGAUUGAAUGAUACCAUGGAUGAUUCAACAAAAACUAGA UAUAAGCAAAUCGUUAAAACUUCUGUUAAUUCUGAUUCAAGUUACAACCAAAAUAAUUAUUUAAAU UCAUAUUCAGACAUAGCUAAAAUGAAAAAGUUAAUGAAUGAUAGUACUAUUUCUAAAAACGAUUUA ACACAGCAACUUAAAAUAUAUAAUGACAUGGAUCGUGUCACCUAUCACAAUAAAGACCUGGACUUU GCAUUUGGUUUAAGUAUGACAUCGAAAAACAUCGCACGAUACGAAAAUAUCAACGGAGAGAACUUA AAAGGUUGGCACACCGGUGCAGGCAUGUCUUAUUUAUAUAACAGCGAUGUCAAACACUAUCGCGA UAACUUCUGGGCAACAGCCGAUAUGACUUGUCUUCCAGGCACUACUACUUUAAAUGAUAUGCCAUC UACUAAUACUAAGAAUGAUAAAUCUUUUGUUGGCGGGACAAAAUUAAAUAAUAAAUACGCAAGCAU CGGUAUGGAUUUUGAAAAUCAGGACAAAACUUUAACUGCCAAAAAAUCAUAUUUCAUAUUAAACGA UAAAAUUGUCUUCUUAGGAACUGGCAUUAAAAGUACUGAUUCAUCAAAGAAUCCAGUUACAAGUGU UGAAAAUCGCAAAGCAAAUGGGUAUAAAUUAUUUAAAGAUGAUAUUGAAAUUACCACUUCAGAUGU UAAUGCUCAGGAAACCCAUUCAGUCUUUUUAGAGUCCAACGAUACUAAAAAGAACAUUGGUUAUCA UUUCUUAGACAAGCCAAAAAUAACUGUAAAAAAAGAAAGUCAUACUGGUAAGUGGAGUGAAAUUAA UAAAAGUCAAAAAAAAGAUGACAAAAAAGAUGAGUAUUAUGAAGUAACUCAAACACAUAAUACAUCU GACAGUAAAUAUGCAUAUGUUUUGUAUCCUGGUUUAUCAAAAAGUGAUUUUAAAUCGAAGAAUAAU AAUGUAAGUAUUGUUAAACAAGAUGAAGAUUUUCAUGUGAUAAAAGAUAAUGAUGGCGUAUUUGC UGGGGUUAAUUAUAGUGAUAAUACUAAAUCUUUUGAUAUAAACGGAAUUACUGUUGAAUUAAAAGA AAAAGGCAUGUUUGUAAUUAAAAAGAAAGAUGAUAAAGCAUAUAAAUGUAGCUUCUAUAAUCCUGA AACUACAAAUACCGCUUCAAAUAUAGAAUCAAAAAUUUUUAUUAAAGGUUACACCAUAACUAAUAAA AGUGUCAUAAACUCUAAUGAUGCUGGUGUAAACUUUGAAUUAACUAAAUAA SEQ IN NO: 48 AUGACAUAUAGAAUGAAGAAAUGGCAAAAAUUGUCCACCAUUACGUUAUUAAUGGCUGGUGUGAU UACUUUGAAUGGUGGUGAAUUCAGAAGUAUUGAUAAACAUCAAAUCGCUGUGGCUGAUACGAAUG UUCAAACGACAGAUUAUGAAAAGUUGAGGAACAUAUGGCUGGACGUUAACUAUGGUUAUGAUAAG UAUGAUGAGAAUAAUCCAGAUAUGAAGAAGAAGUUUGAGGCUACGGAGAAUGAGGCAGAGAAAUU ACUCAAGGAAAUGAAAACUGAAAGUGAUAGGAAAUACUUGUGGGAAAGCUCAAAAGAUUUAGAUAC GAAGUCUGCGGAUAUGACUCGUACCUAUCGUAAUAUUGAGAAAAUCUCAGAAGCGAUGAAACAUAA AAAUACUAAAUUAAAAACAGAUGAAAACAAGACAAAAGUAAAAGAUGCACUUGAGUGGCUGCAUAA AAAUGCAUAUGGAAAAGAACCAGAUAAAAAAGUUGCUGAUUUGACCUCAAACUUUAAAAAUAAAAC UUCUAGAAAUACCAACUUAAAUUGGUGGGAUUAUGAAAUUGGAACACCUAGAGCAUUAACAAAUAC GCUUAUACUCUUACAAGAAGAUUUCACUGAUGAAGAAAAGAAAAAAUAUACAGCUCCUAUUAAAAC UUUCGCCCCAGAUAGUGACAAAAUAUUAUCUUCUGUAGGAAAAUCUGAACCUGCUAAAGGCGGAAA UUUAGUAGACAUUUCUAAAGUAAAACUUUUAGAAAGUAUUAUCGAAGAAGACAAAGAUAUGAUGAA AAAGUCUAUAGAUUCAUUUAAUACAGUCUUCACUUACGCGCAAAAUUCUGCCACUGGAAAAGAACG UAAUGGAUUCUAUAAAGAUGGCUCUUACAUUGAUCAUCAAGACGUCCCAUACACUGGUGCUUAUG GCGUUGUACUAUUAGAGGGUAUUUCUCAAAUGAUGCCGAUGAUAAAAGAAACACCUUUUAAUGAU AGUAACCAAAAUGAUACAACCUUAAAAUCAUGGAUUGACGACGGAUUUAUGCCACUCAUUUAUAAA GGUGAAAUGAUGGAUUUAUCAAGAGGUAGAGCUAUCAGUCGUGAAAAUGAAACGAGUCACUCAGC AUCUGCAACAGUAAUGAAAUCAUUGUUGAGAUUGAGUGAUACCAUGGAUAAGUCUACAAAAGCUAA AUAUAAAAAGAUUGUCAAGACUUCAGUAGAGUCAGAUUCAAGUUAUAAACAAACCGAUUAUUUAAG CUCUUAUUCGGAUAUAAGCAAAAUGAAGUCUUUAAUGGAAGACAGCACUAUUUCUACUAACGGUUU AACACAACAACUUAAAAUAUAUAAUGACAUGGAUCGUGUCACCUAUCACAAUAAAGGCUUAGACUU UGCAUUUGGUUUAAGUAUGACGUCGAAAAACGUCGCACGUUACGAAAGUAUCAACGGAGAGAACU UAAAAGGUUGGCACACUGGUGCUGGAAUGUCUUAUUUAUACAAUAGCGAUGUGAAACACUACCGU GAUAACUUCUGGGCGACAGCUGAUAUGAAACGUUUAGCAGGUACUACAACUUUAGAUAAUGAAGA ACCUAAAAGUACGGAUGUUAAAAAGUCUAGUAAAACUUUUGUAGGAGGAACAAAAUUCGAUGACCA ACAUGCUAGUAUCGGAAUGGAUUUUGAAAAUCAGGACAAAACUUUAACUGCCAAAAAAUCAUAUUU CAUAUUAAACGAUAAAAUUGUCUUCUUAGGAACUGGCAUUAAAAGUACUGAUUCAUCAAAGAAUCC AGUUACAACGAUUGAAAAUCGCAAAGCGAAUGAUUAUAAAUUAUAUAAAGAUGAUACGCAAACAAC CAAUUCCGAUAAUCAGGAAACCAAUUCCCUCUUUUUAGAGUCAACGAAUAGCACUCAAAACAAUAU AGGUUAUCAUUUUUUAAACGAAUCGAAAAUAACUGUAAAAAAAGAAAGUCAUACUGGUAAGUGGAG UGAUAUAAAUAAAAGCCAAAAGGAUAUACAAAAAACUGAUGAGUAUUAUGAAGUAACUCAAAAGCA UUCUAAUACAGAUAGUAAAUAUGCAUAUGUGUUGUAUCCAGGCUUAUCUAAAGAUGUCUUUAAAUC CAAAGCAAGCAAAGUAACUGUCGUUAAGCAAGAAGAUGACUUCCACGUUGUGAAAGAUAAUGAAUC GGUUUGGGCUGGUAUCAAUUAUAGUGAUAGCGCUAAAACUUUUGAAAUUAAUAACACUAAAGUCG AAGUUAAAGCCAAAGGAAUGUUUAUUCUUACAAAGAAAGAUGAUAACACUUAUGAAUGUAGCUUCU AUAAUCCCGAAUCUACAAAUUCCGUUUCAGAUAUUGAAUCUAAAAUUUCAAUGACUGGAUACUCUA UUAUAAACAAAAAUACGUCGACUUCUAAUGAAUCCGGCGUACGCUUUGAAUUAACUAAAUAA SEQ ID NO: 50 ATTGATTCAAAAAATAAACCAGCTAATTCTGATATTAAATTTGAGGTGACTCAAAAGAGTGATGCGGTC AAAGCATTAAAAGAATTGCCTAAATCCGAAAATGTAAAAAATATTTATCAAGATTACGCTGTTACTGAT GTAAAAACTGATAAAAAAGGATTTACGCATTATACATTGCAACCGAGTGTTGATGGTGTTCATGCACCT GACAAAGAAGTGAAAGTACACGCAGACAAATCAGGAAAAGTCGTTTTAATCAATGGGGATACTGATGC GAAGAAAGTAAAGCCAACGAATAAAGTGACATTAAGTAAAGATGACGCAGCCGACAAAGCATTTAAAG CAGTTAAGATTGATAAGAATAAAGCGAAAAATCTTAAAGATAAAGTCATTAAAGAAAACAAAGTTGAAA TCGATGGTGACAGTAATAAATACGTTTATAATGTTGAGTTAATTACAGTGACACCAGAAATTTCACATT GGAAAGTTAAAATTGATGCTCAAACTGGCGAAATTTTAGAAAAAATGAACTTAGTTAAAGAAGCTGCA GAAACTGGTAAAGGAAAAGGTGTACTTGGCGATACAAAAGATATCAATATCAATAGTATTGACGGTGG ATTTAGCCTAGAAGATTTAACGCATCAAGGTAAATTATCAGCATTTAGCTTTAATGATCAAACAGGTCA AGCAACATTGATTACTAATGAAGATGAAAACTTCGTAAAAGATGAGCAACGTGCTGGCGTAGATGCAA ATTATTACGCTAAACAAACATATGATTATTACAAAGACACATTTGGTCGTGAATCATATGACAACCAAG GTAGTCCAATTGTTTCATTAACGCATGTTAATAACTACGGTGGTCAAGATAACAGAAATAATGCCGCAT GGATCGGTGACAAAATGATCTATGGTGATGGTGATGGTCGCACATTCACAAGTTTATCGGGTGCAAAT GACGTAGTAGCACACGAATTAACACACGGTGTGACACAAGAGACAGCGAACTTAGAATATAAGGACC AGTCAGGCGCTCTAAATGAAAGCTTTTCAGATGTTTTTGGATACTTTGTAGATGACGAGGATTTCTTAA TGGGTGAAGATGTCTACACACCTGGAAAAGAGGGAGACGCTTTACGCAGCATGTCAAACCCAGAACA ATTTGGTCAACCAGCTCATATGAAAGACTATGTATTCACTGAAAAAGATAATGGTGGCGTACATACGAA TTCTTAA SEQ ID NO: 51 AUUGAUUCAAAAAAUAAACCAGCUAAUUCUGAUAUUAAAUUUGAGGUGACUCAAAAGAGUGAUGCG GUCAAAGCAUUAAAAGAAUUGCCUAAAUCCGAAAAUGUAAAAAAUAUUUAUCAAGAUUACGCUGUU ACUGAUGUAAAAACUGAUAAAAAAGGAUUUACGCAUUAUACAUUGCAACCGAGUGUUGAUGGUGU UCAUGCACCUGACAAAGAAGUGAAAGUACACGCAGACAAAUCAGGAAAAGUCGUUUUAAUCAAUGG GGAUACUGAUGCGAAGAAAGUAAAGCCAACGAAUAAAGUGACAUUAAGUAAAGAUGACGCAGCCGA CAAAGCAUUUAAAGCAGUUAAGAUUGAUAAGAAUAAAGCGAAAAAUCUUAAAGAUAAAGUCAUUAA AGAAAACAAAGUUGAAAUCGAUGGUGACAGUAAUAAAUACGUUUAUAAUGUUGAGUUAAUUACAGU GACACCAGAAAUUUCACAUUGGAAAGUUAAAAUUGAUGCUCAAACUGGCGAAAUUUUAGAAAAAAU GAACUUAGUUAAAGAAGCUGCAGAAACUGGUAAAGGAAAAGGUGUACUUGGCGAUACAAAAGAUA UCAAUAUCAAUAGUAUUGACGGUGGAUUUAGCCUAGAAGAUUUAACGCAUCAAGGUAAAUUAUCAG CAUUUAGCUUUAAUGAUCAAACAGGUCAAGCAACAUUGAUUACUAAUGAAGAUGAAAACUUCGUAA AAGAUGAGCAACGUGCUGGCGUAGAUGCAAAUUAUUACGCUAAACAAACAUAUGAUUAUUACAAAG ACACAUUUGGUCGUGAAUCAUAUGACAACCAAGGUAGUCCAAUUGUUUCAUUAACGCAUGUUAAUA ACUACGGUGGUCAAGAUAACAGAAAUAAUGCCGCAUGGAUCGGUGACAAAAUGAUCUAUGGUGAU GGUGAUGGUCGCACAUUCACAAGUUUAUCGGGUGCAAAUGACGUAGUAGCACACGAAUUAACACA CGGUGUGACACAAGAGACAGCGAACUUAGAAUAUAAGGACCAGUCAGGCGCUCUAAAUGAAAGCU UUUCAGAUGUUUUUGGAUACUUUGUAGAUGACGAGGAUUUCUUAAUGGGUGAAGAUGUCUACACA CCUGGAAAAGAGGGAGACGCUUUACGCAGCAUGUCAAACCCAGAACAAUUUGGUCAACCAGCUCAU AUGAAAGACUAUGUAUUCACUGAAAAAGAUAAUGGUGGCGUACAUACGAAUUCUUAA

[0228] The polypeptides of the present invention are also designated as follows herein:

TABLE-US-00003 SEQ ID NO: 1: SAR1837 SEQ ID NO: 9: SAR0277 SEQ ID NO: 2: SAR1608 SEQ ID NO: 10: SAR2716 SEQ ID NO: 3: SAR2457 SEQ ID NO: 11: SAR2496 SEQ ID NO: 4: SAR0839 SEQ ID NO: 12: SAR1795 SEQ ID NO: 5: SAR1402 SEQ ID NO: 13: SAR2723 SEQ ID NO: 6: SAR1022 SEQ ID NO: 14: SAR2753 SEQ ID NO: 7: SAR1995 SEQ ID NO: 15: SAR1892 SEQ ID NO: 8: SAR0436 SEQ ID NO: 16: SAR2292 SEQ ID NO: 49: USA300HOU_2637_28_439

Sequence CWU 1

1

511140PRTStaphylococcus aureus 1Met Ala Lys Gly Asn Leu Phe Lys Ala Ile Leu Gly Ile Gly Gly Ala 1 5 10 15 Val Ala Ala Val Leu Val Thr Arg Lys Asp Ser Arg Asp Lys Leu Lys 20 25 30 Ala Glu Tyr Asn Lys Tyr Lys Gln Asp Pro Gln Ser Tyr Lys Asp Asn 35 40 45 Ala Lys Asp Lys Ala Thr Gln Leu Gly Thr Ile Ala Asn Glu Thr Ile 50 55 60 Lys Glu Val Lys Thr Asn Pro Lys Glu Tyr Ala Asn Arg Leu Lys Asn 65 70 75 80 Asn Pro Lys Ala Phe Phe Glu Glu Glu Lys Ser Lys Phe Thr Glu Tyr 85 90 95 Asp Asn Lys Thr Asp Glu Ser Ile Glu Lys Gly Lys Phe Asp Asp Glu 100 105 110 Gly Gly Ala Ala Pro Asn Asn Asn Leu Arg Ile Val Thr Glu Glu Asp 115 120 125 Leu Lys Lys Asn Lys Asn Ala Leu Ser Asp Lys Glu 130 135 140 2193PRTStaphylococcus aureus 2Met Lys Lys Leu Val Ser Ile Val Gly Ala Thr Leu Leu Leu Ala Gly 1 5 10 15 Cys Gly Ser Gln Asn Leu Ala Pro Leu Glu Glu Lys Thr Thr Asp Leu 20 25 30 Arg Glu Asp Asn His Gln Leu Lys Leu Asp Ile Gln Glu Leu Asn Gln 35 40 45 Gln Ile Ser Asp Ser Lys Ser Lys Ile Lys Gly Leu Glu Lys Asp Lys 50 55 60 Glu Asn Ser Lys Lys Thr Ala Ser Asn Asn Thr Lys Ile Lys Leu Met 65 70 75 80 Asn Val Thr Ser Thr Tyr Tyr Asp Lys Val Ala Lys Ala Leu Lys Ser 85 90 95 Tyr Asn Asp Ile Glu Lys Asp Val Ser Lys Asn Lys Gly Asp Lys Asn 100 105 110 Val Gln Ser Lys Leu Asn Gln Ile Ser Asn Asp Ile Gln Ser Ala His 115 120 125 Thr Ser Tyr Lys Asp Ala Ile Asp Gly Leu Ser Leu Ser Asp Asp Asp 130 135 140 Lys Lys Thr Ser Lys Asn Ile Asp Lys Leu Asn Ser Asp Leu Asn His 145 150 155 160 Ala Phe Asp Asp Ile Lys Asn Gly Tyr Gln Asn Lys Asp Lys Lys Gln 165 170 175 Leu Thr Lys Gly Gln Gln Ala Leu Ser Lys Leu Asn Leu Asn Ala Lys 180 185 190 Ser 3209PRTStaphylococcus aureus 3Met Lys Lys Leu Val Thr Gly Leu Leu Ala Leu Ser Leu Phe Leu Ala 1 5 10 15 Ala Cys Gly Gln Asp Ser Asp Gln Gln Lys Asp Ser Asn Lys Glu Lys 20 25 30 Asp Asp Lys Ala Lys Thr Glu Gln Gln Asp Lys Lys Thr Asn Asp Ser 35 40 45 Ser Lys Asp Lys Lys Asp Asn Lys Asp Asp Ser Lys Asp Val Asn Lys 50 55 60 Asp Asn Lys Asp Asn Ser Ala Asn Asp Asn Gln Gln Gln Ser Asn Ser 65 70 75 80 Asn Ala Thr Asn Asn Asp Gln Asn Gln Thr Asn Asn Asn Gln Ser Asn 85 90 95 Ser Gly Gln Thr Thr Asn Asn Gln Lys Ser Ser Tyr Val Ala Pro Tyr 100 105 110 Tyr Gly Gln Asn Ala Ala Pro Val Ala Arg Gln Ile Tyr Pro Phe Asn 115 120 125 Gly Asn Lys Ser Gln Ala Leu Gln Gln Leu Pro Asn Phe Gln Thr Ala 130 135 140 Leu Asn Ala Ala Asn Asn Glu Ala Asn Lys Phe Gly Asn Gly His Lys 145 150 155 160 Val Tyr Asn Asp Tyr Ser Ile Glu Glu His Asn Gly Asn Tyr Lys Tyr 165 170 175 Val Phe Ser Phe Lys Asp Pro Asn Val Asn Gly Lys Tyr Ser Ile Val 180 185 190 Thr Val Asp Tyr Thr Gly Gln Ala Met Val Thr Asp Pro Asn Tyr Gln 195 200 205 Gln 4242PRTStaphylococcus aureus 4Met Lys Lys Val Met Gly Ile Leu Leu Ala Ser Thr Leu Ile Leu Gly 1 5 10 15 Ala Cys Gly His His Gln Asp Ser Ala Lys Lys Glu Ser Thr Ser His 20 25 30 Lys Lys Lys Glu Asn Asp Asn Glu Glu Leu Asn Glu Glu Leu Lys Glu 35 40 45 Phe Lys Ser Lys Lys Asn Met Asp Ile Lys Ile Lys Gly Asp Thr Ile 50 55 60 Val Ser Asp Lys Phe Glu Ala Lys Ile Lys Glu Pro Phe Ile Ile Asn 65 70 75 80 Glu Lys Asp Glu Lys Lys Lys Tyr Ile Ala Phe Lys Met Glu Ile Thr 85 90 95 Ala Lys Lys Asp Asp Lys Asp Leu Asn Pro Ser Ser Ile Ser His Asp 100 105 110 Tyr Ile Asn Ile Thr Gln Asp Asp Lys Asn Thr Val Asn Lys Leu Arg 115 120 125 Asp Gly Tyr Leu Leu Ser Asp Lys Asn Tyr Lys Asp Trp Thr Glu His 130 135 140 Asn Gln Asp Gln Ile Lys Lys Gly Lys Thr Ala Gln Ala Met Phe Ile 145 150 155 160 Tyr Glu Leu Arg Gly Asp Gly Asn Ile Asn Leu Asn Val His Lys Tyr 165 170 175 Ser Glu Asp Lys Thr Val Asp Ser Lys Ser Phe Lys Phe Ser Lys Leu 180 185 190 Lys Thr Glu Asp Phe Ser His Arg Ala Glu Thr Arg Glu Glu Val Glu 195 200 205 Lys Lys Glu Lys Glu Phe Glu Glu Glu Tyr Lys Lys Glu Gln Glu Arg 210 215 220 Glu Lys Glu Lys Glu Lys Gln Lys Asp Asp Asp His Ser Gly Leu Asp 225 230 235 240 Glu Val 5327PRTStaphylococcus aureus 5Met Lys Lys Trp Gln Phe Val Gly Thr Thr Ala Leu Gly Ala Thr Leu 1 5 10 15 Leu Leu Gly Ala Cys Gly Gly Gly Asn Gly Gly Ser Gly Asn Ser Asp 20 25 30 Leu Lys Gly Glu Ala Lys Gly Asp Gly Ser Ser Thr Val Ala Pro Ile 35 40 45 Val Glu Lys Leu Asn Glu Lys Trp Ala Gln Asp His Ser Asp Ala Lys 50 55 60 Ile Ser Ala Gly Gln Ala Gly Thr Gly Ala Gly Phe Gln Lys Phe Ile 65 70 75 80 Ala Gly Asp Ile Asp Phe Ala Asp Ala Ser Arg Pro Ile Lys Asp Glu 85 90 95 Glu Lys Gln Lys Leu Gln Asp Lys Asn Ile Lys Tyr Lys Glu Phe Lys 100 105 110 Ile Ala Gln Asp Gly Val Thr Val Ala Val Asn Lys Glu Asn Asp Phe 115 120 125 Val Asp Glu Leu Asp Lys Gln Gln Leu Lys Ala Ile Tyr Ser Gly Lys 130 135 140 Ala Lys Thr Trp Lys Asp Val Asn Ser Lys Trp Pro Asp Lys Lys Ile 145 150 155 160 Asn Ala Val Ser Pro Asn Ser Ser His Gly Thr Tyr Asp Phe Phe Glu 165 170 175 Asn Glu Val Met Asn Lys Glu Asp Ile Lys Ala Glu Lys Asn Ala Asp 180 185 190 Thr Asn Ala Ile Val Ser Ser Val Thr Lys Asn Lys Glu Gly Ile Gly 195 200 205 Tyr Phe Gly Tyr Asn Phe Tyr Val Gln Asn Lys Asp Lys Leu Lys Glu 210 215 220 Val Lys Ile Lys Asp Glu Asn Gly Lys Ala Thr Glu Pro Thr Lys Lys 225 230 235 240 Thr Ile Gln Asp Asn Ser Tyr Ala Leu Ser Arg Pro Leu Phe Ile Tyr 245 250 255 Val Asn Glu Lys Ala Leu Lys Asp Asn Lys Val Met Ser Glu Phe Ile 260 265 270 Lys Phe Val Leu Glu Asp Lys Gly Lys Ala Ala Glu Glu Gly Gly Tyr 275 280 285 Val Ala Ala Pro Glu Lys Thr Tyr Lys Ser Gln Leu Asp Asp Leu Lys 290 295 300 Ala Phe Ile Asp Lys Asn Gln Lys Ser Asp Asp Lys Lys Ser Asp Asp 305 310 315 320 Lys Lys Ser Glu Asp Lys Lys 325 6357PRTStaphylococcus aureus 6Met Lys Gly Lys Phe Leu Lys Val Ser Ser Leu Phe Val Ala Thr Leu 1 5 10 15 Thr Thr Ala Thr Leu Val Ser Ser Pro Ala Ala Asn Ala Leu Ser Ser 20 25 30 Lys Ala Met Asp Asn His Pro Gln Gln Thr Gln Thr Asp Lys Gln Gln 35 40 45 Thr Pro Lys Ile Gln Lys Gly Gly Asn Leu Lys Pro Leu Glu Gln Arg 50 55 60 Glu Arg Ala Asn Val Ile Leu Pro Asn Asn Asp Arg His Gln Ile Thr 65 70 75 80 Asp Thr Thr Asn Gly His Tyr Ala Pro Val Thr Tyr Ile Gln Val Glu 85 90 95 Ala Pro Thr Gly Thr Phe Ile Ala Ser Gly Val Val Val Gly Lys Asp 100 105 110 Thr Leu Leu Thr Asn Lys His Ile Val Asp Ala Thr His Gly Asp Pro 115 120 125 His Ala Leu Lys Ala Phe Ala Ser Ala Ile Asn Gln Asp Asn Tyr Pro 130 135 140 Asn Gly Gly Phe Thr Ala Glu Gln Ile Thr Lys Tyr Ser Gly Glu Gly 145 150 155 160 Asp Leu Ala Ile Val Lys Phe Ser Pro Asn Glu Gln Asn Lys His Ile 165 170 175 Gly Glu Val Val Lys Pro Ala Thr Met Ser Asn Asn Ala Glu Thr Gln 180 185 190 Val Asn Gln Asn Ile Thr Val Thr Gly Tyr Pro Gly Asp Lys Pro Val 195 200 205 Ala Thr Met Trp Glu Ser Lys Gly Lys Ile Thr Tyr Leu Lys Gly Glu 210 215 220 Ala Met Gln Tyr Asp Leu Ser Thr Thr Gly Gly Asn Ser Gly Ser Pro 225 230 235 240 Val Phe Asn Glu Lys Asn Glu Val Ile Gly Ile His Trp Gly Gly Val 245 250 255 Pro Asn Gln Phe Asn Gly Ala Val Phe Ile Asn Glu Asn Val Arg Asn 260 265 270 Phe Leu Lys Gln Asn Ile Glu Asp Ile Asn Phe Ala Asn Asp Asp His 275 280 285 Pro Asn Asn Pro Asp Asn Pro Asp Asn Pro Asn Asn Pro Asp Asn Pro 290 295 300 Asn Asn Pro Asp Asn Pro Asn Asn Pro Asp Asn Pro Asp Asn Pro Asn 305 310 315 320 Asn Pro Asp Asn Pro Asn Asn Pro Asp Asn Pro Asn Asn Pro Asp Gln 325 330 335 Pro Asn Asn Pro Asn Asn Pro Asp Asn Gly Asp Asn Asn Asn Ser Asp 340 345 350 Asn Pro Asp Ala Ala 355 7399PRTStaphylococcus aureus 7Met Lys Arg Thr Leu Val Leu Leu Ile Thr Ala Ile Phe Ile Leu Ala 1 5 10 15 Ala Cys Gly Asn His Lys Asp Asp Gln Ala Gly Lys Asp Asn Gln Lys 20 25 30 His Asn Asn Ser Ser Asn Gln Val Lys Glu Ile Ala Thr Asp Lys Asn 35 40 45 Val Gln Gly Asp Asn Tyr Arg Thr Leu Leu Pro Phe Lys Glu Ser Gln 50 55 60 Ala Arg Gly Leu Leu Gln Asp Asn Met Ala Asn Ser Tyr Asn Gly Gly 65 70 75 80 Asp Phe Glu Asp Gly Leu Leu Asn Leu Ser Lys Glu Val Phe Pro Thr 85 90 95 Asp Lys Tyr Leu Tyr Gln Asp Gly Gln Phe Leu Asp Lys Lys Thr Ile 100 105 110 Asn Ala Tyr Leu Asn Leu Lys Tyr Thr Lys Arg Glu Ile Asp Lys Met 115 120 125 Ser Glu Lys Asp Lys Lys Asp Lys Lys Ala Asn Glu Asn Leu Gly Leu 130 135 140 Asn Pro Ser His Glu Gly Glu Thr Asp Pro Glu Lys Ile Ala Glu Lys 145 150 155 160 Ser Pro Ala Tyr Leu Ser Asn Ile Leu Glu Gln Asp Phe Tyr Gly Gly 165 170 175 Gly Asp Thr Lys Gly Lys Asn Ile Lys Gly Met Thr Ile Gly Leu Ala 180 185 190 Met Asn Ser Val Tyr Tyr Tyr Lys Lys Glu Lys Asp Gly Pro Thr Phe 195 200 205 Ser Lys Lys Leu Asp Asp Ser Glu Val Lys Lys Gln Gly Lys Gln Met 210 215 220 Ala Ser Glu Ile Leu Ser Arg Leu Arg Glu Asn Asp Asp Leu Lys Asp 225 230 235 240 Ile Pro Ile His Phe Ala Ile Tyr Lys Gln Ser Ser Glu Asp Ser Ile 245 250 255 Thr Pro Gly Glu Phe Ile Thr Gln Ala Thr Ala Glu Lys Ser Gln Thr 260 265 270 Lys Leu Asn Glu Trp His Asn Ile Asn Glu Lys Ser Ala Leu Leu Pro 275 280 285 Ser Ser Thr Ala Ala Asp Tyr Asp Glu Asn Leu Asn Asn Asn Phe Lys 290 295 300 Gln Phe Asn Asp Asn Leu Gln Ser Tyr Phe Ser Asn Phe Thr Gln Ala 305 310 315 320 Val Gly Lys Val Lys Phe Val Asp Lys Lys Pro Gln Arg Leu Val Val 325 330 335 Asp Leu Pro Ile Asp Tyr Tyr Gly Gln Ala Glu Thr Ile Gly Ile Thr 340 345 350 Gln Tyr Val Thr Glu Gln Ala Asn Lys Tyr Phe Asp Lys Ile Asp Asn 355 360 365 Tyr Glu Ile Arg Ile Lys Asp Gly Asn Gln Pro Arg Ala Leu Ile Ser 370 375 380 Lys Thr Lys Asp Asp Lys Glu Pro Gln Val His Ile Tyr Ser Asn 385 390 395 8495PRTStaphylococcus aureus 8Met Arg Glu Asn Phe Lys Leu Arg Lys Met Lys Val Gly Leu Val Ser 1 5 10 15 Val Ala Ile Thr Met Leu Tyr Ile Met Thr Asn Gly Gln Ala Glu Ala 20 25 30 Ser Glu Ala Asn Glu Lys Pro Ser Thr Asn Gln Glu Ser Lys Val Val 35 40 45 Ser Gln Thr Glu Gln Asn Ser Lys Glu Thr Lys Thr Val Glu Ser Asn 50 55 60 Lys Asn Phe Val Lys Leu Asp Thr Ile Lys Pro Gly Ala Gln Lys Ile 65 70 75 80 Thr Gly Thr Thr Leu Pro Asn His Tyr Val Leu Leu Thr Val Asp Gly 85 90 95 Lys Ser Ala Asp Ser Val Glu Asn Gly Gly Leu Gly Phe Val Glu Ala 100 105 110 Asn Asp Lys Gly Glu Phe Glu Tyr Pro Leu Asn Asn Arg Lys Ile Val 115 120 125 His Asn Gln Glu Ile Glu Val Ser Ser Ser Ser Pro Asp Leu Gly Glu 130 135 140 Asp Glu Glu Asp Glu Glu Val Glu Glu Ala Ser Thr Asp Lys Ala Gly 145 150 155 160 Val Glu Glu Glu Ser Thr Glu Ala Lys Val Thr Tyr Thr Thr Pro Arg 165 170 175 Tyr Glu Lys Ala Tyr Glu Ile Pro Lys Glu Gln Leu Lys Glu Lys Asp 180 185 190 Gly His His Gln Val Phe Ile Glu Pro Ile Thr Glu Gly Ser Gly Ile 195 200 205 Ile Lys Gly His Thr Ser Val Lys Gly Lys Val Ala Leu Ser Ile Asn 210 215 220 Asn Lys Phe Ile Asn Phe Glu Glu Ser Val Lys Gly Gly Val Ser Lys 225 230 235 240 Glu Asp Thr Lys Ala Ser Ser Asp Gly Ile Trp Met Pro Ile Asp Asp 245 250 255 Lys Gly Tyr Phe Asn Phe Asp Phe Lys Thr Lys Arg Phe Asp Asn Leu 260 265 270 Glu Leu Lys Glu Gly Asn Asp Ile Ser Leu Thr Phe Ala Pro Asp Asp 275 280 285 Glu Glu Asp Ala Leu Lys Pro Leu Ile Phe Lys Thr Lys Val Thr Ser 290 295 300 Leu Glu Asp Ile Asp Lys Ala Glu Thr Lys Tyr Asp His Thr Lys Leu 305 310 315 320 Asn Lys Val Lys Val Leu Asp Asn Val Lys Glu Asp Leu His Val Asp 325 330 335 Glu Ile Tyr Gly Ser Leu Tyr His Thr Asp Lys Gly Lys Gly Ile Leu 340 345 350 Asp Lys Glu Gly Thr Lys Val Ile Lys Gly Lys Thr Lys Phe Ala Asn 355 360 365 Ala Val Val Lys Val Asp Ser Glu Leu Gly Glu Ala Gln Leu Phe Pro 370 375 380 Asp Leu Gln Val Asn Glu Lys Gly Glu Phe Ser Phe Asp Ser His Gly 385 390 395 400 Ala Gly Phe Arg Leu Gln Asn Gly Glu Lys Leu Asn Phe Thr Val Val

405 410 415 Asp Pro Ile Thr Gly Asp Leu Leu Ser Asn Glu Phe Val Ser Lys Glu 420 425 430 Ile Asp Ile Glu Glu Thr Pro Glu Gln Lys Ala Asp Arg Glu Phe Asp 435 440 445 Glu Lys Leu Glu Asn Thr Pro Ala Tyr Tyr Lys Leu Tyr Gly Asp Lys 450 455 460 Ile Val Gly Phe Asp Thr Asn Asp Phe Pro Ile Thr Trp Phe Tyr Pro 465 470 475 480 Leu Gly Glu Lys Lys Val Glu Arg Thr Thr Pro Lys Leu Glu Lys 485 490 495 9507PRTStaphylococcus aureus 9Met Ser Lys Lys Leu Lys Ile Ile Ile Pro Ile Ile Ile Val Leu Leu 1 5 10 15 Leu Ile Gly Gly Ile Ala Trp Gly Val Tyr Ala Phe Phe Ala Asn Thr 20 25 30 Pro Lys Asn Thr Tyr Leu Lys Ser Glu Gln Gln Thr Ala Lys Met Tyr 35 40 45 Lys Asp Tyr Phe Asn Asp Arg Phe Glu Asn Glu Val Lys Phe Gln Glu 50 55 60 Lys Met Lys Asp Asn Ser Phe Leu Ser Ser Leu Glu Leu Ser Ala Asp 65 70 75 80 Ala Ser Asp Glu Ile Val Lys Gly Leu Gly Ile Pro Lys Ser Val Val 85 90 95 Asn Ala Ser Lys Ile Lys Met Ser Tyr Gly His Asp Pro Lys Lys Glu 100 105 110 Lys Ser Met Ile Asn Leu Glu Pro Thr Ile Ala Asp Ser Ala Leu Gly 115 120 125 Lys Phe Gln Leu Ala Ala Asp Lys Asp Lys His Tyr Phe Glu Ser Pro 130 135 140 Leu Phe Lys Gly Lys Tyr Ser Val Asn Asn Ser Asp Leu Leu Ser Thr 145 150 155 160 Tyr Ser Lys Leu Thr Gly Glu Asp Glu Glu Thr Ala Lys Glu Asn Gly 165 170 175 Ile Thr Asn Gln Gln Leu Asn Leu Asn Thr Leu Phe Ser Asn Ala Gln 180 185 190 Ala Gln Gln Ser Asp Tyr Ser Lys Ile Ala Glu Lys Tyr Ser Glu Leu 195 200 205 Ile Val Asp Lys Leu Asp Asp Asp Asn Phe Asp Lys Gly Lys Lys Glu 210 215 220 Glu Ile Lys Val Asn Gly Glu Lys Tyr Lys Val Arg Pro Val Thr Leu 225 230 235 240 Thr Leu Ser Arg Ala Asp Thr Lys Lys Ile Thr Leu Ala Val Leu Glu 245 250 255 Glu Ala Lys Lys Asp Lys Asp Leu Lys Lys Leu Met Glu Glu Gln Gly 260 265 270 Thr Thr Lys Asp Phe Glu Lys Asp Ile Lys Lys Ala Ile Asp Asp Val 275 280 285 Lys Glu Thr Lys Lys Asp Glu Phe Ala Lys Ile Gln Ser Lys Ile Tyr 290 295 300 Thr Glu Lys His Thr Ile Val Lys Arg Glu Ile Thr Ile Thr Asp Lys 305 310 315 320 Glu Asn Asn Lys Thr Lys Ile Lys Gly Thr Asn Thr Leu Glu Asp Asp 325 330 335 Lys Leu Lys Leu Asp Tyr Ala Leu Asp Phe Asp Gln Asp Lys Tyr Thr 340 345 350 Tyr Ala Glu Ala Lys Tyr Thr Ile Lys Gly Val Ser Ser Lys Glu Lys 355 360 365 Asp Asn Lys Tyr Ser Asp Lys Tyr Glu Phe Gly Lys Lys Thr Glu Tyr 370 375 380 Asp Glu Ser Lys Ile Lys Leu Asp Asn Gln Glu Lys Val Asp Gly Thr 385 390 395 400 Lys Arg Gln Asp Lys Gly Lys Ile Thr Val Ala Leu Asp Lys Tyr Ser 405 410 415 Asp Glu Asn Glu Phe Thr Phe Glu Asn Asn Ile Asp Ser Asp Val Lys 420 425 430 Asn Asn Thr Gln Lys Ser Thr Leu Asn Ile Gly Ile Lys Tyr Ala Glu 435 440 445 Glu Pro Ile Asn Phe Ile Leu Lys Ser Ser Thr Lys Leu Lys Ala Asp 450 455 460 Ile Asp Phe Asp Asp Ser Gly Ala Lys Asp Phe Asn Ser Leu Ser Ser 465 470 475 480 Lys Asp Arg Glu Lys Leu Glu Lys Glu Ile Glu Lys Asn Gly Gly Lys 485 490 495 Met Phe Glu Ser Ile Leu Lys Lys Ala Ser Lys 500 505 10509PRTStaphylococcus aureus 10Met Arg Lys Phe Ser Arg Tyr Ala Phe Thr Ser Met Ala Thr Val Thr 1 5 10 15 Leu Leu Ser Ser Leu Thr Pro Ala Ala Leu Ala Ser Asp Thr Asn His 20 25 30 Lys Pro Ala Thr Ser Asp Ile Asn Phe Glu Ile Thr Gln Lys Ser Asp 35 40 45 Ala Val Lys Ala Leu Lys Glu Leu Pro Lys Ser Glu Asn Val Lys Asn 50 55 60 His Tyr Gln Asp Tyr Ser Val Thr Asp Val Lys Thr Asp Lys Lys Gly 65 70 75 80 Phe Thr His Tyr Thr Leu Gln Pro Ser Val Asp Gly Val His Ala Pro 85 90 95 Asp Lys Glu Val Lys Val His Ala Asp Lys Ser Gly Lys Val Val Leu 100 105 110 Ile Asn Gly Asp Thr Asp Ala Lys Lys Val Lys Pro Thr Asn Lys Val 115 120 125 Thr Leu Ser Lys Asp Glu Ala Ala Asp Lys Ala Phe Asn Ala Val Lys 130 135 140 Ile Asp Lys Asn Lys Ala Lys Asn Leu Gln Asp Asp Val Ile Lys Glu 145 150 155 160 Asn Lys Val Glu Ile Asp Gly Asp Ser Asn Lys Tyr Ile Tyr Asn Ile 165 170 175 Glu Leu Ile Thr Val Thr Pro Glu Ile Ser His Trp Lys Val Lys Ile 180 185 190 Asp Ala Asp Thr Gly Ala Val Val Glu Lys Thr Asn Leu Val Lys Glu 195 200 205 Ala Ala Ala Thr Gly Thr Gly Lys Gly Val Leu Gly Asp Thr Lys Asp 210 215 220 Ile Asn Ile Asn Ser Ile Asp Gly Gly Phe Ser Leu Glu Asp Leu Thr 225 230 235 240 His Gln Gly Lys Leu Ser Ala Tyr Asn Phe Asn Asp Gln Thr Gly Gln 245 250 255 Ala Thr Leu Ile Thr Asn Glu Asp Glu Asn Phe Val Lys Asp Asp Gln 260 265 270 Arg Ala Gly Val Asp Ala Asn Tyr Tyr Ala Lys Gln Thr Tyr Asp Tyr 275 280 285 Tyr Lys Asn Thr Phe Gly Arg Glu Ser Tyr Asp Asn His Gly Ser Pro 290 295 300 Ile Val Ser Leu Thr His Val Asn His Tyr Gly Gly Gln Asp Asn Arg 305 310 315 320 Asn Asn Ala Ala Trp Ile Gly Asp Lys Met Ile Tyr Gly Asp Gly Asp 325 330 335 Gly Arg Thr Phe Thr Asn Leu Ser Gly Ala Asn Asp Val Val Ala His 340 345 350 Glu Leu Thr His Gly Val Thr Gln Glu Thr Ala Asn Leu Glu Tyr Lys 355 360 365 Asp Gln Ser Gly Ala Leu Asn Glu Ser Phe Ser Asp Val Phe Gly Tyr 370 375 380 Phe Val Asp Asp Glu Asp Phe Leu Met Gly Glu Asp Val Tyr Thr Pro 385 390 395 400 Gly Lys Glu Gly Asp Ala Leu Arg Ser Met Ser Asn Pro Glu Gln Phe 405 410 415 Gly Gln Pro Ser His Met Lys Asp Tyr Val Tyr Thr Glu Lys Asp Asn 420 425 430 Gly Gly Val His Thr Asn Ser Gly Ile Pro Asn Lys Ala Ala Tyr Asn 435 440 445 Val Ile Gln Ala Ile Gly Lys Ser Lys Ser Glu Gln Ile Tyr Tyr Arg 450 455 460 Ala Leu Thr Glu Tyr Leu Thr Ser Asn Ser Asn Phe Lys Asp Cys Lys 465 470 475 480 Asp Ala Leu Tyr Gln Ala Ala Lys Asp Leu Tyr Asp Glu Gln Thr Ala 485 490 495 Glu Gln Val Tyr Glu Ala Trp Asn Glu Val Gly Val Glu 500 505 11515PRTStaphylococcus aureus 11Met Lys Lys Lys Leu Gly Met Leu Leu Leu Val Pro Ala Val Thr Leu 1 5 10 15 Ser Leu Ala Ala Cys Gly Asn Asp Asp Gly Lys Asp Lys Asp Gly Lys 20 25 30 Val Thr Ile Lys Thr Thr Val Tyr Pro Leu Gln Ser Phe Ala Glu Gln 35 40 45 Ile Gly Gly Lys His Val Lys Val Ser Ser Ile Tyr Pro Ala Gly Thr 50 55 60 Asp Leu His Ser Tyr Glu Pro Thr Gln Lys Asp Ile Leu Ser Ala Ser 65 70 75 80 Lys Ser Asp Leu Phe Met Tyr Thr Gly Asp Asn Leu Asp Pro Val Ala 85 90 95 Lys Lys Val Ala Ser Thr Ile Lys Asp Lys Asp Lys Lys Leu Ser Leu 100 105 110 Glu Asp Lys Leu Asp Lys Ala Lys Leu Leu Thr Asp Gln His Glu His 115 120 125 Gly Glu Glu His Glu His Glu Gly His Asp His Gly Lys Glu Glu His 130 135 140 His His His Gly Gly Tyr Asp Pro His Val Trp Leu Asp Pro Lys Ile 145 150 155 160 Asn Gln Thr Phe Ala Lys Glu Ile Lys Asp Glu Leu Val Lys Lys Asp 165 170 175 Pro Lys His Lys Asp Asp Tyr Glu Lys Asn Tyr Lys Lys Leu Asn Asp 180 185 190 Asp Leu Lys Lys Ile Asp Asn Asp Met Lys Gln Val Thr Lys Asp Lys 195 200 205 Gln Gly Asn Ala Val Phe Ile Ser His Glu Ser Ile Gly Tyr Leu Ala 210 215 220 Asp Arg Tyr Gly Phe Val Gln Lys Gly Ile Gln Asn Met Asn Ala Glu 225 230 235 240 Asp Pro Ser Gln Lys Glu Leu Thr Lys Ile Val Lys Glu Ile Arg Asp 245 250 255 Ser Asn Ala Lys Tyr Ile Leu Tyr Glu Asp Asn Val Ala Asn Lys Val 260 265 270 Thr Glu Thr Ile Arg Lys Glu Thr Asp Ala Lys Pro Leu Lys Phe Tyr 275 280 285 Asn Met Glu Ser Leu Asn Lys Glu Gln Gln Lys Lys Asp Asn Ile Thr 290 295 300 Tyr Gln Ser Leu Met Lys Ser Asn Ile Glu Asn Ile Gly Lys Ala Leu 305 310 315 320 Asp Ser Gly Val Lys Val Lys Asp Asp Lys Ala Glu Ser Lys His Asp 325 330 335 Lys Ala Ile Ser Asp Gly Tyr Phe Lys Asp Glu Gln Val Lys Asp Arg 340 345 350 Glu Leu Ser Asp Tyr Ala Gly Glu Trp Gln Ser Val Tyr Pro Tyr Leu 355 360 365 Lys Asp Gly Thr Leu Asp Glu Val Met Glu His Lys Ala Glu Asn Asp 370 375 380 Pro Lys Lys Ser Ala Lys Asp Leu Lys Ala Tyr Tyr Asp Lys Gly Tyr 385 390 395 400 Lys Thr Asp Ile Thr Asn Ile Asp Ile Lys Gly Asn Glu Ile Thr Phe 405 410 415 Thr Lys Asp Gly Thr Lys His Thr Gly Lys Tyr Glu Tyr Asn Gly Lys 420 425 430 Lys Thr Leu Lys Tyr Pro Lys Gly Asn Arg Gly Val Arg Phe Met Phe 435 440 445 Lys Leu Val Asp Gly Asn Asp Lys Asp Leu Pro Lys Phe Ile Gln Phe 450 455 460 Ser Asp His Asn Ile Ala Pro Lys Lys Ala Glu His Phe His Ile Phe 465 470 475 480 Met Gly Asn Asp Asn Asp Ala Leu Leu Lys Glu Met Asp Asn Trp Pro 485 490 495 Thr Tyr Tyr Pro Ser Lys Leu Asn Lys Asp Gln Ile Lys Glu Glu Met 500 505 510 Leu Ala His 515 12564PRTStaphylococcus aureus 12Met Val Leu Tyr Ile Ile Leu Ala Ile Ile Val Ile Ile Leu Ile Ala 1 5 10 15 Val Gly Val Leu Phe Tyr Leu Arg Ser Asn Lys Arg Gln Ile Ile Glu 20 25 30 Lys Ala Ile Glu Arg Lys Asn Glu Ile Glu Thr Leu Pro Phe Asp Gln 35 40 45 Asn Leu Ala Gln Leu Ser Lys Leu Asn Leu Lys Gly Glu Thr Lys Thr 50 55 60 Lys Tyr Asp Ala Met Lys Lys Asp Asn Val Glu Ser Thr Asn Lys Tyr 65 70 75 80 Leu Ala Pro Val Glu Glu Lys Ile His Asn Ala Glu Ala Leu Leu Asp 85 90 95 Lys Phe Ser Phe Asn Ala Ser Gln Cys Glu Ile Asp Asp Ala Asn Glu 100 105 110 Leu Met Asp Ser Tyr Glu Gln Ser Tyr Gln Gln Gln Leu Glu Asp Val 115 120 125 Asn Glu Ile Ile Ala Leu Tyr Lys Asp Asn Asp Glu Leu Tyr Asp Lys 130 135 140 Cys Lys Val Asp Tyr Arg Glu Met Lys Arg Asp Val Leu Ala Asn Arg 145 150 155 160 His Gln Phe Gly Glu Ala Ala Ser Leu Leu Glu Thr Glu Ile Glu Lys 165 170 175 Phe Glu Pro Arg Leu Glu Gln Tyr Glu Val Leu Lys Ala Asp Gly Asn 180 185 190 Tyr Val Gln Ala His Asn His Ile Ala Ala Leu Asn Glu Gln Met Lys 195 200 205 Gln Leu Arg Ser Tyr Met Glu Glu Ile Pro Glu Leu Ile Arg Glu Thr 210 215 220 Gln Lys Glu Leu Pro Gly Gln Phe Gln Asp Leu Lys Tyr Gly Cys Arg 225 230 235 240 Asp Leu Lys Val Glu Gly Tyr Asp Leu Asp His Val Lys Val Asp Ser 245 250 255 Thr Leu Gln Ser Leu Lys Thr Glu Leu Ser Phe Val Glu Pro Leu Ile 260 265 270 Ser Arg Leu Glu Leu Glu Glu Ala Asn Asp Lys Leu Ala Asn Ile Asn 275 280 285 Asp Lys Leu Asp Asp Met Tyr Asp Leu Ile Glu His Glu Val Lys Ala 290 295 300 Lys Asn Asp Val Glu Glu Thr Lys Asp Ile Ile Thr Asp Asn Leu Phe 305 310 315 320 Lys Ala Lys Asp Met Asn Tyr Thr Leu Gln Thr Glu Ile Glu Tyr Val 325 330 335 Arg Glu Asn Tyr Tyr Ile Asn Glu Ser Asp Ala Gln Ser Val Arg Gln 340 345 350 Phe Glu Asn Glu Ile Gln Ser Leu Ile Ser Val Tyr Asp Asp Ile Leu 355 360 365 Lys Glu Met Ser Lys Ser Ala Val Arg Tyr Ser Glu Val Gln Asp Asn 370 375 380 Leu Gln Tyr Leu Glu Asp His Val Thr Val Ile Asn Asp Lys Gln Glu 385 390 395 400 Lys Leu Gln Asn His Leu Ile Gln Leu Arg Glu Asp Glu Ala Glu Ala 405 410 415 Glu Asp Asn Leu Leu Arg Val Gln Ser Lys Lys Glu Glu Val Tyr Arg 420 425 430 Arg Leu Leu Ala Ser Asn Leu Thr Ser Val Pro Glu Arg Phe Ile Ile 435 440 445 Met Lys Asn Glu Ile Asp His Glu Val Arg Asp Val Asn Glu Gln Phe 450 455 460 Ser Glu Arg Pro Ile His Val Lys Gln Leu Lys Asp Lys Val Ser Lys 465 470 475 480 Ile Val Ile Gln Met Asn Thr Phe Glu Asp Glu Ala Asn Asp Val Leu 485 490 495 Val Asn Ala Val Tyr Ala Glu Lys Leu Ile Gln Tyr Gly Asn Arg Tyr 500 505 510 Arg Lys Asp Tyr Ser Asn Val Asp Lys Ser Leu Asn Glu Ala Glu Arg 515 520 525 Leu Phe Lys Asn Asn Arg Tyr Lys Arg Ala Ile Glu Ile Ala Glu Gln 530 535 540 Ala Leu Glu Ser Val Glu Pro Gly Val Thr Lys His Ile Glu Glu Glu 545 550 555 560 Val Ile Lys Gln 13619PRTStaphylococcus aureus 13Met Pro Lys Asn Lys Ile Leu Ile Tyr Leu Leu Ser Thr Thr Leu Val 1 5 10 15 Leu Pro Thr Leu Val Ser Pro Thr Ala Tyr Ala Asp Thr Pro Gln Lys 20 25 30 Asp Thr Thr Ala Lys Thr Thr Ser His Asp Ser Lys Lys Ser Thr Asp 35 40 45 Asp Glu Thr Ser Lys Asp Thr Thr Ser Lys Asp Ile Asp Lys Ala Asp 50 55 60 Asn Asn Asn Thr Ser Asn Gln Asp Asn Asn Asp Lys Lys Val Lys Thr 65 70 75 80 Ile Asp Asp Ser Thr Ser Asp Ser Asn Asn Ile Ile Asp Phe Ile Tyr 85 90 95 Lys Asn Leu Pro Gln Thr Asn Ile Asn Gln Leu Leu Thr Lys Asn Lys

100 105 110 Tyr Asp Asp Asn Tyr Ser Leu Thr Thr Leu Ile Gln Asn Leu Phe Asn 115 120 125 Leu Asn Ser Asp Ile Ser Asp Tyr Glu Gln Pro Arg Asn Gly Glu Lys 130 135 140 Ser Thr Asn Asp Ser Asn Lys Asn Ser Asp Asn Ser Ile Lys Asn Asp 145 150 155 160 Thr Asp Thr Gln Ser Ser Lys Gln Asp Lys Ala Asp Asn Gln Lys Ala 165 170 175 Pro Lys Ser Asn Asn Thr Lys Pro Ser Thr Ser Asn Lys Gln Pro Asn 180 185 190 Ser Pro Lys Pro Thr Gln Pro Asn Gln Ser Asn Ser Gln Pro Ala Ser 195 200 205 Asp Asp Lys Val Asn Gln Lys Ser Ser Ser Lys Asp Asn Gln Ser Met 210 215 220 Ser Asp Ser Ala Leu Asp Ser Ile Leu Asp Gln Tyr Ser Glu Asp Ala 225 230 235 240 Lys Lys Thr Gln Lys Asp Tyr Ala Ser Gln Ser Lys Lys Asp Lys Asn 245 250 255 Glu Lys Ser Asn Thr Lys Asn Pro Gln Leu Pro Thr Gln Asp Glu Leu 260 265 270 Lys His Lys Ser Lys Pro Ala Gln Ser Phe Asn Asn Asp Val Asn Gln 275 280 285 Lys Asp Thr Arg Ala Thr Ser Leu Phe Glu Thr Asp Pro Ser Ile Ser 290 295 300 Asn Asn Asp Asp Ser Gly Gln Phe Asn Val Val Asp Ser Lys Asp Thr 305 310 315 320 Arg Gln Phe Val Lys Ser Ile Ala Lys Asp Ala His Arg Ile Gly Gln 325 330 335 Asp Asn Asp Ile Tyr Ala Ser Val Met Ile Ala Gln Ala Ile Leu Glu 340 345 350 Ser Asp Ser Gly Arg Ser Ala Leu Ala Lys Ser Pro Asn His Asn Leu 355 360 365 Phe Gly Ile Lys Gly Ala Phe Glu Gly Asn Ser Val Pro Phe Asn Thr 370 375 380 Leu Glu Ala Asp Gly Asn Gln Leu Tyr Ser Ile Asn Ala Gly Phe Arg 385 390 395 400 Lys Tyr Pro Ser Thr Lys Glu Ser Leu Lys Asp Tyr Ser Asp Leu Ile 405 410 415 Lys Asn Gly Ile Asp Gly Asn Arg Thr Ile Tyr Lys Pro Thr Trp Lys 420 425 430 Ser Glu Ala Asp Ser Tyr Lys Asp Ala Thr Ser His Leu Ser Lys Thr 435 440 445 Tyr Ala Thr Asp Pro Asn Tyr Ala Lys Lys Leu Asn Ser Ile Ile Lys 450 455 460 His Tyr Gln Leu Thr Gln Phe Asp Asp Glu Arg Met Pro Asp Leu Asp 465 470 475 480 Lys Tyr Glu Arg Ser Ile Lys Asp Tyr Asp Asp Ser Ser Asp Glu Phe 485 490 495 Lys Pro Phe Arg Glu Val Ser Asp Asn Met Pro Tyr Pro His Gly Gln 500 505 510 Cys Thr Trp Tyr Val Tyr Asn Arg Met Lys Gln Phe Gly Thr Ser Ile 515 520 525 Ser Gly Asp Leu Gly Asp Ala His Asn Trp Asn Asn Arg Ala Gln Tyr 530 535 540 Arg Asp Tyr Gln Val Ser His Thr Pro Lys Arg His Ala Ala Val Val 545 550 555 560 Phe Glu Ala Gly Gln Phe Gly Ala Asp Gln His Tyr Gly His Val Ala 565 570 575 Phe Val Glu Lys Val Asn Ser Asp Gly Ser Ile Val Ile Ser Glu Ser 580 585 590 Asn Val Lys Gly Leu Gly Ile Ile Ser His Arg Thr Ile Asn Ala Ala 595 600 605 Ala Ala Glu Glu Leu Ser Tyr Ile Thr Gly Lys 610 615 14681PRTStaphylococcus aureus 14Met Met Lys Ser Gln Asn Lys Tyr Ser Ile Arg Lys Phe Ser Val Gly 1 5 10 15 Ala Ser Ser Ile Leu Ile Ala Thr Leu Leu Phe Leu Ser Gly Gly Gln 20 25 30 Ala Gln Ala Ala Glu Lys Gln Val Asn Met Gly Asn Ser Gln Glu Asp 35 40 45 Thr Val Thr Ala Gln Ser Ile Gly Asp Gln Gln Thr Arg Glu Asn Ala 50 55 60 Asn Tyr Gln Arg Glu Asn Gly Val Asp Glu Gln Gln His Thr Glu Asn 65 70 75 80 Leu Thr Lys Asn Leu His Asn Asp Lys Thr Ile Ser Glu Glu Asn His 85 90 95 Arg Lys Thr Asp Asp Leu Asn Lys Asp Gln Leu Lys Asp Asp Lys Lys 100 105 110 Ser Ser Leu Asn Asn Lys Asn Ile Gln Arg Asp Thr Thr Lys Asn Asn 115 120 125 Asn Ala Asn Pro Arg Asp Val Asn Gln Gly Leu Glu Gln Ala Ile Asn 130 135 140 Asp Gly Lys Gln Ser Lys Val Ala Ser Gln Gln Gln Ser Lys Glu Ala 145 150 155 160 Asp Asn Ser Gln Asp Leu Asn Ala Asn Asn Asn Leu Pro Ser Gln Ser 165 170 175 Arg Thr Lys Val Ser Pro Ser Leu Asn Lys Ser Asp Gln Thr Ser Gln 180 185 190 Arg Glu Ile Val Asn Glu Thr Glu Ile Glu Lys Val Gln Pro Gln Gln 195 200 205 Lys Asn Gln Ala Asn Asp Lys Ile Thr Asp His Asn Phe Asn Asn Glu 210 215 220 Gln Glu Val Lys Pro Gln Lys Asp Glu Lys Thr Leu Ser Val Ser Asp 225 230 235 240 Leu Lys Asn Asn Gln Lys Ser Pro Val Glu Pro Thr Lys Asp Asn Asp 245 250 255 Lys Lys Asn Gly Leu Asn Leu Leu Lys Ser Ser Ala Val Ala Thr Leu 260 265 270 Pro Asn Lys Gly Thr Lys Glu Leu Thr Ala Lys Ala Lys Gly Asp Gln 275 280 285 Thr Asn Lys Val Ala Lys Gln Gly Gln Tyr Lys Asn Gln Asp Pro Ile 290 295 300 Val Leu Val His Gly Phe Asn Gly Phe Thr Asp Asp Ile Asn Pro Ser 305 310 315 320 Val Leu Ala His Tyr Trp Gly Gly Asn Lys Met Asn Ile Arg Gln Asp 325 330 335 Leu Glu Glu Asn Gly Tyr Lys Ala Tyr Glu Ala Ser Ile Ser Ala Phe 340 345 350 Gly Ser Asn Tyr Asp Arg Ala Val Glu Leu Tyr Tyr Tyr Ile Lys Gly 355 360 365 Gly Arg Val Asp Tyr Gly Ala Ala His Ala Ala Lys Tyr Gly His Glu 370 375 380 Arg Tyr Gly Lys Thr Tyr Glu Gly Ile Tyr Lys Asp Trp Lys Pro Gly 385 390 395 400 Gln Lys Val His Leu Val Gly His Ser Met Gly Gly Gln Thr Ile Arg 405 410 415 Gln Leu Glu Glu Leu Leu Arg Asn Gly Ser Arg Glu Glu Ile Glu Tyr 420 425 430 Gln Lys Lys His Ser Gly Glu Ile Ser Pro Leu Phe Lys Gly Asn Asn 435 440 445 Asp Asn Met Ile Ser Ser Ile Thr Thr Leu Gly Thr Pro His Asn Gly 450 455 460 Thr His Ala Ser Asp Leu Ala Gly Asn Glu Ala Leu Val Arg Gln Ile 465 470 475 480 Val Phe Asp Ile Gly Lys Met Phe Gly Asn Lys Asn Ser Arg Val Asp 485 490 495 Phe Gly Leu Ala Gln Trp Gly Leu Lys Gln Lys Pro Asn Glu Ser Tyr 500 505 510 Ile Asp Tyr Val Lys Arg Val Lys Gln Ser Asn Leu Trp Lys Ser Lys 515 520 525 Asp Asn Gly Phe Tyr Asp Leu Thr Arg Glu Gly Ala Thr Asp Leu Asn 530 535 540 Arg Lys Thr Ser Leu Asn Pro Asn Ile Val Tyr Lys Thr Tyr Thr Gly 545 550 555 560 Glu Ala Thr His Lys Ala Leu Asn Ser Asp Arg Gln Lys Ala Asp Leu 565 570 575 Asn Met Phe Phe Pro Phe Val Ile Thr Gly Asn Leu Ile Gly Lys Ala 580 585 590 Thr Glu Lys Glu Trp Arg Glu Asn Asp Gly Leu Val Ser Val Ile Ser 595 600 605 Ser Gln His Pro Phe Asn Gln Ala Tyr Thr Asn Ala Thr Asp Lys Ile 610 615 620 Gln Lys Gly Ile Trp Gln Val Thr Pro Thr Lys His Asp Trp Asp His 625 630 635 640 Val Asp Phe Val Gly Gln Asp Ser Ser Asp Thr Val Arg Thr Arg Glu 645 650 655 Glu Leu Gln Asp Phe Trp His His Leu Ala Asp Asp Leu Val Lys Thr 660 665 670 Glu Lys Val Thr Asp Thr Lys Gln Ala 675 680 15806PRTStaphylococcus aureus 15Met Thr Asn Lys Met Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu 1 5 10 15 Leu Met Thr Gly Val Ile Ala Leu Asn Asn Gly Glu Phe Arg Asn Val 20 25 30 Asp Lys His Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Pro Asp 35 40 45 Tyr Glu Lys Leu Lys Lys Thr Trp Leu Asp Val Asn Tyr Gly Tyr Asp 50 55 60 Gln Tyr Asp Glu Asn Asn Gln Asp Met Lys Lys Lys Phe Asp Ala Lys 65 70 75 80 Glu Lys Glu Ala Lys Lys Leu Leu Asp Asp Met Lys Thr Asp Thr Asn 85 90 95 Arg Thr Tyr Leu Trp Ser Gly Ala Glu Asn Leu Glu Thr Asn Ser Ser 100 105 110 His Met Thr Lys Thr Tyr Arg Asn Ile Glu Lys Ile Ala Glu Ser Met 115 120 125 Gln His Lys Asn Thr Val Leu Lys Thr Val Glu Asn Lys Leu Lys Ile 130 135 140 Lys Glu Ala Leu Asp Trp Met His Lys Asn Val Tyr Gly Lys Asn Pro 145 150 155 160 Ser Gln Lys Val Glu Asp Leu Thr Lys Asn Arg Lys Gly Gln Thr Thr 165 170 175 Pro Lys Asn Asn Ser Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro 180 185 190 Arg Ala Leu Thr Asn Thr Leu Leu Leu Met Asp Asp Met Leu Thr Lys 195 200 205 Asp Glu Met Lys Asn Tyr Ser Lys Pro Ile Ser Thr Tyr Ala Pro Ser 210 215 220 Ser Asp Lys Ile Leu Ser Ser Val Gly Glu Ser Glu Asp Ala Lys Gly 225 230 235 240 Gly Asn Leu Val Asp Ile Ser Lys Val Lys Leu Leu Glu Ser Val Ile 245 250 255 Glu Glu Asp Val Asp Met Leu Lys Lys Ser Ile Asp Ser Phe Asn Lys 260 265 270 Val Phe Thr Tyr Val Gln Asp Ser Ala Thr Gly Lys Gly Arg Asn Gly 275 280 285 Phe Tyr Lys Asp Gly Ser Tyr Ile Asp His Gln Asp Val Pro Tyr Thr 290 295 300 Gly Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met Pro 305 310 315 320 Met Ile Lys Glu Ser Pro Phe Lys Thr Thr Gln Asp Asn Ala Thr Leu 325 330 335 Ser Asn Trp Ile Asp Glu Gly Phe Met Pro Leu Ile Tyr Lys Gly Glu 340 345 350 Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu Thr 355 360 365 Ser His Thr Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu Asn 370 375 380 Asp Thr Met Asp Asp Ser Thr Lys Thr Arg Tyr Lys Gln Ile Val Lys 385 390 395 400 Thr Ser Val Asn Ser Asp Ser Ser Tyr Asn Gln Asn Asn Tyr Leu Asn 405 410 415 Ser Tyr Ser Asp Ile Ala Lys Met Lys Lys Leu Met Asn Asp Ser Thr 420 425 430 Ile Ser Lys Asn Asp Leu Thr Gln Gln Leu Lys Ile Tyr Asn Asp Met 435 440 445 Asp Arg Val Thr Tyr His Asn Lys Asp Leu Asp Phe Ala Phe Gly Leu 450 455 460 Ser Met Thr Ser Lys Asn Ile Ala Arg Tyr Glu Asn Ile Asn Gly Glu 465 470 475 480 Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser Tyr Leu Tyr Asn 485 490 495 Ser Asp Val Lys His Tyr Arg Asp Asn Phe Trp Ala Thr Ala Asp Met 500 505 510 Thr Cys Leu Pro Gly Thr Thr Thr Leu Asn Asp Met Pro Ser Thr Asn 515 520 525 Thr Lys Asn Asp Lys Ser Phe Val Gly Gly Thr Lys Leu Asn Asn Lys 530 535 540 Tyr Ala Ser Ile Gly Met Asp Phe Glu Asn Gln Asp Lys Thr Leu Thr 545 550 555 560 Ala Lys Lys Ser Tyr Phe Ile Leu Asn Asp Lys Ile Val Phe Leu Gly 565 570 575 Thr Gly Ile Lys Ser Thr Asp Ser Ser Lys Asn Pro Val Thr Ser Val 580 585 590 Glu Asn Arg Lys Ala Asn Gly Tyr Lys Leu Phe Lys Asp Asp Ile Glu 595 600 605 Ile Thr Thr Ser Asp Val Asn Ala Gln Glu Thr His Ser Val Phe Leu 610 615 620 Glu Ser Asn Asp Thr Lys Lys Asn Ile Gly Tyr His Phe Leu Asp Lys 625 630 635 640 Pro Lys Ile Thr Val Lys Lys Glu Ser His Thr Gly Lys Trp Ser Glu 645 650 655 Ile Asn Lys Ser Gln Lys Lys Asp Asp Lys Lys Asp Glu Tyr Tyr Glu 660 665 670 Val Thr Gln Thr His Asn Thr Ser Asp Ser Lys Tyr Ala Tyr Val Leu 675 680 685 Tyr Pro Gly Leu Ser Lys Ser Asp Phe Lys Ser Lys Asn Asn Asn Val 690 695 700 Ser Ile Val Lys Gln Asp Glu Asp Phe His Val Ile Lys Asp Asn Asp 705 710 715 720 Gly Val Phe Ala Gly Val Asn Tyr Ser Asp Asn Thr Lys Ser Phe Asp 725 730 735 Ile Asn Gly Ile Thr Val Glu Leu Lys Glu Lys Gly Met Phe Val Ile 740 745 750 Lys Lys Lys Asp Asp Lys Ala Tyr Lys Cys Ser Phe Tyr Asn Pro Glu 755 760 765 Thr Thr Asn Thr Ala Ser Asn Ile Glu Ser Lys Ile Phe Ile Lys Gly 770 775 780 Tyr Thr Ile Thr Asn Lys Ser Val Ile Asn Ser Asn Asp Ala Gly Val 785 790 795 800 Asn Phe Glu Leu Thr Lys 805 16808PRTStaphylococcus aureus 16Met Thr Tyr Arg Met Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu 1 5 10 15 Leu Met Ala Gly Val Ile Thr Leu Asn Gly Gly Glu Phe Arg Ser Ile 20 25 30 Asp Lys His Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Thr Asp 35 40 45 Tyr Glu Lys Leu Arg Asn Ile Trp Leu Asp Val Asn Tyr Gly Tyr Asp 50 55 60 Lys Tyr Asp Glu Asn Asn Pro Asp Met Lys Lys Lys Phe Glu Ala Thr 65 70 75 80 Glu Asn Glu Ala Glu Lys Leu Leu Lys Glu Met Lys Thr Glu Ser Asp 85 90 95 Arg Lys Tyr Leu Trp Glu Ser Ser Lys Asp Leu Asp Thr Lys Ser Ala 100 105 110 Asp Met Thr Arg Thr Tyr Arg Asn Ile Glu Lys Ile Ser Glu Ala Met 115 120 125 Lys His Lys Asn Thr Lys Leu Lys Thr Asp Glu Asn Lys Thr Lys Val 130 135 140 Lys Asp Ala Leu Glu Trp Leu His Lys Asn Ala Tyr Gly Lys Glu Pro 145 150 155 160 Asp Lys Lys Val Ala Asp Leu Thr Ser Asn Phe Lys Asn Lys Thr Ser 165 170 175 Arg Asn Thr Asn Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro Arg 180 185 190 Ala Leu Thr Asn Thr Leu Ile Leu Leu Gln Glu Asp Phe Thr Asp Glu 195 200 205 Glu Lys Lys Lys Tyr Thr Ala Pro Ile Lys Thr Phe Ala Pro Asp Ser 210 215 220 Asp Lys Ile Leu Ser Ser Val Gly Lys Ser Glu Pro Ala Lys Gly Gly 225 230 235 240 Asn Leu Val Asp Ile Ser Lys Val Lys Leu Leu Glu Ser Ile Ile Glu 245 250 255 Glu Asp Lys Asp Met Met Lys Lys Ser Ile Asp Ser Phe Asn Thr Val 260 265 270 Phe Thr Tyr Ala Gln Asn Ser Ala Thr Gly Lys Glu Arg Asn Gly Phe 275 280 285 Tyr Lys Asp Gly

Ser Tyr Ile Asp His Gln Asp Val Pro Tyr Thr Gly 290 295 300 Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met Pro Met 305 310 315 320 Ile Lys Glu Thr Pro Phe Asn Asp Ser Asn Gln Asn Asp Thr Thr Leu 325 330 335 Lys Ser Trp Ile Asp Asp Gly Phe Met Pro Leu Ile Tyr Lys Gly Glu 340 345 350 Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu Thr 355 360 365 Ser His Ser Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu Ser 370 375 380 Asp Thr Met Asp Lys Ser Thr Lys Ala Lys Tyr Lys Lys Ile Val Lys 385 390 395 400 Thr Ser Val Glu Ser Asp Ser Ser Tyr Lys Gln Thr Asp Tyr Leu Ser 405 410 415 Ser Tyr Ser Asp Ile Ser Lys Met Lys Ser Leu Met Glu Asp Ser Thr 420 425 430 Ile Ser Thr Asn Gly Leu Thr Gln Gln Leu Lys Ile Tyr Asn Asp Met 435 440 445 Asp Arg Val Thr Tyr His Asn Lys Gly Leu Asp Phe Ala Phe Gly Leu 450 455 460 Ser Met Thr Ser Lys Asn Val Ala Arg Tyr Glu Ser Ile Asn Gly Glu 465 470 475 480 Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser Tyr Leu Tyr Asn 485 490 495 Ser Asp Val Lys His Tyr Arg Asp Asn Phe Trp Ala Thr Ala Asp Met 500 505 510 Lys Arg Leu Ala Gly Thr Thr Thr Leu Asp Asn Glu Glu Pro Lys Ser 515 520 525 Thr Asp Val Lys Lys Ser Ser Lys Thr Phe Val Gly Gly Thr Lys Phe 530 535 540 Asp Asp Gln His Ala Ser Ile Gly Met Asp Phe Glu Asn Gln Asp Lys 545 550 555 560 Thr Leu Thr Ala Lys Lys Ser Tyr Phe Ile Leu Asn Asp Lys Ile Val 565 570 575 Phe Leu Gly Thr Gly Ile Lys Ser Thr Asp Ser Ser Lys Asn Pro Val 580 585 590 Thr Thr Ile Glu Asn Arg Lys Ala Asn Asp Tyr Lys Leu Tyr Lys Asp 595 600 605 Asp Thr Gln Thr Thr Asn Ser Asp Asn Gln Glu Thr Asn Ser Leu Phe 610 615 620 Leu Glu Ser Thr Asn Ser Thr Gln Asn Asn Ile Gly Tyr His Phe Leu 625 630 635 640 Asn Glu Ser Lys Ile Thr Val Lys Lys Glu Ser His Thr Gly Lys Trp 645 650 655 Ser Asp Ile Asn Lys Ser Gln Lys Asp Ile Gln Lys Thr Asp Glu Tyr 660 665 670 Tyr Glu Val Thr Gln Lys His Ser Asn Thr Asp Ser Lys Tyr Ala Tyr 675 680 685 Val Leu Tyr Pro Gly Leu Ser Lys Asp Val Phe Lys Ser Lys Ala Ser 690 695 700 Lys Val Thr Val Val Lys Gln Glu Asp Asp Phe His Val Val Lys Asp 705 710 715 720 Asn Glu Ser Val Trp Ala Gly Ile Asn Tyr Ser Asp Ser Ala Lys Thr 725 730 735 Phe Glu Ile Asn Asn Thr Lys Val Glu Val Lys Ala Lys Gly Met Phe 740 745 750 Ile Leu Thr Lys Lys Asp Asp Asn Thr Tyr Glu Cys Ser Phe Tyr Asn 755 760 765 Pro Glu Ser Thr Asn Ser Val Ser Asp Ile Glu Ser Lys Ile Ser Met 770 775 780 Thr Gly Tyr Ser Ile Ile Asn Lys Asn Thr Ser Thr Ser Asn Glu Ser 785 790 795 800 Gly Val Arg Phe Glu Leu Thr Lys 805 17423DNAStaphylococcus aureus 17atggcaaaag gtaatttatt taaagcgatt ttaggtatag gtggcgctgt agcagctgta 60cttgttacac gtaaagatag tcgtgacaag ctgaaagcag aatataataa atacaaacaa 120gatcctcaaa gctataaaga taatgctaag gataaagcga cgcaattagg aacaattgca 180aatgaaacaa ttaaagaagt aaaaacaaat ccgaaagaat atgctaatag attaaaaaat 240aatccaaaag catttttcga agaagaaaaa tcaaaattta ccgaatatga caataagact 300gacgaaagta ttgaaaaagg taaatttgat gatgaaggtg gcgcagcacc aaataataat 360ttacgtatcg tcactgaaga agatttaaaa aagaataaaa atgcattgtc tgataaagaa 420taa 42318582DNAStaphylococcus aureus 18atgaaaaaat tggtttcaat tgttggcgca acattattgt tagctggatg tggatcacaa 60aatttagcac cattagaaga aaaaacaaca gatttaagag aagataatca tcaactcaaa 120ctagatattc aagaacttaa tcaacaaatt agtgattcta aatctaaaat taaagggctt 180gaaaaggata aagaaaatag taaaaaaact gcatctaata atacgaaaat taaattgatg 240aatgttacat caacatacta cgacaaagtt gctaaagctt tgaaatccta taacgatatt 300gaaaaggatg taagtaaaaa caaaggcgat aagaatgttc aatcgaaatt aaatcaaatt 360tctaatgata ttcaaagtgc tcacacttca tacaaagatg ctatcgatgg tttatcactt 420agtgatgatg ataaaaaaac gtctaaaaat atcgataaat taaactctga tttgaatcat 480gcatttgatg atattaaaaa tggctatcaa aataaagata aaaaacaact tacaaaagga 540caacaagcgt tgtcaaaatt aaacttaaat gcaaaatcat ga 58219630DNAStaphylococcus aureus 19atgaaaaaat tagttacagg gttattagca ttatcattat ttttagctgc atgtggtcaa 60gatagtgacc aacaaaaaga cagtaataaa gaaaaagatg ataaagcgaa aactgaacaa 120caagataaaa aaacaaatga ttcatctaaa gataagaaag acaataaaga tgatagtaaa 180gacgtaaaca aagataataa agataatagt gcaaacgata accagcaaca atctaattca 240aatgcaacaa acaatgacca aaatcaaacg aataataacc agtcaaacag tggacaaacg 300actaacaatc aaaaatcaag ttacgttgca ccatattatg gacaaaacgc agcgccagtg 360gctcgtcaaa tttatccatt taatggtaat aaatcacaag cattacaaca attgcctaat 420ttccaaacag ctttaaatgc agctaacaac gaagcaaata aatttggtaa tggtcataaa 480gtttataatg attattcaat tgaagaacat aatggtaact ataagtatgt ttttagtttt 540aaagacccaa acgtaaatgg aaaatattca attgtaacgg ttgattatac tggacaagca 600atggttactg atccaaacta ccaacaataa 63020729DNAStaphylococcus aureus 20atgaaaaaag taatggggat attattagca agtacactta tcttaggtgc ttgtggacat 60catcaagata gtgcaaaaaa agagagcact agtcacaaaa agaaagaaaa tgacaatgaa 120gaattaaatg aagaacttaa agaatttaaa agcaaaaaaa atatggatat aaaaattaaa 180ggcgatacta ttgttagtga caaatttgaa gctaaaataa aagaaccgtt tatcatcaat 240gaaaaagatg agaaaaagaa atatatcgct tttaaaatgg aaattactgc taaaaaagac 300gataaagatt taaatccatc ttctatttct catgactata ttaatatcac tcaagatgat 360aaaaatacag taaataaatt aagagatggt tatcttttaa gtgataaaaa ttataaagat 420tggacagaac ataaccaaga tcaaattaaa aaaggcaaaa ctgcacaagc catgtttatc 480tatgagttaa gaggtgatgg aaacattaat ttaaatgtcc ataaatactc agaagataaa 540acagttgatt ctaaatcatt caaatttagt aaacttaaaa ccgaagattt ttctcataga 600gcggaaacaa gggaagaagt agaaaagaaa gaaaaagaat ttgaagaaga gtacaaaaaa 660gaacaagaac gagagaaaga aaaagaaaag caaaaagatg acgaccacag tggtttagat 720gaagtataa 72921984DNAStaphylococcus aureus 21atgaaaaaat ggcaatttgt tggtactaca gctttaggtg caacactatt attaggtgct 60tgtggtggcg gtaatggtgg cagtggtaat agtgatttaa aaggggaagc taaaggggat 120ggctcatcaa cagtagcacc aattgtggag aaattaaatg aaaaatgggc tcaagatcac 180tcggatgcta aaatctcagc aggacaagct ggtacaggtg ctggtttcca aaaattcatt 240gcaggagata tcgacttcgc tgatgcttct agaccaatta aagatgaaga gaagcaaaaa 300ttacaagata agaatatcaa atacaaagaa ttcaaaattg cgcaagatgg tgtaacggtt 360gctgtaaata aagaaaatga ttttgtagat gaattagaca aacagcaatt aaaagcaatt 420tattctggaa aagctaaaac atggaaagat gttaatagta aatggccaga taaaaaaata 480aatgctgtat caccaaactc aagtcatggt acttatgact tctttgaaaa tgaagtaatg 540aataaagaag atattaaagc agaaaaaaat gctgatacaa atgctatcgt ttcttctgta 600acgaaaaaca aagagggaat cggatacttt ggatataact tctacgtaca aaataaagat 660aaattaaaag aagttaaaat caaagatgaa aatggtaaag caacagagcc tacgaaaaaa 720acaattcaag ataactctta tgcattaagt agaccattat tcatttatgt aaatgaaaaa 780gcattgaaag ataataaagt aatgtcagaa tttatcaaat tcgtcttaga agataaaggt 840aaagcagctg aagaaggtgg atatgtagca gcaccagaga aaacatacaa atcacaatta 900gatgatttaa aagcatttat tgataaaaat caaaaatcag acgacaagaa atctgatgat 960aaaaagtctg aagacaagaa ataa 984221074DNAStaphylococcus aureus 22atgaaaggta aatttttaaa agttagttct ttattcgttg caactttgac aacagcgaca 60cttgtgagtt ctccagcagc aaatgcgtta tcttcaaaag ctatggacaa tcatccacaa 120caaacgcaga cagacaaaca gcaaacacct aagattcaaa aaggcggtaa ccttaaacca 180ttagaacaac gtgaacgcgc taatgttata ttaccaaata acgatcgtca ccaaatcaca 240gatacaacga atggtcatta tgcacctgtt acttatattc aagttgaagc acctactggt 300acatttattg cttctggtgt agttgtaggt aaagatacac ttttaacaaa taaacacatc 360gtagatgcta cgcacggtga tcctcatgct ttaaaagcat tcgcttctgc aattaaccaa 420gacaattatc ctaatggtgg tttcactgct gaacaaatca ctaaatattc aggcgaaggt 480gatttagcaa tcgttaaatt ctcccctaat gagcaaaaca aacatattgg cgaagtagtt 540aaaccagcaa caatgagtaa taatgctgaa acacaagtta accaaaatat tactgtaaca 600ggatatcctg gtgataaacc tgtcgcaaca atgtgggaaa gtaaaggaaa aataacgtac 660ttaaaaggtg aagcaatgca atatgattta agtacaactg gtggtaactc aggttcacct 720gtatttaatg aaaaaaatga agtcattggc attcattggg gtggcgttcc aaatcaattt 780aacggtgcag tatttattaa tgaaaatgta cgcaacttct taaaacaaaa tattgaagat 840atcaatttcg caaatgatga ccaccctaac aaccctgata atccagacaa tccaaataat 900ccggacaatc ctaacaaccc tgataaccct aacaaccctg ataatccaga caatcctaat 960aatcctgata accctaacaa cccggacaat ccaaataacc ctgaccaacc taacaaccca 1020aataacccgg acaatggcga taacaataat tcagacaacc ctgacgctgc ataa 1074231200DNAStaphylococcus aureus 23atgaagcgta cattagtatt attgattaca gctatcttta tactcgctgc ttgtggtaac 60cataaggatg accaggctgg aaaagataat caaaaacata acaatagttc aaatcaagta 120aaagaaattg ctacggataa aaatgtacaa ggtgataact atcgtacatt gttaccattt 180aaagaaagcc aggcaagagg acttttacaa gataacatgg caaatagtta taatggcggc 240gactttgaag atggtttatt gaacttaagt aaagaagtgt ttccaacaga caaatatttg 300tatcaagatg gtcaattttt ggacaagaaa acaattaatg cctatttaaa tcttaagtat 360acaaaacgtg aaatcgataa aatgtctgaa aaagataaaa aagacaagaa agcgaatgaa 420aatttaggac ttaatccatc acacgaaggt gaaacagatc ctgaaaagat tgcagaaaaa 480tcaccagcct atttatctaa cattttagag caagattttt atggtggtgg agatacaaaa 540ggtaagaata ttaaaggtat gacgattggt ttagctatga atagtgttta ttactataaa 600aaagaaaaag atggaccgac ttttagtaaa aaactagatg atagcgaagt taaaaagcaa 660ggtaaacaaa tggctagtga gatattatca aggttacgtg aaaatgatga tttaaaagat 720ataccaattc attttgcaat ttataagcaa tcaagtgaag attcaatcac accaggtgaa 780tttatcactc aagcgactgc agaaaagagt caaacaaagc ttaatgaatg gcataatatc 840aatgaaaaat cagctttatt accttcttca acagcagcag attatgatga aaatttaaat 900aataatttca agcaatttaa tgataatttg caatcatatt tttctaattt cacacaagca 960gtaggaaaag ttaaatttgt tgataaaaag ccacaacgat tagtagtaga tttaccaatc 1020gattactatg gacaagctga aacaattggt attacacagt acgttactga acaagcgaat 1080aaatatttcg ataaaatcga taactatgaa attcggatta aagatggtaa ccaaccacgt 1140gctttaatta gtaagacaaa agatgacaaa gaaccgcaag ttcatattta cagtaattaa 1200241488DNAStaphylococcus aureus 24atgagggaaa attttaagtt acgtaaaatg aaagtcgggt tagtatctgt tgcaattaca 60atgttatata tcatgacaaa cggacaagca gaagcatcag aggctaatga gaagccaagt 120acaaatcaag aatcaaaagt tgtttcacag actgaacaaa attcaaaaga aacaaaaaca 180gtagaatcta ataagaactt tgttaaatta gatactatta aacctggagc tcaaaagata 240acgggaacta ctttaccaaa tcactatgtt ttattaacag ttgatgggaa aagtgcggat 300tcagtagaaa atggcggttt gggttttgtt gaagcaaatg acaaaggaga atttgagtac 360cctttaaata atcgtaaaat tgttcataat caagaaattg aggtttcgtc gtcaagccct 420gatttaggtg aagatgaaga agatgaagag gtggaagaag cttcaactga taaagctggc 480gttgaggaag aaagtacaga agctaaagtt acttacacaa caccgcgata tgaaaaagcg 540tatgaaatac cgaaagaaca actaaaagaa aaagatggac atcaccaagt ttttatcgaa 600cctattactg aaggatcagg tattattaaa gggcatacgt ctgtaaaagg taaagttgct 660ttatctatta ataataaatt tattaatttt gaagagagcg ttaagggcgg agttagtaaa 720gaagacacta aagctagttc agatggtatc tggatgccta ttgatgacaa aggatacttt 780aactttgact tcaaaacgaa acgtttcgat aatttagagt taaaagaagg taatgacatt 840tcactaacat ttgcacctga tgatgaagaa gatgcattaa aacctttaat tttcaaaact 900aaagtaacga gcttagaaga tatcgataaa gcagaaacta aatatgacca tactaaactc 960aacaaagtga aagttttaga taatgttaaa gaagatttac atgttgatga aatatatgga 1020agcttatatc atacagacaa aggtaaaggt attcttgata aagaaggtac taaagtaatt 1080aaaggaaaga ctaaattcgc gaatgcagta gtgaaggtag actctgaact aggtgaagca 1140caattattcc ctgatttaca agtaaatgaa aaaggtgaat ttagctttga ctcacatggt 1200gctggtttta gattacaaaa tggagaaaaa ttaaacttca cagtggttga tcctattaca 1260ggtgacttgt taagtaatga gtttgtttct aaagagattg atattgaaga aacacctgaa 1320caaaaagcgg atcgtgagtt tgacgaaaaa cttgaaaata cgcctgctta ctacaagtta 1380tacggcgata aaatagttgg attcgatact aacgatttcc cgattacttg gttctatcca 1440ttgggtgaaa agaaagttga acgtacaaca cctaaattag aaaaataa 1488251524DNAStaphylococcus aureus 25atgtctaaaa agttaaaaat tataattcct attattattg tcttattatt aataggtgga 60atcgcatggg gagtttatgc attttttgca aacacaccga aaaatacata cttaaaaagt 120gaacaacaaa ctgcaaaaat gtataaagat tattttaatg accgttttga aaacgaagtg 180aagttccaag aaaagatgaa agataattca tttttatctt cattagaatt aagcgcagat 240gcatctgatg aaattgttaa agggcttggt attcctaaat ctgttgttaa tgcttcgaaa 300attaaaatgt catatggaca tgatcctaaa aaagagaaat caatgattaa tcttgaacca 360acaatagcag actctgcatt agggaaattc cagttagctg cagataaaga taagcattat 420ttcgaatcac cattatttaa agggaaatat agtgttaata attctgattt attatcaact 480tattcaaaac ttacaggtga agatgaagaa acagcaaaag aaaatggtat tacaaaccaa 540caactaaatt taaatactct tttcagtaat gctcaagcac aacaaagtga ctacagcaaa 600attgccgaaa aatattccga acttattgtc gacaaattag atgacgataa ttttgataaa 660ggtaaaaaag aagaaattaa ggttaatggt gaaaagtaca aagttagacc tgtcacgtta 720acacttagca gagctgacac taaaaaaatt acattagctg tattagaaga agctaaaaag 780gataaagacc ttaaaaaatt aatggaagaa caaggtacta caaaagactt tgaaaaagac 840attaaaaaag caattgacga tgtcaaagaa actaaaaagg atgaatttgc taaaattcaa 900tctaaaattt ataccgaaaa acatacgatt gtaaaacgag aaattactat tacagacaaa 960gaaaataata aaactaaaat caaaggtact aatactttag aagacgataa gttaaaacta 1020gattacgcac ttgatttcga tcaagataaa tacacgtatg ctgaagcgaa atatacaatt 1080aaaggcgtat cttctaagga aaaagacaat aaatacagtg ataaatacga atttggtaaa 1140aagacagaat atgatgaatc aaaaatcaaa ttagataacc aagaaaaagt agatggcaca 1200aaacgtcaag ataaaggtaa aatcactgtc gcgttagata aatatagcga cgaaaatgaa 1260ttcacttttg aaaataatat agattctgac gtaaaaaata acactcagaa atctacgtta 1320aatatcggca tcaaatatgc tgaagaacca attaatttca ttttaaaatc tagcacaaaa 1380ttgaaagcag atattgattt tgatgatagt ggtgcgaaag atttcaatag tctatcttca 1440aaagaccgtg aaaaacttga aaaagaaatc gaaaaaaatg gcggcaaaat gtttgaatca 1500attttaaaaa aggcatctaa ataa 1524261530DNAStaphylococcus aureus 26gtgaggaaat tttcaagata tgcatttaca agtatggcaa cagtaacgtt gctgagctct 60ttgacacctg cagcactagc gagtgatacg aatcacaaac cagcaacttc agatattaat 120tttgaaatca cgcaaaagag tgatgcagtt aaagcattaa aagagttacc taaatctgaa 180aatgtgaaaa atcattatca agattactct gttacagatg taaaaacaga taagaaagga 240ttcacgcatt acacgttaca accgagtgtg gatggtgtgc atgcgcctga caaagaagtg 300aaagtgcatg cggacaaatc gggtaaagtc gttttaatca acggtgatac tgatgcgaag 360aaagtaaagc cgacaaataa agtgacatta agcaaggatg aagcggctga caaagcattt 420aacgcagtta agattgataa aaataaagct aaaaacctcc aagatgacgt tatcaaagaa 480aataaagtcg aaatcgatgg tgacagtaat aaatacattt acaatattga attaattaca 540gtaacaccag aaatttcaca ttggaaagtt aaaattgatg cagacacagg agcagttgtt 600gaaaaaacga acttagttaa agaagcagca gcaactggca caggtaaagg tgtgcttgga 660gatacaaaag atatcaatat caatagtatt gatggtggat ttagtttaga ggatttgacg 720catcaaggta aattatcagc atacaatttt aacgatcaaa caggtcaagc gacattaatt 780actaatgaag atgaaaactt cgtcaaagat gatcaacgtg ctggtgtaga tgcgaattat 840tatgctaaac aaacatatga ttactacaaa aatacatttg gtcgtgagtc ttacgataac 900catggtagtc caatagtctc attaacacat gtaaatcatt atggtggaca agataacaga 960aataacgctg catggattgg agacaaaatg atttatggtg atggcgatgg ccgcacgttt 1020acaaatttat caggtgcaaa tgacgtagta gcacatgagt taacacatgg cgtgacacaa 1080gaaacggcga atttagagta taaagatcaa tctggtgcgt taaatgaaag cttttcagat 1140gtttttggat actttgtaga tgatgaggat ttcttgatgg gtgaagatgt ttacacacca 1200ggaaaagagg gagatgcttt acgaagcatg tcaaacccag aacaatttgg tcaaccatct 1260catatgaaag actatgtata cactgaaaaa gataacggtg gtgtgcatac gaattctggc 1320attccaaata aagcagctta taacgtaatt caagcaatag ggaaatctaa atcagaacaa 1380atttactacc gagcattaac ggaatactta acaagtaatt caaacttcaa agattgtaaa 1440gatgcattat accaagcggc taaagattta tatgacgagc aaacagctga acaagtatat 1500gaagcatgga acgaagttgg cgtcgagtaa 1530271548DNAStaphylococcus aureus 27atgaaaaaga aattaggtat gttacttctt gtaccagccg taactttatc attagccgca 60tgtgggaatg atgatggaaa agataaagat ggcaaggtaa caattaaaac gacagtttat 120ccattgcaat catttgcaga gcaaattggt ggaaaacacg tgaaggtatc atcaatctat 180ccagcaggga cagatttaca tagctatgaa ccaacacaaa aagatatatt aagtgcaagc 240aagtcagact tgtttatgta tacaggggat aatttagatc cggttgctaa gaaagttgca 300tctactatta aagataaaga taaaaaactg tctttagaag ataaattaga taaagcaaag 360cttttaactg atcaacacga acatggtgaa gagcatgaac atgagggaca tgatcatggg 420aaagaagaac atcatcatca tggcggatat gatccacacg tatggttaga tcctaaaatt 480aaccaaactt tcgctaaaga aattaaagat gaattagtga agaaagatcc aaaacataaa 540gatgactatg agaaaaacta caaaaaatta aacgacgatc ttaagaaaat tgataacgat 600atgaagcaag ttactaaaga taagcaaggt aatgcagtat tcatttcaca tgaatcaatt 660ggatacttag ctgatcgtta tggttttgtt caaaaaggta ttcaaaacat gaatgctgaa 720gatccatcac aaaaagaatt gactaaaatt gttaaagaaa ttagagatag caatgctaaa 780tatattcttt acgaagataa tgttgcgaat aaagtgactg aaacaattcg taaagaaaca 840gatgcgaagc ctttaaaatt ctacaacatg gagtctttaa ataaagaaca acagaaaaaa

900gataatatta cctatcaatc attaatgaaa tcgaatattg aaaatatcgg taaagcttta 960gacagtggtg ttaaagtgaa agacgacaaa gctgaaagta aacacgacaa agcaatttct 1020gatgggtatt ttaaagatga gcaagttaaa gaccgtgaat taagcgatta tgctggtgaa 1080tggcaatctg tttaccctta cttaaaagac ggtacgcttg atgaagtgat ggaacataaa 1140gctgaaaatg atccgaagaa atctgctaaa gatttaaaag cttattatga caaaggatat 1200aaaactgata ttactaacat tgatataaaa ggaaatgaaa ttacatttac taaagatggt 1260acgaaacaca ctggtaaata tgaatacaat ggtaagaaaa cattgaaata tcctaaaggt 1320aaccgtggcg tgagatttat gtttaaattg gtcgatggta atgataaaga cttaccgaaa 1380ttcatccaat ttagcgatca caacattgca cctaaaaagg cagaacactt ccatatcttt 1440atgggtaatg ataatgacgc gttattaaaa gaaatggata actggccaac atattatcct 1500tcaaaattaa ataaagacca aatcaaagaa gaaatgttag cgcattaa 1548281695DNAStaphylococcus aureus 28atggtgttat atatcatttt ggcaataatt gtgattatat tgattgctgt aggtgtatta 60ttctatttac gttcaaataa aagacaaata atagaaaaag caatcgaacg taaaaatgaa 120attgaaacgt taccttttga tcaaaacctt gcacaattat ctaagttgaa tttaaaaggt 180gaaacaaaaa cgaaatacga tgcaatgaaa aaggacaacg tagaaagtac aaataagtat 240ctagctcctg tggaagaaaa aatccataat gctgaggctt tattagataa atttagtttc 300aacgcatctc aatgtgaaat tgatgatgca aatgagttga tggatagtta cgaacaaagc 360tatcagcaac aattagaaga tgtaaatgaa attattgcgt tatacaaaga taatgatgaa 420ttatatgaca aatgtaaggt tgattatcgt gaaatgaaac gtgatgtttt agcaaatcgt 480catcaatttg gtgaggcagc aagtcttctt gaaactgaaa ttgaaaaatt cgagccaagg 540ttagagcaat atgaagtact aaaagctgat ggtaattatg tacaagcgca caaccatata 600gctgccttga atgaacaaat gaaacagcta agatcttata tggaagaaat accagaatta 660attagagaaa ctcaaaaaga attacctggt caattccaag atttaaaata tggttgccgt 720gatcttaaag ttgaagggta tgatctggat cacgtaaaag tagacagtac attacaaagc 780ttaaaaacag agcttagttt cgttgaacca ttaattagtc gcttagaatt agaagaagct 840aatgataaac tagctaatat caatgataag ttagatgaca tgtatgattt aattgaacat 900gaagttaaag ctaaaaatga tgtcgaagaa acaaaagata tcattacgga taacttattc 960aaagcaaaag acatgaatta tacattgcaa acagaaattg aatatgtacg tgaaaactac 1020tatataaatg aatctgatgc tcagagtgtt cgtcaatttg aaaatgaaat tcaaagttta 1080atttctgtat atgatgatat tttaaaagaa atgtctaaat ctgctgtacg atatagcgag 1140gttcaggata atttacaata tttagaagat catgtcacag ttattaatga caaacaagaa 1200aagctacaaa atcatctgat tcaattgcgt gaagatgaag cagaagcaga agacaatctg 1260ttacgagtac aatcgaagaa agaagaagtg tatcgtcgat tacttgcttc taacttaaca 1320agcgttcctg aaaggtttat catcatgaaa aatgaaattg atcatgaagt tcgtgatgtt 1380aacgaacaat ttagtgaacg tccaatacac gttaaacagt taaaagataa agtgtctaaa 1440attgtgattc aaatgaatac atttgaagat gaagcaaatg atgttcttgt taatgctgtt 1500tatgcagaga aattaattca atatggaaat agatatcgta aggactatag caatgttgat 1560aagagcttaa atgaagctga acgattattt aaaaataatc gctataagcg tgcgattgaa 1620attgcagagc aagctcttga aagtgttgag ccaggtgtca ctaaacatat tgaagaagaa 1680gttattaagc aatag 1695291860DNAStaphylococcus aureus 29atgcctaaaa ataaaatttt aatttatttg ctatcaacta cgctcgtatt acctacttta 60gtttcaccta ccgcttatgc tgacacacct caaaaagata ctacagctaa gacaacatct 120catgattcca aaaaatctac tgatgatgaa acttctaagg atactacaag taaagatatt 180gataaagcag acaacaataa tactagtaac caagacaata acgacaaaaa agttaaaact 240atagacgaca gcacttcaga ctctaacaat atcattgatt ttatttataa gaatttacca 300caaaccaata taaaccaatt gctaaccaaa aataaatacg atgataatta ctcattaaca 360actttaatcc aaaacttatt caatttaaat tcggatattt ctgattacga acaacctcgt 420aatggtgaaa agtcaacaaa tgattcgaat aaaaacagtg ataatagcat caaaaatgat 480acggatacgc aatcatctaa acaagataaa gcagacaatc aaaaagcacc taaatcaaac 540aatacaaaac caagtacatc taataagcaa ccaaattcgc caaagccaac acaaccaaat 600caatcaaata gtcaaccagc aagtgacgat aaagtaaatc aaaaatcttc atcgaaagat 660aatcaatcaa tgtcagattc ggctttagat tctattttgg atcaatacag tgaagatgca 720aagaaaacac aaaaagatta cgcatctcaa tctaaaaaag acaaaaatga aaaatctaat 780acaaagaatc cacagttacc aacacaagat gaattgaaac ataaatctaa acctgctcaa 840tcattcaata acgatgttaa tcaaaaggat acacgtgcaa catcactatt cgaaacagat 900cctagtatat ctaacaatga tgatagtgga caatttaacg ttgttgactc aaaagataca 960cgtcaatttg tcaaatcaat tgctaaagat gcacaccgca ttggtcaaga taacgatatt 1020tatgcgtctg tcatgattgc ccaagcaatc ttagaatctg actcaggtcg tagtgcttta 1080gctaagtcac caaaccataa tttattcggt atcaaaggtg cttttgaagg gaattctgtt 1140ccttttaaca cattagaagc tgatggtaat caattgtata gtattaatgc tggattccga 1200aaatatccaa gcacgaaaga atcactaaaa gattactctg accttattaa aaatggtatt 1260gatggcaatc gaacaattta taaaccaaca tggaaatcgg aagccgattc ttataaagat 1320gcaacatcac acttatctaa aacatatgct acagatccaa actatgctaa gaaattaaac 1380agtattatta aacactatca attaactcag tttgacgatg aacgtatgcc agatttagat 1440aaatatgaac gttctatcaa ggattatgat gattcatcag atgaattcaa acctttccgc 1500gaggtatctg ataatatgcc atatccacat ggccaatgta cttggtacgt atataaccgt 1560atgaaacaat ttggtacatc tatctcaggt gatttaggtg atgcacataa ttggaataat 1620cgagctcaat accgtgatta tcaagtaagt catacaccaa aacgtcatgc tgctgttgta 1680tttgaggctg gacaatttgg tgcagatcaa cattacggtc atgtagcatt tgttgaaaaa 1740gttaacagtg atggttctat cgttatttca gaatccaatg ttaaaggatt aggtatcatt 1800tctcatagaa ctatcaatgc agctgccgct gaagaattat catatattac aggtaaataa 1860302046DNAStaphylococcus aureus 30atgatgaaaa gtcaaaataa gtatagtatt cgtaaattta gtgtaggtgc atcttccatt 60ttaatagcta cattactatt tttaagtggt ggacaagcac aagcagctga gaagcaagtg 120aatatgggaa attcacagga ggatacagtt acagcacaat ctattgggga tcaacaaact 180agggaaaatg ctaattatca acgtgaaaac ggtgttgacg aacagcaaca tactgaaaat 240ttaactaaga acttgcataa tgataaaaca atatcagaag aaaatcatcg taaaacagat 300gatttgaata aagatcaact aaaggatgat aaaaaatcat cgcttaataa taaaaatatt 360caacgtgata caacaaaaaa taacaatgct aatcctaggg atgtaaatca agggttagaa 420caggctatta atgatggcaa acaaagtaaa gtggcgtcac agcaacagtc aaaagaggca 480gataatagtc aagacttaaa cgctaataac aatctacctt cacaaagtcg aacaaaggta 540tcaccatcat taaataagtc agatcaaaca agtcaacgag aaattgttaa tgagacagaa 600atagagaaag tacaaccgca acaaaagaat caagcgaatg ataaaattac tgaccacaat 660tttaacaatg aacaagaagt gaaacctcaa aaagacgaaa aaacactatc agtttcagat 720ttaaaaaaca atcaaaaatc accagttgaa ccaacaaagg acaatgacaa gaaaaatgga 780ttaaatttat taaaaagtag tgcagtagca acgttaccaa acaaagggac aaaggaactt 840actgcaaaag cgaaaggtga tcaaacgaat aaagttgcca aacaagggca gtataaaaat 900caagatccta tagttttagt gcatggtttc aatgggttta cagatgatat taatccttca 960gtgttagctc attattgggg cggtaataaa atgaacattc gccaagattt agaagaaaat 1020ggttacaaag cttatgaagc aagtataagt gcttttggaa gtaactatga ccgcgcagtt 1080gaactttatt attatatcaa aggcggtcgt gtagattatg gtgcagcaca tgcagcaaaa 1140tatggacatg aacgttatgg aaaaacatac gaaggaattt acaaagactg gaaaccagga 1200cagaaggtac accttgttgg acatagtatg ggtggtcaaa cgatacgtca actagaagaa 1260ttactgcgta atggtagtcg tgaagaaata gagtatcaaa agaaacatag tggcgaaatt 1320tctccactat tcaaaggtaa taatgacaat atgatttcat caattactac tttaggaacg 1380ccacataatg gaacgcatgc ttcagattta gctggtaatg aagctttagt gagacaaatt 1440gtatttgata tcggtaaaat gtttggtaat aaaaattcaa gagtagactt cgggttggct 1500caatggggtc taaaacagaa gccaaatgaa tcatatattg attatgtcaa acgcgttaaa 1560caatctaatt tatggaaatc aaaagataat ggattttacg atctgacgcg tgagggtgca 1620acagatttaa atcgtaaaac gtcgttgaac cctaacattg tgtataaaac atacactggt 1680gaagcaacgc acaaagcatt aaatagcgat agacaaaaag cagacttaaa tatgtttttc 1740ccatttgtga ttactggtaa cttaatcggt aaagctactg aaaaagaatg gcgagaaaac 1800gatggtttag tatccgttat ttcttctcaa catccattta atcaagctta tacaaatgcg 1860acggataaaa ttcaaaaagg catttggcaa gtaacgccta caaaacatga ttgggatcat 1920gttgattttg tcggacaaga tagttctgat acagtgcgca caagagaaga attacaagat 1980ttttggcatc atttagcaga cgatttagtg aaaactgaaa aggtgactga tactaagcaa 2040gcataa 2046312421DNAStaphylococcus aureus 31atgacaaata aaatgaagaa atggcaaaaa ttatccacca ttacgttatt aatgaccgga 60gtgattgctt taaataatgg tgaatttaga aatgttgata aacatcaaat cgctgtggct 120gatacgaatg ttcaaacgcc agattatgaa aaattgaaga agacgtggct cgacgttaac 180tacggttatg atcagtatga tgagaataat caagatatga agaagaagtt tgatgctaaa 240gaaaaagaag ccaagaagtt acttgatgac atgaaaactg atacgaatag aacatatttg 300tggtcaggag ctgaaaacct tgaaactaat tcttctcaca tgacaaaaac ctatcgtaat 360atcgagaaaa tcgcagaatc aatgcaacat aagaatacgg tattaaaaac agttgaaaac 420aagttgaaaa taaaagaagc cctagattgg atgcacaaaa atgtttatgg caagaatcct 480tctcaaaaag tcgaggattt aactaaaaat cgtaaggggc aaactacacc caagaataac 540tcattgaatt ggtgggatta tgaaattggt acgccaagag cattaacaaa tacactactt 600ctaatggatg atatgctcac taaagatgaa atgaaaaatt attcaaaacc tattagtaca 660tatgcaccat ccagtgacaa aattttatct tctgttggtg aatcagaaga tgctaaaggt 720ggaaatttag tggacatttc taaagtaaaa cttttagaaa gtgttattga agaagatgta 780gatatgttga aaaagtctat agattctttt aataaagtgt tcacttatgt tcaagattct 840gccactggta aaggtcgcaa tggattctat aaagatggct cttacattga tcatcaagat 900gtcccttaca ctggtgctta tggtgttgta ctattagagg gtatttctca aatgatgccg 960atgataaaag aatctccttt taaaactaca caagataatg ctacattaag caattggatt 1020gacgaagggt ttatgccatt aatctataaa ggtgaaatga tggatttatc acgaggtaga 1080gctatcagtc gtgaaaatga aacgagtcat acagcgtcag cgactgtaat gaaatcattg 1140ttgagattga atgataccat ggatgattca acaaaaacta gatataagca aatcgttaaa 1200acttctgtta attctgattc aagttacaac caaaataatt atttaaattc atattcagac 1260atagctaaaa tgaaaaagtt aatgaatgat agtactattt ctaaaaacga tttaacacag 1320caacttaaaa tatataatga catggatcgt gtcacctatc acaataaaga cctggacttt 1380gcatttggtt taagtatgac atcgaaaaac atcgcacgat acgaaaatat caacggagag 1440aacttaaaag gttggcacac cggtgcaggc atgtcttatt tatataacag cgatgtcaaa 1500cactatcgcg ataacttctg ggcaacagcc gatatgactt gtcttccagg cactactact 1560ttaaatgata tgccatctac taatactaag aatgataaat cttttgttgg cgggacaaaa 1620ttaaataata aatacgcaag catcggtatg gattttgaaa atcaggacaa aactttaact 1680gccaaaaaat catatttcat attaaacgat aaaattgtct tcttaggaac tggcattaaa 1740agtactgatt catcaaagaa tccagttaca agtgttgaaa atcgcaaagc aaatgggtat 1800aaattattta aagatgatat tgaaattacc acttcagatg ttaatgctca ggaaacccat 1860tcagtctttt tagagtccaa cgatactaaa aagaacattg gttatcattt cttagacaag 1920ccaaaaataa ctgtaaaaaa agaaagtcat actggtaagt ggagtgaaat taataaaagt 1980caaaaaaaag atgacaaaaa agatgagtat tatgaagtaa ctcaaacaca taatacatct 2040gacagtaaat atgcatatgt tttgtatcct ggtttatcaa aaagtgattt taaatcgaag 2100aataataatg taagtattgt taaacaagat gaagattttc atgtgataaa agataatgat 2160ggcgtatttg ctggggttaa ttatagtgat aatactaaat cttttgatat aaacggaatt 2220actgttgaat taaaagaaaa aggcatgttt gtaattaaaa agaaagatga taaagcatat 2280aaatgtagct tctataatcc tgaaactaca aataccgctt caaatataga atcaaaaatt 2340tttattaaag gttacaccat aactaataaa agtgtcataa actctaatga tgctggtgta 2400aactttgaat taactaaata a 2421322427DNAStaphylococcus aureus 32atgacatata gaatgaagaa atggcaaaaa ttgtccacca ttacgttatt aatggctggt 60gtgattactt tgaatggtgg tgaattcaga agtattgata aacatcaaat cgctgtggct 120gatacgaatg ttcaaacgac agattatgaa aagttgagga acatatggct ggacgttaac 180tatggttatg ataagtatga tgagaataat ccagatatga agaagaagtt tgaggctacg 240gagaatgagg cagagaaatt actcaaggaa atgaaaactg aaagtgatag gaaatacttg 300tgggaaagct caaaagattt agatacgaag tctgcggata tgactcgtac ctatcgtaat 360attgagaaaa tctcagaagc gatgaaacat aaaaatacta aattaaaaac agatgaaaac 420aagacaaaag taaaagatgc acttgagtgg ctgcataaaa atgcatatgg aaaagaacca 480gataaaaaag ttgctgattt gacctcaaac tttaaaaata aaacttctag aaataccaac 540ttaaattggt gggattatga aattggaaca cctagagcat taacaaatac gcttatactc 600ttacaagaag atttcactga tgaagaaaag aaaaaatata cagctcctat taaaactttc 660gccccagata gtgacaaaat attatcttct gtaggaaaat ctgaacctgc taaaggcgga 720aatttagtag acatttctaa agtaaaactt ttagaaagta ttatcgaaga agacaaagat 780atgatgaaaa agtctataga ttcatttaat acagtcttca cttacgcgca aaattctgcc 840actggaaaag aacgtaatgg attctataaa gatggctctt acattgatca tcaagacgtc 900ccatacactg gtgcttatgg cgttgtacta ttagagggta tttctcaaat gatgccgatg 960ataaaagaaa caccttttaa tgatagtaac caaaatgata caaccttaaa atcatggatt 1020gacgacggat ttatgccact catttataaa ggtgaaatga tggatttatc aagaggtaga 1080gctatcagtc gtgaaaatga aacgagtcac tcagcatctg caacagtaat gaaatcattg 1140ttgagattga gtgataccat ggataagtct acaaaagcta aatataaaaa gattgtcaag 1200acttcagtag agtcagattc aagttataaa caaaccgatt atttaagctc ttattcggat 1260ataagcaaaa tgaagtcttt aatggaagac agcactattt ctactaacgg tttaacacaa 1320caacttaaaa tatataatga catggatcgt gtcacctatc acaataaagg cttagacttt 1380gcatttggtt taagtatgac gtcgaaaaac gtcgcacgtt acgaaagtat caacggagag 1440aacttaaaag gttggcacac tggtgctgga atgtcttatt tatacaatag cgatgtgaaa 1500cactaccgtg ataacttctg ggcgacagct gatatgaaac gtttagcagg tactacaact 1560ttagataatg aagaacctaa aagtacggat gttaaaaagt ctagtaaaac ttttgtagga 1620ggaacaaaat tcgatgacca acatgctagt atcggaatgg attttgaaaa tcaggacaaa 1680actttaactg ccaaaaaatc atatttcata ttaaacgata aaattgtctt cttaggaact 1740ggcattaaaa gtactgattc atcaaagaat ccagttacaa cgattgaaaa tcgcaaagcg 1800aatgattata aattatataa agatgatacg caaacaacca attccgataa tcaggaaacc 1860aattccctct ttttagagtc aacgaatagc actcaaaaca atataggtta tcatttttta 1920aacgaatcga aaataactgt aaaaaaagaa agtcatactg gtaagtggag tgatataaat 1980aaaagccaaa aggatataca aaaaactgat gagtattatg aagtaactca aaagcattct 2040aatacagata gtaaatatgc atatgtgttg tatccaggct tatctaaaga tgtctttaaa 2100tccaaagcaa gcaaagtaac tgtcgttaag caagaagatg acttccacgt tgtgaaagat 2160aatgaatcgg tttgggctgg tatcaattat agtgatagcg ctaaaacttt tgaaattaat 2220aacactaaag tcgaagttaa agccaaagga atgtttattc ttacaaagaa agatgataac 2280acttatgaat gtagcttcta taatcccgaa tctacaaatt ccgtttcaga tattgaatct 2340aaaatttcaa tgactggata ctctattata aacaaaaata cgtcgacttc taatgaatcc 2400ggcgtacgct ttgaattaac taaataa 242733423RNAStaphylococcus aureus 33auggcaaaag guaauuuauu uaaagcgauu uuagguauag guggcgcugu agcagcugua 60cuuguuacac guaaagauag ucgugacaag cugaaagcag aauauaauaa auacaaacaa 120gauccucaaa gcuauaaaga uaaugcuaag gauaaagcga cgcaauuagg aacaauugca 180aaugaaacaa uuaaagaagu aaaaacaaau ccgaaagaau augcuaauag auuaaaaaau 240aauccaaaag cauuuuucga agaagaaaaa ucaaaauuua ccgaauauga caauaagacu 300gacgaaagua uugaaaaagg uaaauuugau gaugaaggug gcgcagcacc aaauaauaau 360uuacguaucg ucacugaaga agauuuaaaa aagaauaaaa augcauuguc ugauaaagaa 420uaa 42334582RNAStaphylococcus aureus 34augaaaaaau ugguuucaau uguuggcgca acauuauugu uagcuggaug uggaucacaa 60aauuuagcac cauuagaaga aaaaacaaca gauuuaagag aagauaauca ucaacucaaa 120cuagauauuc aagaacuuaa ucaacaaauu agugauucua aaucuaaaau uaaagggcuu 180gaaaaggaua aagaaaauag uaaaaaaacu gcaucuaaua auacgaaaau uaaauugaug 240aauguuacau caacauacua cgacaaaguu gcuaaagcuu ugaaauccua uaacgauauu 300gaaaaggaug uaaguaaaaa caaaggcgau aagaauguuc aaucgaaauu aaaucaaauu 360ucuaaugaua uucaaagugc ucacacuuca uacaaagaug cuaucgaugg uuuaucacuu 420agugaugaug auaaaaaaac gucuaaaaau aucgauaaau uaaacucuga uuugaaucau 480gcauuugaug auauuaaaaa uggcuaucaa aauaaagaua aaaaacaacu uacaaaagga 540caacaagcgu ugucaaaauu aaacuuaaau gcaaaaucau ga 58235630RNAStaphylococcus aureus 35augaaaaaau uaguuacagg guuauuagca uuaucauuau uuuuagcugc auguggucaa 60gauagugacc aacaaaaaga caguaauaaa gaaaaagaug auaaagcgaa aacugaacaa 120caagauaaaa aaacaaauga uucaucuaaa gauaagaaag acaauaaaga ugauaguaaa 180gacguaaaca aagauaauaa agauaauagu gcaaacgaua accagcaaca aucuaauuca 240aaugcaacaa acaaugacca aaaucaaacg aauaauaacc agucaaacag uggacaaacg 300acuaacaauc aaaaaucaag uuacguugca ccauauuaug gacaaaacgc agcgccagug 360gcucgucaaa uuuauccauu uaaugguaau aaaucacaag cauuacaaca auugccuaau 420uuccaaacag cuuuaaaugc agcuaacaac gaagcaaaua aauuugguaa uggucauaaa 480guuuauaaug auuauucaau ugaagaacau aaugguaacu auaaguaugu uuuuaguuuu 540aaagacccaa acguaaaugg aaaauauuca auuguaacgg uugauuauac uggacaagca 600augguuacug auccaaacua ccaacaauaa 63036729RNAStaphylococcus aureus 36augaaaaaag uaauggggau auuauuagca aguacacuua ucuuaggugc uuguggacau 60caucaagaua gugcaaaaaa agagagcacu agucacaaaa agaaagaaaa ugacaaugaa 120gaauuaaaug aagaacuuaa agaauuuaaa agcaaaaaaa auauggauau aaaaauuaaa 180ggcgauacua uuguuaguga caaauuugaa gcuaaaauaa aagaaccguu uaucaucaau 240gaaaaagaug agaaaaagaa auauaucgcu uuuaaaaugg aaauuacugc uaaaaaagac 300gauaaagauu uaaauccauc uucuauuucu caugacuaua uuaauaucac ucaagaugau 360aaaaauacag uaaauaaauu aagagauggu uaucuuuuaa gugauaaaaa uuauaaagau 420uggacagaac auaaccaaga ucaaauuaaa aaaggcaaaa cugcacaagc cauguuuauc 480uaugaguuaa gaggugaugg aaacauuaau uuaaaugucc auaaauacuc agaagauaaa 540acaguugauu cuaaaucauu caaauuuagu aaacuuaaaa ccgaagauuu uucucauaga 600gcggaaacaa gggaagaagu agaaaagaaa gaaaaagaau uugaagaaga guacaaaaaa 660gaacaagaac gagagaaaga aaaagaaaag caaaaagaug acgaccacag ugguuuagau 720gaaguauaa 72937984RNAStaphylococcus aureus 37augaaaaaau ggcaauuugu ugguacuaca gcuuuaggug caacacuauu auuaggugcu 60ugugguggcg guaauggugg cagugguaau agugauuuaa aaggggaagc uaaaggggau 120ggcucaucaa caguagcacc aauuguggag aaauuaaaug aaaaaugggc ucaagaucac 180ucggaugcua aaaucucagc aggacaagcu gguacaggug cugguuucca aaaauucauu 240gcaggagaua ucgacuucgc ugaugcuucu agaccaauua aagaugaaga gaagcaaaaa 300uuacaagaua agaauaucaa auacaaagaa uucaaaauug cgcaagaugg uguaacgguu 360gcuguaaaua aagaaaauga uuuuguagau gaauuagaca aacagcaauu aaaagcaauu 420uauucuggaa aagcuaaaac auggaaagau guuaauagua aauggccaga uaaaaaaaua 480aaugcuguau caccaaacuc aagucauggu acuuaugacu ucuuugaaaa ugaaguaaug 540aauaaagaag auauuaaagc agaaaaaaau gcugauacaa augcuaucgu uucuucugua 600acgaaaaaca aagagggaau cggauacuuu ggauauaacu ucuacguaca aaauaaagau 660aaauuaaaag aaguuaaaau caaagaugaa aaugguaaag caacagagcc uacgaaaaaa 720acaauucaag auaacucuua ugcauuaagu agaccauuau ucauuuaugu aaaugaaaaa 780gcauugaaag auaauaaagu aaugucagaa uuuaucaaau ucgucuuaga agauaaaggu 840aaagcagcug aagaaggugg auauguagca gcaccagaga aaacauacaa aucacaauua 900gaugauuuaa aagcauuuau ugauaaaaau caaaaaucag acgacaagaa aucugaugau

960aaaaagucug aagacaagaa auaa 984381074RNAStaphylococcus aureus 38augaaaggua aauuuuuaaa aguuaguucu uuauucguug caacuuugac aacagcgaca 60cuugugaguu cuccagcagc aaaugcguua ucuucaaaag cuauggacaa ucauccacaa 120caaacgcaga cagacaaaca gcaaacaccu aagauucaaa aaggcgguaa ccuuaaacca 180uuagaacaac gugaacgcgc uaauguuaua uuaccaaaua acgaucguca ccaaaucaca 240gauacaacga auggucauua ugcaccuguu acuuauauuc aaguugaagc accuacuggu 300acauuuauug cuucuggugu aguuguaggu aaagauacac uuuuaacaaa uaaacacauc 360guagaugcua cgcacgguga uccucaugcu uuaaaagcau ucgcuucugc aauuaaccaa 420gacaauuauc cuaauggugg uuucacugcu gaacaaauca cuaaauauuc aggcgaaggu 480gauuuagcaa ucguuaaauu cuccccuaau gagcaaaaca aacauauugg cgaaguaguu 540aaaccagcaa caaugaguaa uaaugcugaa acacaaguua accaaaauau uacuguaaca 600ggauauccug gugauaaacc ugucgcaaca augugggaaa guaaaggaaa aauaacguac 660uuaaaaggug aagcaaugca auaugauuua aguacaacug gugguaacuc agguucaccu 720guauuuaaug aaaaaaauga agucauuggc auucauuggg guggcguucc aaaucaauuu 780aacggugcag uauuuauuaa ugaaaaugua cgcaacuucu uaaaacaaaa uauugaagau 840aucaauuucg caaaugauga ccacccuaac aacccugaua auccagacaa uccaaauaau 900ccggacaauc cuaacaaccc ugauaacccu aacaacccug auaauccaga caauccuaau 960aauccugaua acccuaacaa cccggacaau ccaaauaacc cugaccaacc uaacaaccca 1020aauaacccgg acaauggcga uaacaauaau ucagacaacc cugacgcugc auaa 1074391200RNAStaphylococcus aureus 39augaagcgua cauuaguauu auugauuaca gcuaucuuua uacucgcugc uugugguaac 60cauaaggaug accaggcugg aaaagauaau caaaaacaua acaauaguuc aaaucaagua 120aaagaaauug cuacggauaa aaauguacaa ggugauaacu aucguacauu guuaccauuu 180aaagaaagcc aggcaagagg acuuuuacaa gauaacaugg caaauaguua uaauggcggc 240gacuuugaag augguuuauu gaacuuaagu aaagaagugu uuccaacaga caaauauuug 300uaucaagaug gucaauuuuu ggacaagaaa acaauuaaug ccuauuuaaa ucuuaaguau 360acaaaacgug aaaucgauaa aaugucugaa aaagauaaaa aagacaagaa agcgaaugaa 420aauuuaggac uuaauccauc acacgaaggu gaaacagauc cugaaaagau ugcagaaaaa 480ucaccagccu auuuaucuaa cauuuuagag caagauuuuu augguggugg agauacaaaa 540gguaagaaua uuaaagguau gacgauuggu 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uaagcauuau 420uucgaaucac cauuauuuaa agggaaauau aguguuaaua auucugauuu auuaucaacu 480uauucaaaac uuacagguga agaugaagaa acagcaaaag aaaaugguau uacaaaccaa 540caacuaaauu uaaauacucu uuucaguaau gcucaagcac aacaaaguga cuacagcaaa 600auugccgaaa aauauuccga acuuauuguc gacaaauuag augacgauaa uuuugauaaa 660gguaaaaaag aagaaauuaa gguuaauggu gaaaaguaca aaguuagacc ugucacguua 720acacuuagca gagcugacac uaaaaaaauu acauuagcug uauuagaaga agcuaaaaag 780gauaaagacc uuaaaaaauu aauggaagaa caagguacua caaaagacuu ugaaaaagac 840auuaaaaaag caauugacga ugucaaagaa acuaaaaagg augaauuugc uaaaauucaa 900ucuaaaauuu auaccgaaaa acauacgauu guaaaacgag aaauuacuau uacagacaaa 960gaaaauaaua aaacuaaaau caaagguacu aauacuuuag aagacgauaa guuaaaacua 1020gauuacgcac uugauuucga ucaagauaaa uacacguaug cugaagcgaa auauacaauu 1080aaaggcguau cuucuaagga aaaagacaau aaauacagug auaaauacga auuugguaaa 1140aagacagaau augaugaauc aaaaaucaaa uuagauaacc aagaaaaagu agauggcaca 1200aaacgucaag auaaagguaa aaucacuguc gcguuagaua aauauagcga cgaaaaugaa 1260uucacuuuug 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1440gaugcauuau accaagcggc uaaagauuua uaugacgagc aaacagcuga acaaguauau 1500gaagcaugga acgaaguugg cgucgaguaa 1530431548RNAStaphylococcus aureus 43augaaaaaga aauuagguau guuacuucuu guaccagccg uaacuuuauc auuagccgca 60ugugggaaug augauggaaa agauaaagau ggcaagguaa caauuaaaac gacaguuuau 120ccauugcaau cauuugcaga gcaaauuggu ggaaaacacg ugaagguauc aucaaucuau 180ccagcaggga cagauuuaca uagcuaugaa ccaacacaaa aagauauauu aagugcaagc 240aagucagacu uguuuaugua uacaggggau aauuuagauc cgguugcuaa gaaaguugca 300ucuacuauua aagauaaaga uaaaaaacug ucuuuagaag auaaauuaga uaaagcaaag 360cuuuuaacug aucaacacga acauggugaa gagcaugaac augagggaca ugaucauggg 420aaagaagaac aucaucauca uggcggauau gauccacacg uaugguuaga uccuaaaauu 480aaccaaacuu ucgcuaaaga aauuaaagau gaauuaguga agaaagaucc aaaacauaaa 540gaugacuaug agaaaaacua caaaaaauua aacgacgauc uuaagaaaau ugauaacgau 600augaagcaag uuacuaaaga uaagcaaggu aaugcaguau ucauuucaca ugaaucaauu 660ggauacuuag cugaucguua ugguuuuguu caaaaaggua uucaaaacau gaaugcugaa 720gauccaucac aaaaagaauu gacuaaaauu guuaaagaaa uuagagauag caaugcuaaa 780uauauucuuu acgaagauaa uguugcgaau aaagugacug aaacaauucg uaaagaaaca 840gaugcgaagc cuuuaaaauu cuacaacaug gagucuuuaa auaaagaaca acagaaaaaa 900gauaauauua ccuaucaauc auuaaugaaa ucgaauauug aaaauaucgg uaaagcuuua 960gacaguggug uuaaagugaa agacgacaaa gcugaaagua aacacgacaa agcaauuucu 1020gauggguauu uuaaagauga gcaaguuaaa gaccgugaau uaagcgauua ugcuggugaa 1080uggcaaucug uuuacccuua cuuaaaagac gguacgcuug augaagugau ggaacauaaa 1140gcugaaaaug auccgaagaa aucugcuaaa gauuuaaaag cuuauuauga caaaggauau 1200aaaacugaua uuacuaacau ugauauaaaa ggaaaugaaa uuacauuuac uaaagauggu 1260acgaaacaca cugguaaaua ugaauacaau gguaagaaaa cauugaaaua uccuaaaggu 1320aaccguggcg ugagauuuau guuuaaauug gucgauggua augauaaaga cuuaccgaaa 1380uucauccaau uuagcgauca caacauugca ccuaaaaagg cagaacacuu ccauaucuuu 1440auggguaaug auaaugacgc guuauuaaaa gaaauggaua acuggccaac auauuauccu 1500ucaaaauuaa auaaagacca aaucaaagaa gaaauguuag cgcauuaa 1548441695RNAStaphylococcus aureus 44augguguuau auaucauuuu 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aauuuauuug cuaucaacua cgcucguauu accuacuuua 60guuucaccua ccgcuuaugc ugacacaccu caaaaagaua cuacagcuaa gacaacaucu 120caugauucca aaaaaucuac ugaugaugaa acuucuaagg auacuacaag uaaagauauu 180gauaaagcag acaacaauaa uacuaguaac caagacaaua acgacaaaaa aguuaaaacu 240auagacgaca gcacuucaga cucuaacaau aucauugauu uuauuuauaa gaauuuacca 300caaaccaaua uaaaccaauu gcuaaccaaa aauaaauacg augauaauua cucauuaaca 360acuuuaaucc aaaacuuauu caauuuaaau ucggauauuu cugauuacga acaaccucgu 420aauggugaaa agucaacaaa ugauucgaau aaaaacagug auaauagcau caaaaaugau 480acggauacgc aaucaucuaa acaagauaaa gcagacaauc aaaaagcacc uaaaucaaac 540aauacaaaac caaguacauc uaauaagcaa ccaaauucgc caaagccaac acaaccaaau 600caaucaaaua gucaaccagc aagugacgau aaaguaaauc aaaaaucuuc aucgaaagau 660aaucaaucaa ugucagauuc ggcuuuagau ucuauuuugg aucaauacag ugaagaugca 720aagaaaacac aaaaagauua cgcaucucaa ucuaaaaaag acaaaaauga aaaaucuaau 780acaaagaauc cacaguuacc aacacaagau gaauugaaac auaaaucuaa accugcucaa 840ucauucaaua acgauguuaa ucaaaaggau acacgugcaa caucacuauu cgaaacagau 900ccuaguauau cuaacaauga ugauagugga caauuuaacg uuguugacuc aaaagauaca 960cgucaauuug ucaaaucaau ugcuaaagau gcacaccgca uuggucaaga uaacgauauu 1020uaugcgucug ucaugauugc ccaagcaauc uuagaaucug acucaggucg uagugcuuua 1080gcuaagucac caaaccauaa uuuauucggu aucaaaggug cuuuugaagg gaauucuguu 1140ccuuuuaaca cauuagaagc ugaugguaau caauuguaua guauuaaugc uggauuccga 1200aaauauccaa gcacgaaaga aucacuaaaa gauuacucug accuuauuaa aaaugguauu 1260gauggcaauc gaacaauuua uaaaccaaca uggaaaucgg aagccgauuc uuauaaagau 1320gcaacaucac acuuaucuaa aacauaugcu acagauccaa acuaugcuaa gaaauuaaac 1380aguauuauua aacacuauca auuaacucag uuugacgaug aacguaugcc agauuuagau 1440aaauaugaac guucuaucaa ggauuaugau gauucaucag augaauucaa accuuuccgc 1500gagguaucug auaauaugcc auauccacau ggccaaugua cuugguacgu auauaaccgu 1560augaaacaau uugguacauc uaucucaggu gauuuaggug augcacauaa uuggaauaau 1620cgagcucaau accgugauua ucaaguaagu cauacaccaa aacgucaugc ugcuguugua 1680uuugaggcug gacaauuugg ugcagaucaa cauuacgguc auguagcauu uguugaaaaa 1740guuaacagug augguucuau cguuauuuca gaauccaaug uuaaaggauu agguaucauu 1800ucucauagaa cuaucaaugc agcugccgcu gaagaauuau cauauauuac agguaaauaa 1860462046RNAStaphylococcus aureus 46augaugaaaa gucaaaauaa guauaguauu cguaaauuua guguaggugc aucuuccauu 60uuaauagcua cauuacuauu uuuaaguggu ggacaagcac aagcagcuga gaagcaagug 120aauaugggaa auucacagga ggauacaguu acagcacaau cuauugggga ucaacaaacu 180agggaaaaug cuaauuauca acgugaaaac gguguugacg aacagcaaca uacugaaaau 240uuaacuaaga acuugcauaa ugauaaaaca auaucagaag aaaaucaucg uaaaacagau 300gauuugaaua aagaucaacu aaaggaugau aaaaaaucau cgcuuaauaa uaaaaauauu 360caacgugaua caacaaaaaa uaacaaugcu aauccuaggg auguaaauca aggguuagaa 420caggcuauua augauggcaa acaaaguaaa guggcgucac agcaacaguc aaaagaggca 480gauaauaguc aagacuuaaa cgcuaauaac aaucuaccuu cacaaagucg aacaaaggua 540ucaccaucau uaaauaaguc agaucaaaca agucaacgag aaauuguuaa ugagacagaa 600auagagaaag uacaaccgca acaaaagaau caagcgaaug auaaaauuac ugaccacaau 660uuuaacaaug aacaagaagu gaaaccucaa aaagacgaaa aaacacuauc aguuucagau 720uuaaaaaaca aucaaaaauc accaguugaa ccaacaaagg acaaugacaa gaaaaaugga 780uuaaauuuau uaaaaaguag ugcaguagca acguuaccaa acaaagggac aaaggaacuu 840acugcaaaag cgaaagguga ucaaacgaau aaaguugcca aacaagggca guauaaaaau 900caagauccua uaguuuuagu gcaugguuuc aauggguuua cagaugauau uaauccuuca 960guguuagcuc auuauugggg cgguaauaaa augaacauuc gccaagauuu agaagaaaau 1020gguuacaaag cuuaugaagc aaguauaagu gcuuuuggaa guaacuauga ccgcgcaguu 1080gaacuuuauu auuauaucaa aggcggucgu guagauuaug gugcagcaca ugcagcaaaa 1140uauggacaug aacguuaugg aaaaacauac gaaggaauuu acaaagacug gaaaccagga 1200cagaagguac accuuguugg acauaguaug gguggucaaa cgauacguca acuagaagaa 1260uuacugcgua augguagucg ugaagaaaua gaguaucaaa agaaacauag uggcgaaauu 1320ucuccacuau ucaaagguaa uaaugacaau augauuucau caauuacuac uuuaggaacg 1380ccacauaaug gaacgcaugc uucagauuua gcugguaaug aagcuuuagu gagacaaauu 1440guauuugaua ucgguaaaau guuugguaau aaaaauucaa gaguagacuu cggguuggcu 1500caaugggguc uaaaacagaa gccaaaugaa ucauauauug auuaugucaa acgcguuaaa 1560caaucuaauu uauggaaauc aaaagauaau ggauuuuacg aucugacgcg ugagggugca 1620acagauuuaa aucguaaaac gucguugaac ccuaacauug uguauaaaac auacacuggu 1680gaagcaacgc acaaagcauu aaauagcgau agacaaaaag cagacuuaaa uauguuuuuc 1740ccauuuguga uuacugguaa cuuaaucggu aaagcuacug aaaaagaaug gcgagaaaac 1800gaugguuuag uauccguuau uucuucucaa cauccauuua aucaagcuua uacaaaugcg 1860acggauaaaa uucaaaaagg cauuuggcaa guaacgccua caaaacauga uugggaucau 1920guugauuuug ucggacaaga uaguucugau acagugcgca caagagaaga auuacaagau 1980uuuuggcauc auuuagcaga cgauuuagug aaaacugaaa aggugacuga uacuaagcaa 2040gcauaa 2046472421RNAStaphylococcus aureus 47augacaaaua aaaugaagaa auggcaaaaa uuauccacca uuacguuauu aaugaccgga 60gugauugcuu uaaauaaugg ugaauuuaga aauguugaua aacaucaaau cgcuguggcu 120gauacgaaug uucaaacgcc agauuaugaa aaauugaaga agacguggcu cgacguuaac 180uacgguuaug aucaguauga ugagaauaau caagauauga agaagaaguu ugaugcuaaa 240gaaaaagaag ccaagaaguu acuugaugac augaaaacug auacgaauag aacauauuug 300uggucaggag cugaaaaccu ugaaacuaau ucuucucaca ugacaaaaac cuaucguaau 360aucgagaaaa ucgcagaauc aaugcaacau aagaauacgg uauuaaaaac aguugaaaac 420aaguugaaaa uaaaagaagc ccuagauugg augcacaaaa auguuuaugg caagaauccu 480ucucaaaaag ucgaggauuu aacuaaaaau cguaaggggc aaacuacacc caagaauaac

540ucauugaauu ggugggauua ugaaauuggu acgccaagag cauuaacaaa uacacuacuu 600cuaauggaug auaugcucac uaaagaugaa augaaaaauu auucaaaacc uauuaguaca 660uaugcaccau ccagugacaa aauuuuaucu ucuguuggug aaucagaaga ugcuaaaggu 720ggaaauuuag uggacauuuc uaaaguaaaa cuuuuagaaa guguuauuga agaagaugua 780gauauguuga aaaagucuau agauucuuuu aauaaagugu ucacuuaugu ucaagauucu 840gccacuggua aaggucgcaa uggauucuau aaagauggcu cuuacauuga ucaucaagau 900gucccuuaca cuggugcuua ugguguugua cuauuagagg guauuucuca aaugaugccg 960augauaaaag aaucuccuuu uaaaacuaca caagauaaug cuacauuaag caauuggauu 1020gacgaagggu uuaugccauu aaucuauaaa ggugaaauga uggauuuauc acgagguaga 1080gcuaucaguc gugaaaauga aacgagucau acagcgucag cgacuguaau gaaaucauug 1140uugagauuga augauaccau ggaugauuca acaaaaacua gauauaagca aaucguuaaa 1200acuucuguua auucugauuc aaguuacaac caaaauaauu auuuaaauuc auauucagac 1260auagcuaaaa ugaaaaaguu aaugaaugau aguacuauuu cuaaaaacga uuuaacacag 1320caacuuaaaa uauauaauga cauggaucgu gucaccuauc acaauaaaga ccuggacuuu 1380gcauuugguu uaaguaugac aucgaaaaac aucgcacgau acgaaaauau caacggagag 1440aacuuaaaag guuggcacac cggugcaggc augucuuauu uauauaacag cgaugucaaa 1500cacuaucgcg auaacuucug ggcaacagcc gauaugacuu gucuuccagg cacuacuacu 1560uuaaaugaua ugccaucuac uaauacuaag aaugauaaau cuuuuguugg cgggacaaaa 1620uuaaauaaua aauacgcaag caucgguaug gauuuugaaa aucaggacaa aacuuuaacu 1680gccaaaaaau cauauuucau auuaaacgau aaaauugucu ucuuaggaac uggcauuaaa 1740aguacugauu caucaaagaa uccaguuaca aguguugaaa aucgcaaagc aaauggguau 1800aaauuauuua aagaugauau ugaaauuacc acuucagaug uuaaugcuca ggaaacccau 1860ucagucuuuu uagaguccaa cgauacuaaa aagaacauug guuaucauuu cuuagacaag 1920ccaaaaauaa cuguaaaaaa agaaagucau acugguaagu ggagugaaau uaauaaaagu 1980caaaaaaaag augacaaaaa agaugaguau uaugaaguaa cucaaacaca uaauacaucu 2040gacaguaaau augcauaugu uuuguauccu gguuuaucaa aaagugauuu uaaaucgaag 2100aauaauaaug uaaguauugu uaaacaagau gaagauuuuc augugauaaa agauaaugau 2160ggcguauuug cugggguuaa uuauagugau aauacuaaau cuuuugauau aaacggaauu 2220acuguugaau uaaaagaaaa aggcauguuu guaauuaaaa agaaagauga uaaagcauau 2280aaauguagcu ucuauaaucc ugaaacuaca aauaccgcuu caaauauaga aucaaaaauu 2340uuuauuaaag guuacaccau aacuaauaaa agugucauaa acucuaauga ugcuggugua 2400aacuuugaau uaacuaaaua a 2421482427RNAStaphylococcus aureus 48augacauaua gaaugaagaa auggcaaaaa uuguccacca uuacguuauu aauggcuggu 60gugauuacuu ugaauggugg ugaauucaga aguauugaua aacaucaaau cgcuguggcu 120gauacgaaug uucaaacgac agauuaugaa aaguugagga acauauggcu ggacguuaac 180uaugguuaug auaaguauga ugagaauaau ccagauauga agaagaaguu ugaggcuacg 240gagaaugagg cagagaaauu acucaaggaa augaaaacug aaagugauag gaaauacuug 300ugggaaagcu caaaagauuu agauacgaag ucugcggaua ugacucguac cuaucguaau 360auugagaaaa ucucagaagc gaugaaacau aaaaauacua aauuaaaaac agaugaaaac 420aagacaaaag uaaaagaugc acuugagugg cugcauaaaa augcauaugg aaaagaacca 480gauaaaaaag uugcugauuu gaccucaaac uuuaaaaaua aaacuucuag aaauaccaac 540uuaaauuggu gggauuauga aauuggaaca ccuagagcau uaacaaauac gcuuauacuc 600uuacaagaag auuucacuga ugaagaaaag aaaaaauaua cagcuccuau uaaaacuuuc 660gccccagaua gugacaaaau auuaucuucu guaggaaaau cugaaccugc uaaaggcgga 720aauuuaguag acauuucuaa aguaaaacuu uuagaaagua uuaucgaaga agacaaagau 780augaugaaaa agucuauaga uucauuuaau acagucuuca cuuacgcgca aaauucugcc 840acuggaaaag aacguaaugg auucuauaaa gauggcucuu acauugauca ucaagacguc 900ccauacacug gugcuuaugg cguuguacua uuagagggua uuucucaaau gaugccgaug 960auaaaagaaa caccuuuuaa ugauaguaac caaaaugaua caaccuuaaa aucauggauu 1020gacgacggau uuaugccacu cauuuauaaa ggugaaauga uggauuuauc aagagguaga 1080gcuaucaguc gugaaaauga aacgagucac ucagcaucug caacaguaau gaaaucauug 1140uugagauuga gugauaccau ggauaagucu acaaaagcua aauauaaaaa gauugucaag 1200acuucaguag agucagauuc aaguuauaaa caaaccgauu auuuaagcuc uuauucggau 1260auaagcaaaa ugaagucuuu aauggaagac agcacuauuu cuacuaacgg uuuaacacaa 1320caacuuaaaa uauauaauga cauggaucgu gucaccuauc acaauaaagg cuuagacuuu 1380gcauuugguu uaaguaugac gucgaaaaac gucgcacguu acgaaaguau caacggagag 1440aacuuaaaag guuggcacac uggugcugga augucuuauu uauacaauag cgaugugaaa 1500cacuaccgug auaacuucug ggcgacagcu gauaugaaac guuuagcagg uacuacaacu 1560uuagauaaug aagaaccuaa aaguacggau guuaaaaagu cuaguaaaac uuuuguagga 1620ggaacaaaau ucgaugacca acaugcuagu aucggaaugg auuuugaaaa ucaggacaaa 1680acuuuaacug ccaaaaaauc auauuucaua uuaaacgaua aaauugucuu cuuaggaacu 1740ggcauuaaaa guacugauuc aucaaagaau ccaguuacaa cgauugaaaa ucgcaaagcg 1800aaugauuaua aauuauauaa agaugauacg caaacaacca auuccgauaa ucaggaaacc 1860aauucccucu uuuuagaguc aacgaauagc acucaaaaca auauagguua ucauuuuuua 1920aacgaaucga aaauaacugu aaaaaaagaa agucauacug guaaguggag ugauauaaau 1980aaaagccaaa aggauauaca aaaaacugau gaguauuaug aaguaacuca aaagcauucu 2040aauacagaua guaaauaugc auauguguug uauccaggcu uaucuaaaga ugucuuuaaa 2100uccaaagcaa gcaaaguaac ugucguuaag caagaagaug acuuccacgu ugugaaagau 2160aaugaaucgg uuugggcugg uaucaauuau agugauagcg cuaaaacuuu ugaaauuaau 2220aacacuaaag ucgaaguuaa agccaaagga auguuuauuc uuacaaagaa agaugauaac 2280acuuaugaau guagcuucua uaaucccgaa ucuacaaauu ccguuucaga uauugaaucu 2340aaaauuucaa ugacuggaua cucuauuaua aacaaaaaua cgucgacuuc uaaugaaucc 2400ggcguacgcu uugaauuaac uaaauaa 242749412PRTStaphylococcus aureus 49Ile Asp Ser Lys Asn Lys Pro Ala Asn Ser Asp Ile Lys Phe Glu Val 1 5 10 15 Thr Gln Lys Ser Asp Ala Val Lys Ala Leu Lys Glu Leu Pro Lys Ser 20 25 30 Glu Asn Val Lys Asn Ile Tyr Gln Asp Tyr Ala Val Thr Asp Val Lys 35 40 45 Thr Asp Lys Lys Gly Phe Thr His Tyr Thr Leu Gln Pro Ser Val Asp 50 55 60 Gly Val His Ala Pro Asp Lys Glu Val Lys Val His Ala Asp Lys Ser 65 70 75 80 Gly Lys Val Val Leu Ile Asn Gly Asp Thr Asp Ala Lys Lys Val Lys 85 90 95 Pro Thr Asn Lys Val Thr Leu Ser Lys Asp Asp Ala Ala Asp Lys Ala 100 105 110 Phe Lys Ala Val Lys Ile Asp Lys Asn Lys Ala Lys Asn Leu Lys Asp 115 120 125 Lys Val Ile Lys Glu Asn Lys Val Glu Ile Asp Gly Asp Ser Asn Lys 130 135 140 Tyr Val Tyr Asn Val Glu Leu Ile Thr Val Thr Pro Glu Ile Ser His 145 150 155 160 Trp Lys Val Lys Ile Asp Ala Gln Thr Gly Glu Ile Leu Glu Lys Met 165 170 175 Asn Leu Val Lys Glu Ala Ala Glu Thr Gly Lys Gly Lys Gly Val Leu 180 185 190 Gly Asp Thr Lys Asp Ile Asn Ile Asn Ser Ile Asp Gly Gly Phe Ser 195 200 205 Leu Glu Asp Leu Thr His Gln Gly Lys Leu Ser Ala Phe Ser Phe Asn 210 215 220 Asp Gln Thr Gly Gln Ala Thr Leu Ile Thr Asn Glu Asp Glu Asn Phe 225 230 235 240 Val Lys Asp Glu Gln Arg Ala Gly Val Asp Ala Asn Tyr Tyr Ala Lys 245 250 255 Gln Thr Tyr Asp Tyr Tyr Lys Asp Thr Phe Gly Arg Glu Ser Tyr Asp 260 265 270 Asn Gln Gly Ser Pro Ile Val Ser Leu Thr His Val Asn Asn Tyr Gly 275 280 285 Gly Gln Asp Asn Arg Asn Asn Ala Ala Trp Ile Gly Asp Lys Met Ile 290 295 300 Tyr Gly Asp Gly Asp Gly Arg Thr Phe Thr Ser Leu Ser Gly Ala Asn 305 310 315 320 Asp Val Val Ala His Glu Leu Thr His Gly Val Thr Gln Glu Thr Ala 325 330 335 Asn Leu Glu Tyr Lys Asp Gln Ser Gly Ala Leu Asn Glu Ser Phe Ser 340 345 350 Asp Val Phe Gly Tyr Phe Val Asp Asp Glu Asp Phe Leu Met Gly Glu 355 360 365 Asp Val Tyr Thr Pro Gly Lys Glu Gly Asp Ala Leu Arg Ser Met Ser 370 375 380 Asn Pro Glu Gln Phe Gly Gln Pro Ala His Met Lys Asp Tyr Val Phe 385 390 395 400 Thr Glu Lys Asp Asn Gly Gly Val His Thr Asn Ser 405 410 501239DNAStaphylococcus aureus 50attgattcaa aaaataaacc agctaattct gatattaaat ttgaggtgac tcaaaagagt 60gatgcggtca aagcattaaa agaattgcct aaatccgaaa atgtaaaaaa tatttatcaa 120gattacgctg ttactgatgt aaaaactgat aaaaaaggat ttacgcatta tacattgcaa 180ccgagtgttg atggtgttca tgcacctgac aaagaagtga aagtacacgc agacaaatca 240ggaaaagtcg ttttaatcaa tggggatact gatgcgaaga aagtaaagcc aacgaataaa 300gtgacattaa gtaaagatga cgcagccgac aaagcattta aagcagttaa gattgataag 360aataaagcga aaaatcttaa agataaagtc attaaagaaa acaaagttga aatcgatggt 420gacagtaata aatacgttta taatgttgag ttaattacag tgacaccaga aatttcacat 480tggaaagtta aaattgatgc tcaaactggc gaaattttag aaaaaatgaa cttagttaaa 540gaagctgcag aaactggtaa aggaaaaggt gtacttggcg atacaaaaga tatcaatatc 600aatagtattg acggtggatt tagcctagaa gatttaacgc atcaaggtaa attatcagca 660tttagcttta atgatcaaac aggtcaagca acattgatta ctaatgaaga tgaaaacttc 720gtaaaagatg agcaacgtgc tggcgtagat gcaaattatt acgctaaaca aacatatgat 780tattacaaag acacatttgg tcgtgaatca tatgacaacc aaggtagtcc aattgtttca 840ttaacgcatg ttaataacta cggtggtcaa gataacagaa ataatgccgc atggatcggt 900gacaaaatga tctatggtga tggtgatggt cgcacattca caagtttatc gggtgcaaat 960gacgtagtag cacacgaatt aacacacggt gtgacacaag agacagcgaa cttagaatat 1020aaggaccagt caggcgctct aaatgaaagc ttttcagatg tttttggata ctttgtagat 1080gacgaggatt tcttaatggg tgaagatgtc tacacacctg gaaaagaggg agacgcttta 1140cgcagcatgt caaacccaga acaatttggt caaccagctc atatgaaaga ctatgtattc 1200actgaaaaag ataatggtgg cgtacatacg aattcttaa 1239511239RNAStaphylococcus aureus 51auugauucaa aaaauaaacc agcuaauucu gauauuaaau uugaggugac ucaaaagagu 60gaugcgguca aagcauuaaa agaauugccu aaauccgaaa auguaaaaaa uauuuaucaa 120gauuacgcug uuacugaugu aaaaacugau aaaaaaggau uuacgcauua uacauugcaa 180ccgaguguug augguguuca ugcaccugac aaagaaguga aaguacacgc agacaaauca 240ggaaaagucg uuuuaaucaa uggggauacu gaugcgaaga aaguaaagcc aacgaauaaa 300gugacauuaa guaaagauga cgcagccgac aaagcauuua aagcaguuaa gauugauaag 360aauaaagcga aaaaucuuaa agauaaaguc auuaaagaaa acaaaguuga aaucgauggu 420gacaguaaua aauacguuua uaauguugag uuaauuacag ugacaccaga aauuucacau 480uggaaaguua aaauugaugc ucaaacuggc gaaauuuuag aaaaaaugaa cuuaguuaaa 540gaagcugcag aaacugguaa aggaaaaggu guacuuggcg auacaaaaga uaucaauauc 600aauaguauug acgguggauu uagccuagaa gauuuaacgc aucaagguaa auuaucagca 660uuuagcuuua augaucaaac aggucaagca acauugauua cuaaugaaga ugaaaacuuc 720guaaaagaug agcaacgugc uggcguagau gcaaauuauu acgcuaaaca aacauaugau 780uauuacaaag acacauuugg ucgugaauca uaugacaacc aagguagucc aauuguuuca 840uuaacgcaug uuaauaacua cgguggucaa gauaacagaa auaaugccgc auggaucggu 900gacaaaauga ucuaugguga uggugauggu cgcacauuca caaguuuauc gggugcaaau 960gacguaguag cacacgaauu aacacacggu gugacacaag agacagcgaa cuuagaauau 1020aaggaccagu caggcgcucu aaaugaaagc uuuucagaug uuuuuggaua cuuuguagau 1080gacgaggauu ucuuaauggg ugaagauguc uacacaccug gaaaagaggg agacgcuuua 1140cgcagcaugu caaacccaga acaauuuggu caaccagcuc auaugaaaga cuauguauuc 1200acugaaaaag auaauggugg cguacauacg aauucuuaa 1239

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