WO2000071725A2 - Combination neisserial compositions - Google Patents
Combination neisserial compositions Download PDFInfo
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- WO2000071725A2 WO2000071725A2 PCT/IB2000/000828 IB0000828W WO0071725A2 WO 2000071725 A2 WO2000071725 A2 WO 2000071725A2 IB 0000828 W IB0000828 W IB 0000828W WO 0071725 A2 WO0071725 A2 WO 0071725A2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/095—Neisseria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/22—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Neisseriaceae (F)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55505—Inorganic adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/70—Multivalent vaccine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
Definitions
- This invention relates to compositions comprising combinations of biological molecules from Neisseria bacteria, particularly N. meningitidis and N.gonorrhoeue.
- Neisseria meningitidis and Neisseria gonorrhoeae are non-motile. Gram negative diplococci that are pathogenic in humans.
- serogroups of ⁇ ' . meningitidis have been identified.
- Group A is the pathogen most often implicated in epidemic disease in sub-Saharan Africa.
- Serogroups B and C are responsible for the vast majority of cases in the United States and in most developed countries.
- Serogroups W135 and Y are responsible for the rest of the cases in the United States and developed countries.
- meningococcal vaccine currently in use is a tetravalent polysaccharide vaccine composed of serogroups A. C. Y and W135. Meningococcus B remains a problem, however.
- the polysaccharide approach cannot be used because the menB capsular polysaccharide is a polymer of ⁇ (2-8)-linked ⁇ -acetyl neuraminic acid that is also present in mammalian tissue.
- OMPs outer membrane proteins
- compositions comprising a first biological molecule from a Neisseria bacterium and a second biological molecule from a Neisseria bacterium.
- biological molecule includes proteins and nucleic acids.
- compositions may also comprise further biological molecules, preferably also from Neisseria. That is to say the compositions may comprise two or more biological molecules (eg. 3. 4. 5. 6. 7. 8 etc. ). at least two of which are from a Neisseria bacterium (eg. 3. 4. 5. 6. 7. 8 etc. ).
- Such compositions include those comprising ( i) two or more different Neisserial proteins. (ii) two or more different Neisserial nucleic acids, or (iii) mixtures of one or more Neisserial protein and one or more Neisserial nucleic acid.
- the first and second biological molecules are from different Neisseria species (eg. one is from N meningitidis and one is from N.gonorrhoeae). but they may be from the same species.
- the biological molecules in the compositions may be from different serogroups or strains of the same species.
- the first biological molecule is preferably selected from the group consisting of SEQ IDs 1 -8376. More preferably, it is selected from the group consisting of SEQ IDs 1 -4002 and/or SEQ IDs 4057-8376. It is preferably a purified or isolated biological molecule.
- the second biological molecule is preferably selected from the group consisting of SEQ IDs 1 -8376. More preferably, it is selected from the group consisting of SEQ IDs 1 -4002 and/or SEQ IDs 4057-8376. It is preferably a purified or isolated biological molecule.
- first and second biological molecules may be a Neisserial biological molecule which is not specifically disclosed herein, and which may not have been identified. discovered, made available to the public or purified before this patent application was filed.
- the invention provides a composition comprising one or more of the following pairs of first and second biological molecules (listed by SEQ ID):
Abstract
Compositions comprising a first biological molecule from a Neisseria bacterium and a second biological molecule from a Neiseria bacterium. The term 'biological molecule' includes proteins and nucleic acids. Preferred Neisseria species are N.meningitidis and N. gonorrhoeae
Description
COMBINATION NEISSERIAL COMPOSITIONS
All documents cited herein are incorporated by reference in their entirety.
FIELD OF THE INVENTION
This invention relates to compositions comprising combinations of biological molecules from Neisseria bacteria, particularly N. meningitidis and N.gonorrhoeue.
BACKGROUND ART
Neisseria meningitidis and Neisseria gonorrhoeae are non-motile. Gram negative diplococci that are pathogenic in humans.
Based on the organism's capsular polysaccharide. 12 serogroups of Λ'. meningitidis have been identified. Group A is the pathogen most often implicated in epidemic disease in sub-Saharan Africa. Serogroups B and C are responsible for the vast majority of cases in the United States and in most developed countries. Serogroups W135 and Y are responsible for the rest of the cases in the United States and developed countries.
The meningococcal vaccine currently in use is a tetravalent polysaccharide vaccine composed of serogroups A. C. Y and W135. Meningococcus B remains a problem, however. The polysaccharide approach cannot be used because the menB capsular polysaccharide is a polymer of α(2-8)-linked Λ -acetyl neuraminic acid that is also present in mammalian tissue.
One approach to a menB vaccine uses mixtures of outer membrane proteins (OMPs) To overcome the antigenic variability, multivalent vaccines containing up to nine different porins have been constructed [eg. Poolman JT (1992) Development oϊ' a meningococcal vaccine.
Infect. Agents Dis. 4: 13-28]. Additional proteins to be used in outer membrane vaccines have been the opa and ope proteins, but none of these approaches have been able to overcome the antigenic variability [eg. Ala"Aldeen & Borriello ( 1996) The meningococcal transferrin-binding proteins 1 and 2 are both surface exposed and generate bactericidal antibodies capable of killing homologous and heterologous strains. Vaccine 14(1 ):49-53].
Given the propensity for meningococcal disease during non-epidemic periods to be caused by multiple strains or strain variants [Russel el al. ( 1998) Abstracts of 11th International pathogenic Neisseria conference, page 281 ] together with frequent temporal shifts in the predominant strains in a community, it seems that a universal meningococcal B vaccine will require more than one antigenic species.
DESCRIPTION OF THE INVENTION
Neisserial protein and nucleotide sequences are disclosed in the following documents: WO 99/24578 WO 99G6544 WO 99/57280 WO 97/28273 WO 96/29412 WO 95/03413
Tettelin et al. (2000) Science 287:1809-1815 For ease of reference, the sequences disclosed in these documents are referred to in the present application according to the following table:
The present invention provides compositions comprising a first biological molecule from a Neisseria bacterium and a second biological molecule from a Neisseria bacterium. The term "biological molecule" includes proteins and nucleic acids.
The compositions may also comprise further biological molecules, preferably also from Neisseria. that is to say the compositions may comprise two or more biological molecules (eg. 3. 4. 5. 6. 7. 8 etc. ). at least two of which are from a Neisseria bacterium (eg. 3. 4. 5. 6. 7. 8 etc. ). Such compositions include those comprising ( i) two or more different Neisserial proteins.
(ii) two or more different Neisserial nucleic acids, or (iii) mixtures of one or more Neisserial protein and one or more Neisserial nucleic acid.
In one preferred embodiment, the first and second biological molecules are from different Neisseria species (eg. one is from N meningitidis and one is from N.gonorrhoeae). but they may be from the same species. The biological molecules in the compositions may be from different serogroups or strains of the same species.
The first biological molecule is preferably selected from the group consisting of SEQ IDs 1 -8376. More preferably, it is selected from the group consisting of SEQ IDs 1 -4002 and/or SEQ IDs 4057-8376. It is preferably a purified or isolated biological molecule.
The second biological molecule is preferably selected from the group consisting of SEQ IDs 1 -8376. More preferably, it is selected from the group consisting of SEQ IDs 1 -4002 and/or SEQ IDs 4057-8376. It is preferably a purified or isolated biological molecule.
One or both of the first and second biological molecules may be a Neisserial biological molecule which is not specifically disclosed herein, and which may not have been identified. discovered, made available to the public or purified before this patent application was filed.
In particular, the invention provides a composition comprising one or more of the following pairs of first and second biological molecules (listed by SEQ ID):
301 1-300 and 302-8376
302 , 1-301 and 303-8376
303 1-302 and 304-8376
304 • 1-303 and 305-8376
305 ! 1-304 and 306-8376
306 1-305 ana 307-8376
307 1-306 and 308-8376
308 i 1-307 and 309-8376
309 ! I -308 and 310-8376
310 1 1-309 and 311-8376
311 1-310 and 312-8376
312 1-311 and 313-8376
313 1-312 and 314-8376
314 | 1-313 and 315-8376
315 1-314 and 316-8376
316 1-315 and 317-8376
317 1-316 and 318-8376
318 1-317 and 319-8376 ' 19 1-318 and 320-8376
320 1-319 and 321-8376
321 1-320 and 322-8376
322 1-321 and 323-8376
323 1-322 and 324-8376
324 1-323 and 325-8376
325 1-324 and 326-8376
326 1-325 and 327-8376
327 1-326 and 328-8376
328 1-327 and 329-8376
329 1-328 and 330-8376
330 1-329 and 331-8376
331 1-330 and 332-8376
332 1-331 and 333-8376
333 1-332 and 334-8376
334 1-333 and 335-8376 j
335 1-334 and 336-8376
336 1-335 and 337-8376
337 1-336 and 338-8376
338 1-337 and 339-8376
339 1-338 and 340-8376 j
340 1-339 and 341-8376
341 1-340 and 342-8376
342 1-341 and 343-8376
_>4_! 1-342 and 344-8376
344 1-343 and 345-8376
345 1-344 and 346-8376
346 1-345 and 347-8376
347 1-346 and 348-8376
348 1-347 and 349-8376
349 1-348 and 350-8376
350 1-349 and 351-8376 j
351 1-350 and 352-8376 ι
352 1-351 and 353-8376 1
353 1-352 and 354-8376
354 1-353 and 355-8376 ι
355 1-354 and 356-8376
356 1-355 and 357-8376
414 1-413 and 415-8376
415 1- 14 and 416-8376
416 1-415 and 417-8376
417 i 1-416 and 418-8376
418 1-417 and 419-8376
419 1-418 and 420-8376
420 1-419 and 421-8376
421 1-420 and 422-8376
422 1-421 and 423-8376
423 1-422 and 424-8376
424 i 1-423 and 425-8376
425 . 1-424 and 426-8376
426 1-425 and 427-8376
427 1-426 and 428-8376 ,
428 1-427 and 429-8376
429 j 1-428 and 430-8376
430 1-429 and 431-8376
431 1-430 and 432-8376 !
432 1 1-431 and 433-8376
433 1-432 and 434-8376
434 1-433 and 435-8376
435 1-434 and 436-8376
436 1-435 and 437-8376 ,
437 1-436 and 438-8376 ,
438 1-437 and 439-8376 |
439 1-438 and 440-8376
440 1-439 and 441-8376
441 1-440 and 442-8376
442 1-441 and 443-8376
443 1-442 and 444-8376
444 1-443 and 445-8376
445 1-444 and 446-8376 J
446 1-445 and 447-8376
447 1-446 and 448-8376
448 1-447 and 449-8376
449 1-448 and 450-8376
450 1-449 and 451-8376
451 1-450 and 452-8376
452 1-451 and 453-8376
453 1-452 and 454-8376
454 1-453 and 455-8376
455 1-454 and 456-8376
456 1-455 and 457-8376
457 1-456 and 458-8376
458 1-457 and 459-8376
459 1-458 and 460-8376
460 1-459 and 461-8376 j
461 1-460 and 462-8376 ,'
462 1-461 and 463-8376
463 1-462 and 464-8376
464 1-463 and 465-8376 '
465 1-464 and 466-8376 ι
466 1-465 and 467-8376
467 1-466 and 468-8376 «
468 1-467 and 469-8376
469 1-468 and 470-8376 ,
470 1-469 and 471-8376
585 1-584 and 586-8376
586 1-585 and 587-8376
587 1-586 and 588-8376
588 1-587 and 589-8376
589 1-588 and 590-8376
590 1-589 and 591-8376
591 1-590 and 592-8376
592 1-591 and 593-8376
593 1-592 and 594-8376
594 1-593 and 595-8376
595 1-594 and 596-8376
596 1-595 and 597-8376 ,
597 1-596 and 598-8376
598 1-597 and 599-8376 j
599 1-598 and 600-8376
600 1-599 and 601-8376
601 1-600 and 602-8376
602 1-601 and 603-8376
603 1-602 and 604-8376
604 1-603 and 605-8376
605 1-604 and 606-8376 ,
606 1-605 and 607-8376
607 1-606 and 608-8376 |
608 1-607 and 609-8376
609 1-608 and 610-8376
610 1-609 and 611-8376
611 1-610 and 612-8376
612 1-611 and 613-8376
613 1-612 and 614-8376
614 1-613 and 615-8376
615 1-614 and 616-8376
616 1-615 and 617-8376
617 1-616 and 618-8376 ,
618 1-617 and 619-8376 j
619 1-618 and 620-8376
620 1-619 and 621-8376
621 1-620 and 622-8376
622 1-621 and 623-8376 (
623 1-622 and 624-8376 ,
624 1-623 and 625-8376
625 1-624 and 626-8376 '
626 1-625 and 627-8376
627 1-626 and 628-8376
628 1-627 and 629-8376
629 1-628 and 630-8376 |
630 1-629 and 631-8376
631 1-630 and 632-8376
632 1-631 and 633-8376
633 1-632 and 634-8376
634 1-633 and 635-8376
635 1-634 and 636-8376
636 1-635 and 637-8376
637 1-636 and 638-8376
638 1-637 and 639-8376 J
639 1-638 and 640-8376
640 1-639 and 641-8376
641 1-640 and 642-8376
1155 1 - 1154 and 1156-8376
1156 ■ 1-1155 and 1157-8376
! 1157 1-1156 and 1158-8376
1158 ! 1-1157 and 1159-8376
1159 I 1-1158 and 1160-8376
1160 ! 1-1159 and 1161-8376
, 1161 ' 1-1160 and 1162-8376
J 1162 ! 1-1161 and 1163-8376
1163 , 1-1162 and 1164-8376
1164 , 1-1163 and 1165-8376
1165 I 1-1164 and 1166-8376
1166 i 1-1165 and 1167-8376
1167 ! 1-1166 and 1168-8376
1168 | 1-1167 and 1169-8376
1169 | 1-1168 and 1170-8376
1170 1-1169 and 1171-8376
1171 1-1170 and 1172-8376
1172 1-1171 and 1173-8376
1173 1 1-1172 and 1174-8376
11 4 i 1-1173 and 1175-8376 i 1175 1-1174 and 1176-8376
1176 1-1175 and 1177-8376
1177 1-1176 and 1178-8376
1178 1-1177 and 1179-8376
1179 i-1178and 1180-8376
1180 1-1179 and 1181-8376
1181 1-1180 and 1182-8376
1182 1-1181 and 1183-8376
1183 1-1182 and 1184-8376
1184 1-1183 and 1185-8376
1185 1-1184 and 1186-8376
1186 1-1185 and 1187-8376
1187 1-1186 and 1188-8376
1188 1-1187 and 1189-8376
1189 1-1188 and 1190-8376 |
J 11 0 1-1189 and 1191-8376 j
1191 1-1190 and 1192-8376 j
1192 1-1191 and 1193-8376
1193 1-1192 and 1194-8376
1194 1-1193 and 1195-8376
1195 1-1194 and 1196-8376
1196 1-1195 and 1197-8376
1197 1-1196 and 1198-8376
1198 1-1197 and 1199-8376
1199 1-1198 and 1200-8376
1200 1-1199 and 1201-8376
1201 1-1200 and 1202-8376
1202 1-1201 and 1203-8376
1203 1-1202 and 1204-8376
1204 1-1203 and 1205-8376
1205 1-1204 and 1206-8376
1206 1-1205 and 1207-8376
1207 1-1206 and 1208-8376
1208 1-1207 and 1209-8376
1209 1-1208 and 1210-8376
1210 | 1-1209 and 1211-8376 j
1211 1-1210 and 1212-8376 j
2010 1-2009 and 2011-8376
2011 j 1-2010 and 2012-8376
, 2012 i 1-2011 and 2013-8376
2013 ! 1-2012 and 2014-8376
2014 j 1-2013 and 2015-8376
' 2015 i 1-2014 and 2016-8376
2016 i 1-2015 and 2017-8376
2017 , 1-2016 and 2018-8376
2018 i 1-2017 and 2019-8376
2019 1 1-2018 and 2020-8376
2020 | 1-2019 and 2021-8376
, 2021 1-2020 and 2022-8376
12022 ι 1-2021 and 2023-8376
2023 1-2022 and 2024-8376
' 2024 1-2023 and 2025-8376
2025 1-2024 and 2026-8376
2026 1-2025 and 2027-8376
2027 1-2026 and 2028-8376
2028 I 1-2027 and 2029-8376
2029 1-2028 and 2030-8376 1
2030 1-2029 and 2031-8376
2031 1-2030 and 2032-8376
12032 1-2031 and 2033-8376
! 2033 1-2032 and 2034-8376
2034 1-2033 and 2035-8376
2035 1-2034 and 2036-8376
2036 1-2035 and 2037-8376
2037 1-2036 and 2038-8376 j 2038 1-2037 and 2039-8376
12039 1-2038 and 2040-8376 j 2040 1-2039 and 2041-8376
; 2041 1-2040 and 2042-8376
2042 1-2041 and 2043-8376
2043 1-2042 and 2044-8376
2044 1-2043 and 2045-8376
2045 1-2044 and 2046-8376
2046 1-2045 and 2047-8376 i 2047 1-2046 and 2048-8376
12048 1-2047 and 2049-8376
2049 1-2048 and 2050-8376
, 2050 1-2049 and 2051-8376
[ 2051 1-2050 and 2052-8376
2052 1-2051 and 2053-8376
| 2053 1-2052 and 2054-8376
| 2054 1-2053 and 2055-8376
I 2055 1-2054 and 2056-8376
2056 1-2055 and 2057-8376
2057 1-2056 and 2058-8376
2058 1-2057 and 2059-8376
2059 1-2058 and 2060-8376
2060 1-2059 and 2061-8376
2061 1-2060 and 2062-8376
2062 1-2061 and 2063-8376
2063 1-2062 and 2064-8376
2064 1-2063 and 2065-8376
2065 1-2064 and 2066-8376 I
2066 1-2065 and 2067-8376 ι
12238 1 1-2237 and 2239-8376
2239 I 1-2238 and 2240-8376
2240 1 1-2239 and 2241-8376
2241 I 1-2240 and 2242-8376
2242 , 1-2241 and 2243-8376
2243 1-2242 and 2244-8376
2244 1-2243 and 2245-8376
2245 1-2244 and 2246-8376
2246 1 1-2245 and 2247-8376
2247 1-2246 and 2248-8376
2248 i 1-2247 and 2249-8376
2249 1-2248 and 2250-8376
2250 1-2249 and 2251-8376
2251 1-2250 and 2252-8376
2252 1-2251 and 2253-8376
2253 1-2252 and 2254-8376
2254 1-2253 and 2255-8376
2255 1-2254 and 2256-8376
2256 1-2255 and 2257-8376
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2258 1-2257 and 2259-8376
2259 1-2258 and 2260-8376
2260 1-2259 and 2261-8376
2261 1-2260 and 2262-8376
2262 1-2261 and 2263-8376
2263 ^ 1-2262 and 2264-8376
2264 1-2263 and 2265-8376
2265 1-2264 and 2266-8376
2266 1-2265 and 2267-8376
2267 1-2266 and 2268-8376
2268 1-2267 and 2269-8376
2269 1-2268 and 2270-8376
2270 1-2269 and 2271-8376
2271 I-2270 and 2272-8376
~>->η-ι 1-2271 and 2273-8376
~> ~> ~] '\ 1-2272 and 2274-8376
2274 1-2273 and 2275-8376
2275 1-2274 and 2276-8376
2276 1-2275 and 2277-8376
2277 1-2276 and 2278-8376
2278 1-2277 and 2279-8376
2279 1-2278 and 2280-8376
2280 1-2279 and 2281-8376
2281 1-2280 and 2282-8376
2282 1-2281 and 2283-8376
2283 1-2282 and 2284-8376
2284 1-2283 and 2285-8376
2285 1-2284 and 2286-8376
2286 1-2285 and 2287-8376
2287 1-2286 and 2288-8376
2288 1-2287 and 2289-8376
2289 1-2288 and 2290-8376
2290 1-2289 and 2291-8376
2291 1 -2290 and 2292-8376
2292 1-2291 and2293-8376
2293 1-2292 and 2294-8376
2294 1-2293 and 2295-8376
2694 1-2693 and 2695-8376
2695 1-2694 and 2696-8376
2696 ' 1-2695 and 2697-8376
2697 1-2696 and 2698-8376
2698 i 1-2697 and 2699-8376
2699 | 1-2698 and 2700-8376
2700 1-2699 and 2701-8376
12701 | 1-2700 and 2702-8376
! 2702 | 1-2701 and 2703-8376
2703 1-2702 and 2704-8376
2704 1-2703 and 2705-8376
2705 1-2704 and 2706-8376
2706 1-2705 and 2707-8376
2707 1-2706 and 2708-8376
2708 1-2707 and 2709-8376
2709 1-2708 and 2710-8376
2710 1-2709 and 2711-8376
2711 1-2710 and 2712-8376 i
12712 i 1-2711 and 2713-8376 i 713 | 1-2712 and 2714-8376
2714 1-2713 and 2715-8376 ι
2715 1-2714 and 2716-8376 1
2716 1-2715 and 2717-8376
2717 1-2716 and 2718-8376
2718 1-2717 and 2719-8376
2719 1-2718 and 2720-8376
2720 1-2719 and 2721-8376
2721 1-2720 and 2722-8376
2722 1-2721 and 2723-8376
2723 1-2722 and 2724-8376
2724 1-2723 and 2725-8376
2725 1-2724 and 2726-8376
2726 1-2725 and 2727-8376
2727 1-2726 and 2728-8376
I 2728 1-2727 and 2729-8376
2729 | 1-2728 and 2730-8376
2730 1-2729 and 2731-8376
27 1 1-2730 and 2732-8376 j
2732 1-2731 and 2733-8376 |
2733 1-2732 and 2734-8376 i
2734 1-2733 and 2735-8376 1
2735 1-2734 and 2736-8376 |
2736 1-2735 and 2737-8376 i
2737 1-2736 and 2738-8376 I
2738 1-2737 and 2739-8376 t
2739 1-2738 and 2740-8376
2740 1-2739 and 2741-8376 |
2741 1-2740 and 2742-8376
2742 1-2741 and 2743-8376
2743 1-2742 and 2744-8376 ,
2744 1-2743 and 2745-8376
2745 1-2744 and 2746-8376 I
2746 1-2745 and 2747-8376 .
2747 1-2746 and 2748-8376
2748 1-2747 and 2749-8376 '
2749 1 1-2748 and 2750-8376
2750 ! 1-2749 and 2751-8376
2900 1 -2899 and 2901 -8376
29SS 1-2957 and 2959-8376
2959 1-2958 and 2960-8376
2960 i 1-2959 and 2961-8376
2961 1-2960 and 2962-8376
2962 1-2961 and 2963-8376
2963 I 1-2962 and 2964-8376
2964 1-2963 and 2965-8376
296^ 1-2964 and 2966-8376
2966 1 1-2965 and 2967-8376
2967 1 1-2966 and 2968-8376
2968 1-2967 and 2969-8376
2969 1-2968 and 2970-8376
2970 t 1-2969 and 2971-8376
2971 1 1-2970 and 2972-8376
2972 | 1-2971 and 2973-8376
2973 l 1-2972 and 2974-8376
2974 [ 1-2973 and 2975-8376
297^ i 1-2974 and 2976-8376
2976 1-2975 and 2977-8376
2920 1 -2919 and 2921 -8376 29— 1-2976 and 2978-8376
2921 -2920 and 2922-8376 29-7& 1-2977 and 2979-8376
, 3036 1-3035 and 3037-8376
I 3037 > 1-3036 and 3038-8376 i 3038 i 1-3037 and 3039-8376
3039 1-3038 and 3040-8376
3040 1-3039 and 3041-8376
3041 I 1-3040 and 3042-8376
3042 1-3041 and 3043-8376
3043 1-3042 and 3044-8376
3044 1-3043 and 3045-8376
3045 1-3044 and 3046-8376
3046 , 1-3045 and 3047-8376
3047 1-3046 and 3048-8376
3048 1 1-3047 and 3049-8376
3049 j 1-3048 and 3050-8376
3050 . 1-3049 and 3051-8376
3051 1-3050 and 3052-8376
3052 1-3051 and 3053-8376
3053 1-3052 and 3054-8376
3054 1-3053 and 3055-8376 i 3055 1-3054 and 3056-8376
3056 1-3055 and 3057-8376
3057 1-3056 and 3058-8376
3058 1-3057 and 3059-8376
3059 1-3058 and 3060-8376
3060 1-3059 and 3061-8376
3061 1-3060 and 3062-8376
3062 1-3061 and 3063-8376
3063 1-3062 and 3064-8376
3064 1-3063 and 3065-8376
3065 1-3064 and 3066-8376
3066 1-3065 and 3067-8376
3067 1-3066 and 3068-8376
3068 1-3067 and 3069-8376
3069 1-3068 and 3070-8376
3070 1-3069 and 3071-8376
3071 1-3070 and 3072-8376
13072 1-3071 and 3073-8376
3073 1-3072 and 3074-8376
3074 1-3073 and 3075-8376
3075 1-3074 and 3076-8376
3076 1-3075 and 3077-8376
3077 1-3076 and 3078-8376
3078 1-3077 and 3079-8376
3079 1-3078 and 3080-8376
3080 , I -3079 and 3081-8376
3081 1-3080 and 3082-8376
3082 1-3081 and 3083-8376
3083 1-3082 and 3084-8376
3084 1-3083 and 3085-8376
3085 1-3084 and 3086-8376
3086 1-3085 and 3087-8376
3087 , 1-3086 and 3088-8376
3088 1-3087 and 3089-8376
3089 1-3088 and 3090-8376
3090 j 1-3089 and 3091-8376
3091 1-3090 and 3092-8376 j
3092 1-3091 and 3093-8376 |
| 3264 1-3263 and 3265-8376
3265 I -3264 and 3266-8376
3266 1-3265 and 3267-8376
3267 1-3266 and 3268-8376
3268 1 -3267 and 3269-8376
3269 1-3268 and 3270-8376
3270 1-3269 and 3271-8376
3271 1-3270 and 3272-8376
3272 ■ 1-3271 and 3273-8376
3273 I 1-3272 and 3274-8376
3274 i I -3273 and 3275-8376
3275 i 1-3274 and 3276-8376
3276 1-3275 and 3277-8376
3277 i 1-3276 and 3278-8376
3278 i 1-3277 and 3279-8376
3279 I 1-3278 and 3280-8376
3280 1-3279 and 3281-8376
3281 1-3280 and 3282-8376
3282 1-3281 and 3283-8376
3283 1-3282 and 3284-8376
3284 1-3283 and 3285-8376
3285 , 1-3284 and 3286-8376
3286 1-3285 and 3287-8376
3287 | 1-3286 and 3288-8376
3288 1-3287 and 3289-8376
3289 1-3288 and 3290-8376
3290 1-3289 and 3291-8376
3291 1-3290 and 3292-8376
3292 1-3291 and 3293-8376
3293 1-3292 and 3294-8376
3294 1-3293 and 3295-8376
3295 1-3294 and 3296-8376
3296 1-3295 and 3297-8376
3297 1-3296 and 3298-8376
3298 1-3297 and 3299-8376
3299 ι-3298 and 3300-8376
3300 1-3299 and 3301-8376
3301 1-3300 and 3302-8376
3302 1-3301 and 3303-8376
3303 1-3302 and 3304-8376
3304 1-3303 and 3305-8376
3305 1-3304 and 3306-8376
3306 1-3305 and 3307-8376
3307 1-3306 and 3308-8376
3308 1-3307 and 3309-8376
3309 1-3308 and 3310-8376
3310 1-3309 and 3311-8376
3311 1-3310 and 3312-8376 j.12 1-3311 and 3313-8376
JJ 1_> 1-3312 and 3314-8376
3314 1-3313 and 3315-8376
3315 1-3314 and 3316-8376
3316 1-3315 and 3317-8376
3317 1-3316 and 3318-8376
3318 1-3317 and 3319-8376
3319 1-3318 and 3320-8376
3320 1-3319 and 3321-8376
3720 1-3719 and 3721-8376
3721 ' 1-3720 and 3722-8376
3722 , 1-3721 and 3723-8376
3723 , 1-3722 and 3724-8376
3724 1 1-3723 and 3725-8376
, 3725 i 1-3724 and 3726-8376
13726 1-3725 and 3727-8376
372- , 1-3726 and 3728-8376
3728 i 1-3727 and 3729-8376
3729 i 1-3728 and 3730-8376
3730 | 1-3729 and 3731-8376
3731 I 1-3730 and 3732-8376
3732 j 1-3731 and 3733-8376
3733 I 1-3732 and 3734-8376
3734 1-3733 and 3735-8376
3735 1-3734 and 3736-8376
3736 1-3735 and 3737-8376
3737 1-3736 and 3738-8376
3738 1-3737 and 3739-8376 , ' 3739 1-3738 and 3740-8376 ,
3740 1-3739 and 3741-8376
3741 1-3740 and 3742-8376
3742 1-3741 and 3743-8376
3743 1-3742 and 3744-8376
3744 1-3743 and 3745-8376
3745 1-3744 and 3746-8376
3746 1-3745 and 3747-8376
3747 1-3746 and 3748-8376
3748 1-3747 and 3749-8376
3749 1-3748 and 3750-8376
3750 I -3749 and 3751-8376
3751 1-3750 and 3752-8376
3752 1-3751 and 3753-8376
3753 1-3752 and 3754-8376
3754 1-3753 and 3755-8376 j 3755 1-3754 and 3756-8376
3756 1-3755 and 3757-8376
3757 1-3756 and 3758-8376
3758 1-3757 and 3759-8376
3759 1-3758 and 3760-8376
3760 1-3759 and 3761-8376
3761 1-3760 and 3762-8376
3762 1-3761 and 3763-8376
3763 1-3762 and 3764-8376
3764 1-3763 and 3765-8376
3765 1-3764 and 3766-8376
3766 , 1-3765 and 3767-8376
3767 1-3766 and 3768-8376
3768 1-3767 and 3769-8376
3769 | 1-3768 and 3770-8376
3770 | 1-3769 and 3771-8376
3771 , 1-3770 and 3772-8376
3772 | 1-3771 and 3773-8376
3773 | 1-3772 and 3774-8376
3774 I 1-3773 and 3775-8376
3775 ■ 1-3774 and 3776-8376
3776 i 1-3775 and 3777-8376 !
4119 l 1-4118 and 4120-8376
4120 l 1-4119 and 4121-8376
4121 1 1-4120 and 4122-8376
, 4122 1 1-4121 and 4123-8376
| 4123 I 1-4122 and 4124-8376
4124 I 1-4123 and 4125-8376
4125 i 1-4124 and 4126-8376
4126 1-4125 and 4127-8376
4127 i 1-4126 and 4128-8376
4128 | 1-4127 and 4129-8376
4129 1 1-4128 and 4130-8376
4130 1-4129 and 4131-8376
4131 1-4130 and 4132-8376
4132 1-4131 and 4133-8376
4133 1-4132 and 4134-8376
4134 1-4133 and 4135-8376
4135 1-4134 and 4136-8376
4136 1-4135 and 4137-8376
14137 1-4136 and 4138-8376
4138 1-4137 and 4139-8376
4139 1-4138 and 4140-8376
4140 1-4139 and 4141-8376
4141 1-4140 and 4142-8376
4142 1-4141 and 4143-8376
4143 1-4142 and 4144-8376
4144 1-4143 and 4145-8376
4145 1-4144 and 4146-8376
4146 1-4145 and 4147-8376
4147 1-4146 and 4148-8376
4148 1-4147 and 4149-8376
4149 1-4148 and 4150-8376
4150 1-4149 and 4151-8376
4151 1-4150 and 4152-8376 i 4152 1-4151 and 4153-8376
4153 1-4152 and 4154-8376
4154 1-4153 and 4155-8376
4155 1-4154 and 4156-8376
4156 1-4155 and 4157-8376
4157 1-4156 and 4158-8376
4158 1-4157 and 4159-8376
4159 1-4158 and 4160-8376
4160 1-4159 and 4161-8376
4161 1-4160 and 4162-8376
4162 1-4161 and 4163-8376
4163 1-4162 and 4164-8376
4164 1-4163 and 4165-8376
4165 1-4164 and 4166-8376
4166 1-4165 and 4167-8376
4167 1-4166 and 4168-8376
4168 1-4167 and 4169-8376
4169 1-4168 and 4170-8376
4170 1-4169 and 4171-8376
4171 1-4170 and 4172-8376
4172 1-4171 and 4173-8376
4173 1-4172 and 4174-8376 174 1-4173 and 4175-8376
4175 1-4174 and 4176-8376 |
4404 1-4403 and 4405-8376 i 4405 1-4404 and 4406-8376
| 4406 1-4405 and 4407-8376
4407 1-4406 and 4408-8376 i 4408 1-4407 and 4409-8376
| 4409 1-4408 and 4410-8376
4410 i -4409 and 4411 -8376
14411 1-4410 and 4412-8376
! 4412 1-4411 and 4413-8376
4413 1-4412 and 4414-8376
4414 1-4413 and 4415-8376
441 1-4414 and 4416-8376
4416 1-4415 and 4417-8376
4417 1-4416 and 4418-8376
4418 1-4417 and 4419-8376
4419 1-4418 and 4420-8376
4420 1-4419 and 4421-8376
4421 1-4420 and 4422-8376
4422 1-4421 and 4423-8376
4423 1-4422 and 4424-8376 ,
4424 1-4423 and 4425-8376
4425 1-4424 and 4426-8376
4426 i 1-4425 and 4427-8376
4427 1-4426 and 4428-8376
4428 1-4427 and 4429-8376
4429 1-4428 and 4430-8376
4430 ( 1-4429 and 4431-8376
4431 , 1-4430 and 4432-8376
4432 ! 1-4431 and 4433-8376
4433 1 1-4432 and 4434-8376
4434 1-4433 and 4435-8376
4435 l 1-4434 and 4436-8376
4436 i 1-4435 and 4437-8376
4437 1-4436 and 4438-8376 i 4438 1-4437 and 4439-8376
4439 1-4438 and 4440-8376
, 4440 1-4439 and 4441-8376
4441 1-4440 and 4442-8376
4442 1-4441 and 4443-8376
4443 1-4442 and 4444-8376
4444 1-4443 and 4445-8376
4445 1-4444 and 4446-8376
4446 1-4445 and 4447-8376
4447 1-4446 and 4448-8376
4448 i 1-4447 and 4449-8376
' 4449 1-4448 and 4450-8376
14450 1-4449 and 4451-8376
4451 1-4450 and 4452-8376
4452 1-4451 and 4453-8376
4453 1-4452 and 4454-8376
4454 1-4453 and 4455-8376
4455 1-4454 and 4456-8376
4456 1-4455 and 4457-8376
4457 1-4456 and 4458-8376
4458 1-4457 and 4459-8376
4459 1-4458 and 4460-8376
4460 1-4459 and 4461-8376 '
4518 1-4517 and 4519-8376
4519 1-4518 and 4520-8376
4520 1-4519 and 4521-8376
4521 1-4520 and 4522-8376
4522 , 1-4521 and 4523-8376
4523 1-4522 and 4524-8376
4524 1-4523 and 4525-8376
4525 1-4524 and 4526-8376
4526 i-4525 and 4527-8376
4527 1-4526 and 4528-8376
4528 l 1-4527 and 4529-8376
4529 . 1-4528 and 4530-8376
4530 - 1-4529 and 4531-8376
4531 1-4530 and 4532-8376
4532 1-4531 and 4533-8376
4533 1-4532 and 4534-8376
4534 1-4533 and 4535-8376
4535 1-4534 and 4536-8376
4536 1-4535 and 4537-8376
4537 1-4536 and 4538-8376
4538 1-4537 and 4539-8376
4539 1-4538 and 4540-8376
4540 1-4539 and 4541-8376
4541 1-4540 and 4542-8376
4542 1-4541 and 4543-8376
4543 1-4542 and 4544-8376
4544 1-4543 and 4545-8376
4545 1-4544 and 4546-8376
4546 1-4545 and 4547-8376
4547 1-4546 and 4548-8376
4548 1-4547 and 4549-8376
4549 1-4548 and 4550-8376
4550 1-4549 and 4551-8376
4551 1-4550 and 4552-8376
4552 1-4551 and 4553-8376
4553 1-4552 and 4554-8376
4554 1-4553 and 4555-8376
4555 1-4554 and 4556-8376
4556 1-4555 and 4557-8376
4557 1-4556 and 4558-8376
4558 1-4557 and 4559-8376
4559 1-4558 and 4560-8376
4560 1-4559 and 4561-8376
4561 1-4560 and 4562-8376
4562 1-4561 and 4563-8376
4563 1-4562 and 4564-8376
4564 1-4563 and 4565-8376
4565 1-4564 and 4566-8376
4566 1-4565 and 4567-8376
4567 1-4566 and 4568-8376
4568 1-4567 and 4569-8376
4569 1-4568 and 4570-8376
4570 1-4569 and 4571-8376
4571 1-4570 and 4572-8376
4572 1-4571 and 4573-8376
4573 1-4572 and 4574-8376 j
4574 1-4573 and 4575-8376 I
4803 1-4802 and 4804-8376
4804 1-4803 and 4805-8376
4805 1-4804 and 4806-8376
4806 1-4805 and 4807-8376
4807 ■ 1-4806 and 4808-8376
4808 ! 1-4807 and 4809-8376
4809 1-4808 and 4810-8376
4810 1-4809 and 4811-8376
4811 1-4810 and 4812-8376
4812 1-4811 and 4813-8376
4813 l 1-4812 and 4814-8376
4814 ■ 1-4813 and 4815-8376
4815 1-4814 and 4816-8376
4816 i 1-4815 and 4817-8376
4817 1 1-4816 and 4818-8376
4818 1-4817 and 4819-8376
4819 I 1-4818 and 4820-8376
4820 i 1-4819 and 4821-8376
4821 1-4820 and 4822-8376
4822 1-4821 and 4823-8376
4823 1-4822 and 4824-8376
4824 1-4823 and 4825-8376
4825 I 1-4824 and 4826-8376
4826 j 1-4825 and 4827-8376
4827 | 1-4826 and 4828-8376
4828 , 1-4827 and 4829-8376
4829 I 1-4828 and 4830-8376
4830 ! 1-4829 and 4831-8376
4831 i 1-4830 and 4832-8376
4832 j 1-4831 and 4833-8376
4833 j 1-4832 and 4834-8376
4834 1 1-4833 and 4835-8376
4835 | 1-4834 and 4836-8376
4836 < 1-4835 and 4837-8376
4837 1-4836 and 4838-8376
4838 1-4837 and 4839-8376
4839 1-4838 and 4840-8376
4840 1 1-4839 and 4841-8376
4841 , 1-4840 and 4842-8376
4842 1-4841 and 4843-8376
4843 1-4842 and 4844-8376
4844 ■ 1-4843 and 4845-8376
4845 1-4844 and 4846-8376
4846 1-4845 and 4847-8376
4847 1-4846 and 4848-8376
4848 1-4847 and 4849-8376
4849 1-4848 and 4850-8376
4850 1-4849 and 4851-8376
4851 1-4850 and 4852-8376
4852 . 1-4851 and 4853-8376
4853 - 1-4852 and 4854-8376
4854 1-4853 and 4855-8376
4855 1-4854 and 4856-8376
4856 1-4855 and 4857-8376
4857 1-4856 and 4858-8376
4858 1-4857 and 4859-8376
4859 1-4858 and 4860-8376
J_ι
15773 1-5772 and 5774-8376
5774 1-5773 and 5775-8376
5775 1-5774 and 5776-8376
5776 ' 1-5775 and 5777-8376
577- , 1-5776 and 5778-8376
5778 1-5777 and 5779-8376
5779 1-5778 and 5780-8376
, 5780 1-5779 and 5781-8376
5781 1-5780 and 5782-8376
5782 1-5781 and 5783-8376
5783 , 1-5782 and 5784-8376
5784 1-5783 and 5785-8376
5785 , 1-5784 and 5786-8376
5786 1-5785 and 5787-8376
5787 1-5786 and 5788-8376
5788 1-5787 and 5789-8376 5789 1-5788 and 5790-8376
5790 1-5789 and 5791-8376 |
5791 1-5790 and 5792-8376
5792 1-5791 and 5793-8376
5793 I 1-5792 and 5794-8376
5794 1-5793 and 5795-8376
5795 1 1-5794 and 5796-8376
5796 1-5795 and 5797-8376
5797 j 1-5796 and 5798-8376
5798 i 1-5797 and 5799-8376
5799 i 1-5798 and 5800-8376
5800 | 1-5799 and 5801-8376
5801 ! 1-5800 and 5802-8376
5802 1-5801 and 5803-8376
5803 I 1-5802 and 5804-8376
5804 1-5803 and 5805-8376
5805 1-5804 and 5806-8376
, 5806 1-5805 and 5807-8376 j
; 5807 1-5806 and 5808-8376
5808 1-5807 and 5809-8376
5809 1 1-5808 and 5810-8376
5810 1-5809 and 5811-8376
5811 , 1-5810 and 5812-8376
5812 1-5811 and 5813-8376
5813 • 1-5812 and 5814-8376
5814 1-5813 and 5815-8376
5815 1-5814 and 5816-8376
5816 1-5815 and 5817-8376
5817 1-5816 and 5818-8376
5818 1-5817 and 5819-8376
5819 1-5818 and 5820-8376
5820 1-5819 and 5821-8376
5821 1-5820 and 5822-8376
5822 1-5821 and 5823-8376
5823 1-5822 and 5824-8376
5824 1-5823 and 5825-8376
5825 1-5824 and 5826-8376
5826 1-5825 and 5827-8376
5827 1-5826 and 5828-8376 1
5828 1-5827 and 5829-8376 |
5886 1-5885 and 5887-8376
5887 1-5886 and 5888-8376
5888 1-5887 and 5889-8376
5889 1-5888 and 5890-8376
5890 1-5889 and 5891-8376
5891 1-5890 and 5892-8376
5892 1-5891 and 5893-8376
5893 1-5892 and 5894-8376
5894 1-5893 and 5895-8376
5895 1-5894 and 5896-8376
5896 1-5895 and 5897-8376
5897 1-5896 and 5898-8376
5898 1-5897 and 5899-8376
5899 1-5898 and 5900-8376
5900 1-5899 and 5901-8376
5901 1-5900 and 5902-8376
5902 1-5901 and 5903-8376
5903 1-5902 and 5904-8376
5904 1-5903 and 5905-8376
5905 1-5904 and 5906-8376
5906 1-5905 and 5907-8376
5907 1-5906 and 5908-8376
5908 1-5907 and 5909-8376
5909 1-5908 and 5910-8376
5910 1-5909 and 5911-8376
5911 1-5910 and 5912-8376
5912 1-5911 and 5913-8376
5913 1-5912 and 5914-8376
5914 1-5913 and 5915-8376
5915 1-5914 and 5916-8376
5916 1-5915 and 5917-8376
5917 1-5916 and 5918-8376
5918 1-5917 and 5919-8376
5919 1-5918 and 5920-8376
5920 1-5919 and 5921-8376
5921 1-5920 and 5922-8376 |
5922 1-5921 and 5923-8376
5923 1-5922 and 5924-8376
5924 1-5923 and 5925-8376
5925 1-5924 and 5926-8376
5926 1-5925 and 5927-8376
5927 1-5926 and 5928-8376
5928 1-5927 and 5929-8376
5929 1-5928 and 5930-8376
5930 1-5929 and 5931-8376
5931 1-5930 and 5932-8376
5932 1-5931 and 5933-8376
5933 i 1-5932 and 5934-8376
5934 , 1-5933 and 5935-8376
5935 ! 1-5934 and 5936-8376
5936 i 1-5935 and 5937-8376
5937 | 1-5936 and 5938-8376
5938 | 1-5937 and 5939-8376
5939 | 1-5938 and 5940-8376
5940 1-5939 and 5941-8376
5941 1-5940 and 5942-8376 ,
5942 1-5941 and 5943-8376 i
, 6114 , 1-6113 and 6115-8376
' 6115 I 1-6114 and 6116-8376 i 6116 1-6115 and 6117-8376
6117 1 1-6116 and 6118-8376
6118 i 1-6117 and 6119-8376 j 6119 i 1-6118 and 6120-8376
6120 , 1-6119 and 6121-8376
; 6121 i 1-6120 and 6122-8376 i 6122 1-6121 and 6123-8376 i 6123 1-6122 and 6124-8376
6124 1 1-6123 and 6125-8376 j 6125 1-6124 and 6126-8376
| 6126 1-6125 and 6127-8376
| 6127 1-6126 and 6128-8376
I 6128 1-6127 and 6129-8376
I 6129 1-6128 and 6130-8376 f 6130 1-6129 and 6131-8376
16131 1-6130 and 6132-8376
6132 1-6131 and6133-8376
6133 1-6132 and 6134-8376 j
6134 1-6133 and 6135-8376
16135 1-6134 and 6136-8376
6136 1-6135 and 6137-8376
6137 1-6136 and 6138-8376
6138 1-6137 and 6139-8376
6139 1-6138 and 6140-8376
6140 1-6139 and 6141-8376
6141 1-6140 and 6142-8376
6142 1-6141 and 6143-8376
6143 1-6142 and 6144-8376
6144 1-6143 and 6145-8376
6145 1-6144 and 6146-8376
6146 1-6145 and 6147-8376
6147 1-6146 and 6148-8376
6148 1-6147 and 6149-8376
6149 1-6148 and 6150-8376 j
6150 1-6149 and 6151-8376
6151 1-6150 and 6152-8376
6152 1-6151 and 6153-8376
6153 1-6152 and 6154-8376
6154 1-6153 and 6155-8376
6155 1-6154 and 6156-8376 i 6156 | 1-6155 and 6157-8376
16157 ι 1-6156 and 6158-8376
| 6158 | 1-6157 and 6159-8376
6159 ! 1-6158 and 6160-8376
6160 1 1-6159 and 6161-8376
16161 1-6160 and 6162-8376
6162 ' 1-6161 and 6163-8376
| 6163 ] 1-6162 and 6164-8376
6164 1-6163 and 6165-8376
6165 i 1-6164 and 6166-8376
6166 . 1-6165 and 6167-8376
6167 i 1-6166 and 6168-8376
6168 1-6167 and 6169-8376
6169 1-6168 and 6170-8376
6170 1-6169 and 6171-8376
6285 1-6284 and 6286-8376
6286 1-6285 and 6287-8376
6287 1-6286 and 6288-8376
6288 i 1-6287 and 6289-8376
6289 | 1-6288 and 6290-8376
6290 ' 1-6289 and 6291-8376
6291 , 1-6290 and 6292-8376
6292 1-6291 and 6293-8376
6293 1-6292 and 6294-8376
6294 i 1-6293 and 6295-8376
6295 | 1-6294 and 6296-8376
6296 1-6295 and 6297-8376
6297 , 1-6296 and 6298-8376
6298 1-6297 and 6299-8376
6299 1-6298 and 6300-8376
6300 1-6299 and 6301-8376
6301 1-6300 and 6302-8376
6302 1-6301 and 6303-8376
6303 1-6302 and 6304-8376
6304 1-6303 and 6305-8376
6305 1-6304 and 6306-8376
6306 1-6305 and 6307-8376
6307 1-6306 and 6308-8376
6308 1-6307 and 6309-8376
6309 1-6308 and 6310-8376
6310 1-6309 and 6311-8376
6311 1-6310 and 6312-8376
6312 1-6311 and 6313-8376
6313 1-6312 and 6314-8376
6314 1-6313 and 6315-8376
6315 1-6314 and 6316-8376
6316 1-6315 and 6317-8376
6317 1-6316 and 6318-8376
6318 1-6317 and 6319-8376
6319 1-6318 and 6320-8376
6320 1-6319 and 6321-8376
6321 1-6320 and 6322-8376
6322 1-6321 and 6323-8376
6323 1-6322 and 6324-8376
6324 1-6323 and 6325-8376
6325 1-6324 and 6326-8376
6326 1-6325 and 6327-8376
6327 1-6326 and 6328-8376
6328 1-6327 and 6329-8376
6329 1-6328 and 6330-8376
6330 , 1-6329 and 6331-8376
6331 1 1-6330 and 6332-8376
6332 1-6331 and 6333-8376
6333 | 1-6332 and 6334-8376
6334 l 1-6333 and 6335-8376
6335 1 1-6334 and 6336-8376
6336 i 1-6335 and 6337-8376
6337 , 1-6336 and 6338-8376
6338 1-6337 and 6339-8376
6339 i 1-6338 and 6340-8376
6340 i 1-6339 and 6341-8376
6341 1-6340 and 6342-8376
6570 1-6569 and 6571-8376
6571 1-6570 and 6572-8376
6572 1-6571 and 6573-8376
6573 1-6572 and 6574-8376
6574 l 1-6573 and 6575-8376
6575 1-6574 and 6576-8376
6576 ■ 1-6575 and 6577-8376
6577 1-6576 and 6578-8376
6578 1-6577 and 6579-8376
6579 , 1-6578 and 6580-8376
6580 , 1-6579 and 6581-8376
6581 1-6580 and 6582-8376
6582 1-6581 and 6583-8376
6583 i 1-6582 and 6584-8376
6584 l 1-6583 and 6585-8376
6585 ' 1-6584 and 6586-8376
6586 1-6585 and 6587-8376
6587 j 1-6586 and 6588-8376
6588 1-6587 and 6589-8376
6589 1-6588 and 6590-8376
6590 i 1-6589 and 6591-8376
6591 1-6590 and 6592-8376
6592 1-6591 and 6593-8376
6593 1-6592 and 6594-8376
6594 1-6593 and 6595-8376
6595 1-6594 and 6596-8376
6596 1-6595 and 6597-8376
6597 1-6596 and 6598-8376
6598 1-6597 and 6599-8376
6599 1-6598 and 6600-8376
6600 1-6599 and 6601-8376
6601 1-6600 and 6602-8376
6602 1-6601 and 6603-8376
6603 1-6602 and 6604-8376
6604 1-6603 and 6605-8376
6605 1-6604 and 6606-8376
6606 1-6605 and 6607-8376
6607 1-6606 and 6608-8376
6608 1-6607 and 6609-8376
6609 1-6608 and 6610-8376
6610 1-6609 and 6611-8376
6611 1-6610 and 6612-8376
6612 1-6611 and 6613-8376
6613 1-6612 and 6614-8376
6614 1-6613 and 6615-8376
6615 1-6614 and 6616-8376
6616 1-6615 and 6617-8376
6617 1-6616 and 6618-8376
6618 1-6617 and 6619-8376
6619 1-6618 and 6620-8376
6620 1-6619 and 6621-8376
6621 1-6620 and 6622-8376
6622 1-6621 and 6623-8376
6623 1-6622 and 6624-8376
6624 1-6623 and 6625-8376
6625 1-6624 and 6626-8376 I
6626 1-6625 and 6627-8376 i
Thus the invention includes each of the 35074500 possible pairs of SEQ IDs 1 -8376 (1&2. 1&3. 1&4. 1&5 ... 1&8375. 1&8376. 2&3. 2&4. 2&5 ... 2&8375. 2&8376. 3&4 ... 1000&1001. 1000& 1002 ... 1000&8376 ... S374&8375. S374&8376. 8375&8376) although, for reasons of space, these are not listed in full here.
Details as to how the molecules which make up the SEQ IDs 1 -4056 can be produced and used can be found from the relevant international applications and these details need not be repeated here. Similar principles apply to SEQ IDs 4057-8376.
SEQ IDs 1-8376 in the compositions of the invention may be supplemented or substituted with molecules comprising sequences homologous (ie having sequence identity) to SEQ IDs 1-8376. Depending on the particular sequence, the degree of identity is preferably greater than 50% (eg. 65%. 80%. 90%. or more), and include mutants and allelic variants. Sequence identity between the proteins is preferably determined by the Smith-Waterman homology search
algorithm as implemented in the MPSRCH program (Oxford Molecular), using an affine gap search with parameters gap open penal 7v= 12 and gap extension penalty=l .
SEQ IDs 1 -8376 in the compositions of the invention may be supplemented or substituted with molecules comprising fragments of SEQ IDs 1-8376. Such fragments should comprise at least n consecutive monomers from the molecules and. depending on the particular sequence, n is either (i) 7 or more for protein molecules (eg. 8, 10. 12. 14. 16. 18. 20 or more), preferably such that the fragment comprises an epitope from the sequence, or (ii) 10 or more for nucleic acid molecules (eg 12. 14. 15. 18. 20. 25. 30. 35. 40 or more).
Where the composition includes a protein that exists in different nascent and mature forms, the mature form of the protein is preferably used. For example, the mature form of the NspA protein (SEQ IDs 4008-4033: WO96/29412: Figure 29) lacking the signal peptide may be used.
In the case of protein molecules, SEQ IDs 1 -8376 in the compositions of the invention may be supplemented or substituted with an antibody that binds to the protein. This antibody may be monoclonal or polyclonal.
In the case of nucleic acid molecules. SEQ IDs 1-8376 in the compositions of the invention may be supplemented or substituted with nucleic acid which can hybridise to the Neisserial nucleic acid, preferably under "high stringency" conditions (eg. 65°C in a O. lxSSC, 0.5% SDS solution).
It will be appreciated that any nucleic acid in the compositions can take various forms (eg. single stranded, double stranded, vectors, probes etc. ). In addition, the term "nucleic acid" includes DNA and RNA. and also their analogues, such as those containing modified backbones, and also peptide nucleic acids (PNA) etc.
In certain embodiments, the composition comprises molecules from different Neisseria species. such as one or more N meningitidis molecule and one or more N.gonorrhoeae molecule. In some embodiments, the composition may comprise molecules from different serogroups and/or strains of the same species, such as strains A and B of N. meningitidis. Further embodiments comprise mixtures of one or more N. meningitidis molecules from different strains and also one or more N.gonorrhoeae molecules.
Many proteins are relatively conserv ed between different species, serogroups and strains of N. meningitidis and N.gonorrhoeae (eg. SEQ IDs 52. 54. 58). PCT 1B00/00642 includes a more
detailed experimental analysis of conserved regions in these proteins. To ensure maximum cross-strain recognition and reactivity, regions of proteins that are conserved between different Neisserial species, serogroups and strains can be used in the compositions of the present invention. The invention therefore provides proteins which comprise stretches of amino acid sequence that are shared across the majority of Neisseria. particularly N. meningitidis and N.gonorrhoeae. Preferably, therefore, the composition comprises a protein comprising a fragment of a Neisserial protein (preferably a protein from SEQ IDs 1 -8376. or more preferably SEQ IDs 1 -4002). wherein said fragment consists of n consecutive conserved amino acids. Depending on the particular protein, n is 7 or more (eg. 8. 10. 12. 14. 16. 18. 20 or more). The fragment preferably comprises an antigenic or immunogenic region of the Neisserial protein. A "conserved" amino acid is one that is present in a particular Neisserial protein in at least x% of Neisseria (or. preferably, in at least x% of combined N. meningitidis and N.gonorrhoeae strains). The value of x may be 50% or more eg. 66%. 75%. 80%. 90%. 95% or even 100% (ie. the amino acid is found in the protein in question in all Neisseria). In order to determine whether an amino acid is "conserved" in a particular Neisserial protein, it is necessary to compare that amino acid residue in the sequences of the protein in question from a plurality of different Neisseria (a "reference population"). Suitable definitions of "reference populations" can be found in PCT/IB00/00642. Amino acid sequences of different Neissieriae can easily be compared using computers. This will typically involve the alignment of a number of sequences using an algorithm such as CLUSTAL [Thompson et al. (1994) Nucleic Acids Res 22:4673- 4680: Trends Biochem Sci ( 1998) 23:403-405] or. preferably. PILEUP [part of the GCG Wisconsin package, preferably version 9.0]. Conserved amino acids are readily apparent in a multiple sequence alignment - at the amino acid position in question a majority of the aligned sequences will contain a particular amino acid. Conserved amino acids can be made more visually apparent by using a program such as BOXSHADE [available, for instance, at the NIH on-line]. PRETTYBOX [GCG Wisconsin, version 10] or JALVIEW [available on-line at EBI].
Specific compositions according to the invention therefore include those comprising:
■ two or more biological molecules selected from SEQ IDs 1 -4002:
■ one or more biological molecules selected from SEQ IDs 1 -4002 combined with one or more biological molecules selected from SEQ IDs 4003-8376:
■ one or more biological molecules selected from SEQ IDs 1 -4002 combined with the NspA protein (as disclosed in WO96/29412: see also Figure 29 herein), preferably in mature form:
■ one or more biological molecules selected from SEQ IDs 1 -8376 (preferably SEQ IDs 1-4002) combined with transferrin binding protein A (TbpA) and/or B (TbpB). such as the TbpA and TbpB disclosed in WO00/2581 1 (or immunogenic fragments thereof).
■ one or more fragments of proteins selected from SEQ IDs 1 -4002. with the fragment preferably comprising a stretch of conserved amino acids;
■ a combination of different proteins, wherein the combination as a whole includes one or more proteins that is recognised by each strain in a reference population, although each individual protein in the combination may not itself be recognised by each strain in the reference population ie. each member of a reference population recognises at least one protein in the combination.
The invention also provides the compositions of the invention for use as medicaments (eg. as immunogenic compositions or vaccines) or as diagnostic reagents. It also provides the use of the compositions in the manufacture of: (i) a medicament for treating or preventing infection due to Neisserial bacteria: (ii) a diagnostic reagent for detecting the presence of Neisserial bacteria or of antibodies raised against Neisserial bacteria; and/or (iii) a reagent which can raise antibodies against Neisserial bacteria.
The invention also provides a method of treating a patient, comprising administering to the patient a therapeutically effective amount of a composition according to the invention.
The invention further provides a process for producing a composition according to the invention, comprising the step of bringing one or more of SEQ IDs 1 -8376 into combination with one or more other of SEQ IDs 1 -8376.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows SDS-PAGE results for the expression of ORFs 6. 7, 13. 65-1. 72. 73-1. 105-1, 137-1, 143-1 and 147-1. The left-hand lanes show molecular weight markers (set Ml ).
Figure 2 shows (A) SDS-PAGE results for ORF9 (B) the position of the N meningitidis immunoreactive band in a Western blot against a Nmeningitidis outer membrane vesicle preparation (C) FACS analysis.
Figure 3 shows SDS-PAGE results for the expression of ORFs 2-1. 5-1. 22-1. 132-1 and 4. The left-hand lanes show molecular weisht markers ( set Ml ).
Figures 4 to 28 show a hydrophilicity plot (upper), antigenic index (middle), and AMPHI regions (lower) for ORFs 2. 5. 6. 7. 9. 13a. 15. 22. 23. 27. 28. 32. 65. 72. 73. 76. 79. 89. 105, 106-1. 132. 137. 138. 143 and 147.
Figure 29 shows sequence variability of NspA from various strains of meningococcus B. These sequences may be used as alternatives to the NspA of WO 96/29412 (SEQ IDs 4008-4033).
Figure 30 shows the binding of polyclonal anti-rNspA by indirect fluorescence flow cytometry to encapsulated and non-encapsulated menB strains. Figure 31 shows similar data for encapsulated strains 8047. CU385 & M986 (31 A) and non-encapsulated strains BZ232. MC58, NG3/88 & NGB 165 (31 B).
Figure 32 shows a model of NspA secondary structure.
Figure 33 shows FACS analysis of non-encapsulated strain M7 (37A) and ethanol-treated (to disrupt the capsule) strains 2996. N44776. MC58. 1000. BZ232. BZ133. NG6/88. BZ198, NG3/88, 297-0, BZ147 and BZ169 (37B) using a tetravalent mixture.
Figure 34 shows FACS analysis of M7 strain using a pentavalent mixture at 1 :400 (34A), 1 :200 (34B) & 1 : 100 (34C) dilutions.
EXAMPLES
Example 1 - Expression and purification experiments
ORFs 6, 7. 13. 65-1. 72. 73-1. 105-1. 137-1. 143-1 and 147-1 disclosed in W099/24578 were expressed in E.coli and purified, as set out in the following table:
NOTE. ORFΑ 1 was expressed as a i ra ment ( amino acids 41 - 161 )
The protocols used to express inese ten ORFs uere essentiaih the same as those described in W099/24578. using pGEX ana pET \ ectors. Examples of the PCR primers used to amplify the ORFs are in the follow inn table:
ORF Primer Sequence Restriction sites
ORF65-1 Forward CGCGGATCCCΛTATG-TTTATGAACAAATTTTCC BamHI-Ndel Reverse CCCGCTCGΛG-TTTGCTTTCGATAGAΛCGG Xhol
ORF73-1 , Forward ! CGCGGATCCCATATG-GCCGGCGTGCTGATG BamHI-Ndel Reverse ι CCCGCTCGAG-TTCATCTTTTTCATGTTCG Xhol
ORF105-1 Forward CGCGGATCCCATATG-CCGACCGTCCGTT BamHI-Ndel Reverse CCCGCTCGAG-TAAACGAATGCCGTCCAG Xhol
ORF 143-1 Forward CGCGGATCCCATATG-GAATCAACACTTTCAC BamHI-Ndel Reverse CCCGCTCGAG-CACGCGGTTGCTGTAAC Xhol
ORF147-1 Forward CCGGAATTCTACATATG-TTTCAGAAACATTTGCAG EcoRI-Ndel Reverse CCCGCTCGΛG-TTTGTTTTTCCAAGACΛGΛG Xhol
SDS-PAGE results for the ten expressed ORFs are show n in Figure i .
The ORF7-His fusion was used to immunise mice. The sera w ere used in an ELISA assay, essentially as described in W 99 2457S. and
e posim e results.
The following proteins w ere also expressed and purified i results not shown i:
ORF His-fusion GST-fusion 1 E ^pressed as a ( Fragment amino
I expression expression fragment acid positions orfl (s) - i — 1 - 43- 1087 or l (β) n.d. I i - 1 051 - 1457
01135-1 - I - 1 orfl I n.d. n.d. ! - 25-619 ort'46 - - - 25-433 orfόl n.d. n.d. - 1 -575
orf83- 15-3 13 orfl 00- 1 n.d. 21 -376 orfl 14- 1 n.d. 1 - 1423 orfl 24- 1 n.d. n.d. ortl 31 - l n.α. 22- 1:
"he following PCR primers were used to amplif. these ORFs.
ORF Primer Sequence Restriction sites
ORFl (s) Forward CGCGGATCCGCTAGC-GGACACACTTATTTCGG BamHI-Nhel Reverse CCCGCTCGAG-CAGCGCGTCΛAGGCTT Xhol
ORFl (β) Forward CGCGGATCCGCTAGC-GAGTTCCGCCTGCATAA BamHI-Nhel Reverse CCCGCTCGAG-CCAGCGGTAGCCTAATT Xhol
ORF35-1 Forward CGCGGATCCGCTAGC-AGGGGCGACGACGTG BamHI-Nhel Reverse CCCGCTCGAG-AAACAGCCATTTGAGCGA Xhol
ORF41 Forward CGCGGATCCCATATG-TATTTGAAACAGCTCCAAG BamHI-Ndel Reverse CCCGCTCGAG-TTCTGGGTGAATGTTA Xhol
ORF46 ( Forward i CGCGGATCCCΛTATG-TCΛGATTTGGCΛAACGATC BamHI-Ndel I Reverse I CCCGCTCGAG-CGTATC r.ΛTTTCACGTGC Xhol
ORF61 Forward CGCGGATCCGCTAGC-ACGGTTTTGAAGCTTTCGC BamHI-Nhel Reverse CCCGCTCGAG-AATGACGAGGTTGTCCG Xhol
ORF83-1 Forward CGCGGATCCCATATG-TGCGGCACACTGACCG BamHI-Ndel Reverse CCCGCTCGAG-GCCGCCTTTGCGGC Xhol
ORFlO -l Forward CGCGGATCCCATλTG-TCGGGCATTTACACCGG BamHI-Ndel Reverse CCCGCTCGAG-TTCGTCGAAAACCTTTGC Xhol
ORF1 14-1 Forward CGCGGATCCCATATG-AATAAAGGTTTACATCGCAT BamHI-Ndel Reverse CCCGCTCGAG-AATCGCTGCACCGGCT Xhol
ORF124-1 , Forward I CGCGGATCCCATATG-ACTGCCTTTTCGACA I BamHI-Ndel ! Reverse I CCCGCTCGAG-GCGTG.AAGCGTCAGGA ! XhoI
Each of these ORFs can be combined with one or more of SEQ IDs 1 -8376.
Example 2 - ORF9 expression and purification
ORF9 disclosed in W099/24578 was cloned in the pET vector and expressed in E.coli. The purified ORF-His fusion protein was analysed by SDS-PAGE. as shown in Figure 2A. Mice were immunised w ith the purified ORF9-His and sera were used for Western blot analysis (Figure 2B . FACS analysis ( Figure 2C . and ELISA assay. The protocols used w ere essentially the same as those set out in W099/24578.
The results confirm that ORF9 is a surface-exposed protein. ORF9 is suitable for combining with one or more other of SEQ IDs 1 -8376.
Example 3 - Further expression experiments
Further expression and purification experiments were carried out in E.coli for ORFs 2- 1. 5-1. 22-1 and 132-1 disclosed in W099/24578. as set out in the following table:
ORF His-fusion GST-fusion Purification MW (kDa)
2- 1 1- GST-fusion ! 26
5-1 i *■
1 GST-fusion 1
1 ^
22-1 - 1 His-fusion 49
132-1 - ! GST-fusion : *
The protocols used to express these four ORFs w ere essentially the same as those described in W099/24578. using pGEX and pET \ ectors. Examples of the PCR primers used to amplify the ORFs are in the follow ine table:
SDS-PAGE results for the four expressed ORFs are shown in Figure 3
Each of these ORFs can be combined w ith one or more of SEQ IDs 1 -8376
Example 4 - ORF4 lipoprotein expression and purification
ORF4 is disclosed in W099724578 as containing a hpopeptide signal sequence ( LPSS). The full length ORF was amplified using the following PCR primers:
orf4-I_ for ΓGCGGATCCCATATGAAAACCTTCTTCAAAACC
orf4-L rev CCCGCTCGAGTTATTTGGCTGCGCCTTC
The amplified DNA fragment was cloned into the v ector pET21 b+ for expression as a C-terminus His-tagged fusion. A log phase culture of E coli containing pET21 b-orf4-LPSS was induced with 1 0 mM IPTG lor 3 h at 30°C. collected
centrifugation tor 10 min at 8000g. and resuspended in PBS. The suspension was sonicated on ice and Triton \- l 14 added to a final concentration of 0 6% ( \ \ ) The material was incubated on ice tor 20 minutes then warmed to 37°C until phase separation occurred ( indicated
a high degree ot cloudiness). After centrifugation for 10 min at l O.OOO at 20°C the upper aqueous phase was discarded, and the lower detergent phase collected w ithout disrupting the bacterial pellet To the detergent phase was added 13 \ oiumes of 20 m Histidine. 2 mM EDTA. 30 mM NaCl (pH 5.8). This was centπfuged for 10 mm at 4°C and the supernatant combined batchw ise at 4°C for 30 min. with Q Sepharose Fast Flow resin ( Pharmacia ) The mixture w as centπfuged. the supernatant retained and the resin w ashed w ith 20mM Histidine. 2mM EDTA. 30 mM NaCl (pH 5.8). Triton X-100 0 3% < \ \ ) and eluted with 1 \1 NaCl in the same buffer The majority of Orf4 lipoprotein was found in the supernatant obtained arter binding Final purification was accomplished b> cnromatograprn on Hi-TraD TM 0 ( Pharmacia ) The bmding-suDernatant was admsted to pH 7 0 b> the addition ot 0 I M HCI and aDDiied to a Hi-TrapTM Q column
equilibrated with 50mM Tris-HCl (pH 7.0). 2mM EDTA. 0.3% Triton X-100. l OmM NaCl. The column was washed with 5.0 ml of the equilibration buffer and a NaCl gradient from lOmM to IM was applied. Two electrophoretically distinct forms of the protein eluted. One in the wash and the other in the NaCl gradient between 150mM and 300mM NaCl. The protein obtained in the wash was used for immunization of mice. This form of the protein probably represents the fully processed, lipidated molecule.
The 31kDa purified lipoprotein can be seen in Figure 3. ORF4 is suitable for combining with one or more other of SEQ IDs 1 -8376.
Example 5 - Computer prediction Computer analysis of ORFs 2. 5. 6a. 7. 9. 13a. 15. 22. 23. 27. 28. 32. 65. 72. 73, 76. 79. 89. 105. 106-1. 132. 137. 138. 143 and 147 ( as disclosed in W099/24578) was performed. Figures 4 to 28 show, for each of these ORFs. a hydrophilicity plot (upper), an antigenic index plot (middle), and an AMPHI analysis (lower). The AMPHI program has been used to predict T-cell epitopes [Gao et al. ( 1989) J. Immunol. M3:3007; Roberts et al. ( 1996) AIDS Res Hum Retrovir 12:593; Quakvi et al. ( 1992) Scand J Immunol suppl. l l :9) and is available in the Protean package of DNASTAR. Inc. (1228 South Park Street. Madison. Wisconsin 53715 USA).
Each of these ORFs can be combined with one or more other of SEQ IDs 1 -8376.
Example 6 - Tetravalent mixture
A mixture of proteins 919 (W099 '57280). 225 (WO99/57280). ORF4 (WO99/24578. example 26) and ORF40 (WO99/36544. example 1 ) was produced and assessed by ELISA and FACS. The ELISA titres against 13 test strains were as follows:
The FACS results are shown in Figure 33. It is evident that the tetravalent mixture gives excellent results, regardless of the particular menB strain used. In addition, antisera raised against the mixture in strain 2996 is bactericidal at up to 1 :2048 dilution.
Example 7 - Pentavalent mixture
A mixture of proteins ORF4-L (the lipidated protein - see example 4 above). ORF37 (WO99/24578. example 1 ). ORF40 (WO99/36544. example 1 ), 502 (WO99/57280. pages 687- 690) and 8 (WO99/57280. pages 165-167) was produced. The ELISA titres against 13 test strains were as follows:
The FACS results are shown in Figure 34. It is evident that the pentavalent mixture gives excellent results, regardless of the paπicular menB strain used. In addition, antisera raised against the mixture in strain 2996 is bacteriostatic.
Example 8 - trivalent mixture
Proteins ORFl (e.g. example 77 of WO99/24578: see also WO99/55873). -287" (e.g. Figure 21 of WO99/57280: also SEQ IDs 3103-3108 therein) and *919* (e.g. WO99/57280 Figure 23 and SEQ IDs 3069-3074 therein) were combined and adjuvanted with Al(OH)3. The proteins were from the 2996 strain of MenB.
This mixture was also combined with a MenC polysaccharide conjugate antigen [e.g. Costantino et al. (1992) 'accine 10:691 -698]. OMVs were used as controls.
The mixture was used in a bactericidal assay against the homologous strain and also heterologous MenB strains. Titres were as follows:
Proteins 287. 919 and 953 are disclosed in WO99/57280. These proteins from N. meningitidis serogroup B strain 2996 were expressed and tested in a bactericidal assay against strain 2996, alone and in combinations. OMVs from 2996 were used as a positive control.
Figure 35 shows FACS data for the individual antigens and for the four combinations.
It is evident that the antigen mixtures are more effective than the antigens in isolation and. in particular, that combinations of 919-|-953 give surprisingly good results.
The individual antigens from 2996 and combinations were also tested against different serogroup A. B & C strains (i.e. heterologous challenge). Bactericidal titres were as follows:
It is apparent that the antigen mixtures are useful in conferring cross-strain activity.
In a second set of experiments, titres for the individual antigens were as follows:
The three proteins used in this example were expressed and used in the following forms:
(1) Protein 287 was expressed in E.coli as a GST fusion:
(2) Protein 919 was expressed in E.coli without its leader peptide. without its mature N-terminal cysteine. and without any fusion partners ("919-untag"); and
(3) Protein 953 was expressed using a histidine tag. Three immunisations were administered with Freund's adjuvants - the first included CFA. and the final two included IFA.
Example 10 - further polyvalent combinations
Further combinations of antigens were tested in CD1 mice:
"his" indicates expression and immunisation with a histidine-tagged protein;
•ORF4-L" is the lipidated form of ORF4; "GST" indicates expression and immunisation with a GST fusion protein;
"919-untag" is as defined in Example 9; "MenC glycoconj" is the MenC glycoconjugate described in Example 8.
Further combinations of antigens were tested in guinea pigs:
Example 11 - NspA combinations
XspA protein is disclosed in WO96/29412. and is represented herein as SEQ IDs 4008-4033. The academic literature disclosure of this protein [Martin et al. (1997) J. Exp. Med 185 1 173- 1 183] reported the protein to be highly conserved between Neisseria strains (99%> cross- reactivity of anti-NspA antibodies with 250 meningococcal A. B & C strains) and also efficient protection against deadly challenge with live bacteria. There have also been reports that NspA adsorbed on alum elicits serum meningococcal bactericidal antibody responses in rabbits and monkeys [Martin et al. (1998) Abstracts of 11th International pathogenic Neisseria conference, page 198]. On the basis of these data. rNspA (recombinant NspA) is being developed as a vaccine for the prevention of meningococcal disease caused by all serogroups.
Despite sequence conservation, however, it has surprisingly been discovered that rNspA cell surface epitopes are detected on only 65% of the serogroup B strains tested below, and susceptibility to anti-NspA bactericidal activity is also less than that reported by Martin et al. These results contrast with Martin et al. and suggest that a rNspA-based meningococcal B v accines will need to be supplemented with additional antigens in order to be effective.
The N. meningitidis strains tested in this example were isolated from patients residing in different countries over a period of more than 30 years (see table on page 72). These strains were selected to be representative of widely divergent 'clonal' groups, as defined by multilocus isoenzyme typing [Seiler et al. ( 1996) Mol. Microbiol. 19:841 -856] and/or multilocus sequence typing [Maiden et al. (1998) PNAS USA 95:3140-45]. Strain M7. which is derived from strain XMB. contains a transposon insertion that blocks capsular polysaccharide biosynthesis [Stephens et al. ( 1991 ) Infect. Immun. 59:4097-4102]. but all the other strains are encapsulated.
Based on the nucleotide sequence in Martin et al. ( 1997). PCR primers were designed and the NspA gene from strain 8047 was amplified. The sequence, including the promoter region, was cloned into pSK4- plasmid (rNspA). A plasmid pTrc.NspA.1 encoding a protein in which a portion of the signal sequence has been replaced with a poly-histidine tag was also used. Both plasmids were expressed in E.coli strain BL21(DE3) and the proteins were purified. In E.coli. rNspA is secreted, rather than being associated with the outer membrane. The protein was partially purified from the culture medium by precipitation with 55%> w/v ammonium sulphate, and had an apparent MW of 18.6kDa. confirmed by Western Blot.
The two forms of NspA (rNspA and denature His-tage NspA) were injected into 6-week old female CD-I mice to raise antisera. The ability of these to bind to the surface of N. eningitidis strain B was determined using flow cytometric detection of indirect fluorescence assay [Granoff et al. (1998) J.Immunol 160:5028-36]. The results for strains NMB and M7 (an acapsulated mutant of NMB) are shown in Figure 30. As expected, anti-group B polysaccharide n Ab SEAM-3 [Granoff et al] only binds to the encapsulated strain, whereas the positive anti-Pl .2 (PorA) control mAb binds to both strains. The antisera raised against rNspA is able to bind both strains. Antisera against the His-tag NspA gave negative results, however. These antisera were also negative for strains 8047. CU385 and M986 (Figure 31 A), but by Western Blot these antisera gave positive results.
These data suggest that antibodies prepared using His-tag NspA recognise epitopes that are present in denatured NspA. but not native NspA as found on the cell-surface in vivo. In contrast, antibodies prepared against rNspA seem to recognise conformational NspA epitopes.
The flow cytometric assay was applied to the strains shown in the table on page 72. Figure 31 A shows that murine antibodies raised against rNspA bind to the surface of strain 8047 (the strain from which the nspA gene was cloned) and strain CU385. but not to M986. Figure 3 IB shows similar negative results for strains BZ232. MC58. NG3/88 and NGP165. In all of these negative cases, however, the anticapsular mAb control was positive.
The table on page 72 summarises the flow cytometry results. Although NspA is reported o be accessible at the surface of all intact N .meningitidis strains tested [Martin et al. (1997) J. Exp. Med 185 1 173-1 183; Plante et al. (1999) Infect, lmmun. 67:2855-61 ]. only 1 1 of the 17 test strains (65%) reacted with the anti-rNspA sera. There was no apparent relationship between cell-surface expression in a given strain and classification (by serotype. subtype, or electrophoretic type), or with year or country of isolation.
In an attempt to explain the differences in reactivity with the anti-rNspA sera, the nspA genes from five of the six negative strains (BX232, NG3/88, NGP165. M136 & M986) and from three of the positive strains (8047. CU385 & NG6/88) were sequenced. The sequence for the sixth negative strain (MC58) was already available from the complete genome sequence.
The nspA sequences for all ten strains were highly conserved, varying at most by 5 nucleotides from the prototype sequence of Martin et al. The most variant protein had only 3 amino acid differences (see Figure 29). With one exception, all of the amino acid variants involved the
same respective residues in discrete segments of the protein. These include the signal peptide, which is not present in the mature protein, and two short segments in the 50 C-terminal residues. These differences do not explain the antisera results, as there are examples of identical variant sequences in strains that were positive and those that were negative (compare Ml 36 & 8047; NGP165 & NG6/88; MC58 & CU385).
As neither lack of the gene nor polymorphism explained the antiserum results, the amount of NspA protein in the outer membranes of five strains (8047, CU385 & NG6/88 - all positive for anti-rNspA; M986 & Ml 36 - both negative) were tested. Bacterial cell pellets were extracted with lauryl sarcosinate, and the insoluble outer membrane fractions were analysed. An 18.6kDa band was seen for all five strains, and this was cross-reactive with anti-His-tag-NspA by Western Blot. Thus strain differences in nspA expression also failed to explain the results.
The ability of anti-rNspA to bind to the bacterial cell surface could be influenced by the amount of polysaccharide capsule present. The quantity of capsular polysaccharide produced by the 17 test strains was therefore assessed by inhibition ELISA.
Extracts of capsular polysaccharide were prepared based on a method described by Corn et al. [J. Infect. Dis. (1993) 167:356-64]. Individual bacterial clones were grown to an OD62o 0.5-0.7 in 7 mL of Mueller-Hinton broth. Bacteria were collected by centrifugation at 5000g for 15 min, washed in O.όmL of 10 mM Hepes, pH 8.0, and then resuspended in 0.6 mL of the same buffer containing 10 mM EDTA and incubated at 37°C for 1 hr. The cells were pelleted at 10,000g for 1 minute and the relative amount of meningococcal B polysaccharide antigen released into the supernatant was determined by an inhibition ELISA, performed as described by Azmi et al. [Infect. Immun. (1995) 63:1906-13]. The solid phase antigen in the ELISA was meningococcal B polysaccharide-ADH-biotin absorbed to avidin-coated microtiter plates [Granoff et al.]. The meningococcal B polysaccharide-reactive human paraprotein LIP [Azmi et al.] was used as the primary antibody (0.2 μg/ml). In the absence of inhibitor, this concentration of antibody was sufficient to given an OD of ~0.7 to 1.0 after 30 minutes incubation with substrate [Azmi et al.]. The titre of polysaccharide released into the supernatant was measured by determining the dilution of supernatant that resulted in 50%> inhibition of antibody binding. Controls in this assay included an EDTA extract prepared from the strain M7, which does not produce any capsular polysaccharide, and purified meningococal B polysaccharide. To ensure that all of the capsular polysaccharide was released by the EDTA treatment, the same inhibition ELISA was performed using the cell pellet resuspended in the same buffer and volume as the capsule
extract. The observable inhibitory activity from the cell pellet was between 0 and 10% of the activity observed in the capsule extracts with the latter, higher percentage coming from cell pellets of strains that produce the largest amounts of capsule.
The results for each strain are shown in the table on page 72. On average, the six negative anti- rNspA strains produced three-fold more capsular polysaccharide than the eleven positive strains (respective reciprocal geometric mean dilutions of 676 vs. 224, p<0.05). This may explain the results obtained with the antiserum - conceivably, the presence of larger amounts of capsule could interfere with the ability of the anti-rNspA antibody to bind to NspA epitopes which, in strains with lower amounts of capsule, are accessible.
The complement-dependent bactericidal activity of the anti-rNspA antisera were tested using an assay similar to that described by Mandrell et al. [J. Infect. Dis. (1995) 172:1279-89]. The complement source was human serum from a healthy adult with no detectable anti-capsular antibody to group B polysaccharide and no intrinsic bactericidal activity against the test strain. Serum bactericidal titres were defined as the serum dilution resulting in a 50% decrease in CFU/ml after 60 minutes incubation of bacteria in the reaction mixture, compared to the control CFU/ml at time zero.
Typically, bacteria incubated with a negative control antibody showed a 150-200%) increase in CFU/ml during the 60 minutes of incubation. The positive control antibody [anti-capsular IgG2a mAb SEAM 12, Granoff et al.] showed complement-mediated bactericidal activity against all 17 strains. In contrast, the six strains that were negative for anti-rNspA antisera binding by flow assay were resistant, showing no bactericidal or bacteriostatic effects. Ten of the other eleven positive strains were either killed by complement and the antisera (SWZ107, J351, CU385, NG6/88, BZ198, H44/76, NMB & 8047) or were inhibited (H355 & S3446); strain 1000, however, was not affected.
The ability of the anti-rNspA antisera to confer passive protection against meningococcal B bacteremia was tested in infant rats using a method adapted from Saukkonen [J Infect. Dis. (1988) 158:209-212]. Briefly, 6-7 day old rats were randomly distributed to nursing mothers. Groups of 5-6 animals were challenged IP with lOOμl of approximately 5000 CFU of N. meningitidis group B bacteria. One strain negative for NspA surface epitopes (M986) and one positive strain (8047) were tested, each of which having been passaged three times in infant rats. Immediately before administration, the bacterial suspension was mixed with different dilutions of test or control antibody (positive control: anticapsular mAb; negative control:
anti-E.eo/t). 18 hours after challenge, blood specimens were obtained from the heart. Aliquots were plated onto chocolate agar, and CFU/ml was determined after overnight incubation at 37°C in 5% CO2.
The protective activities of the various co-administered antibodies were as follows:
As can be seen, a dose of 2μg per rat of the positive anticapsular control was protective against both strains. A 1 :5 or 1 :25 dilution of anti-rNspA antiserum protected against bacteremia caused by strain 8047. Neither dilution was effective in preventing M986 bacteremia, however.
Despite the positive conclusions of Martin et al. , therefore, NspA does not seem to be effective in preventing meningococcal B infection. Approximately one third of strains have decreased cell-surface expression of NspA epitopes when grown in vitro, are resistant to anti-NspA induced complement-mediated bacteriolysis, and are resistant to passive antiserum immunisation. These strains produce large amounts of capsular polysaccharide, and would thus be expected to have the greatest virulence. The ability of a vaccine containing only NspA to confer broad protective immunity against meningococcal B thus has to be doubted.
Compositions comprising NspA [SΕQ IDs 4008-4033; Figure 29] therefore advantageously comprise further antigens. A preferred aspect of the invention is thus a combination of NspA protein with one or more further Neisserial antigens.
Example 12 - NspA fragments
A model of the secondary structure of NspA is shown in Figure 32, containing eight transmembrane β-strands and 4 surface-exposed connecting loops. This fits the pattern of alternating hydrophobic and hydrophilic amino acids in NspA. which is characteristic of many β-barrel porins [Weiss et al. (1990) EEES Letts 267:268-272]
The grey shaded areas in the model indicate segments that are >40%> identical and >70%> similar to encoded amino acid sequences of opacity proteins (Opa) from N. meningitidis, N. gonorrhoeae, N. flavius, N. sicca, and H influenzae identified in a BLAST search of the non- redundant GenBank CDS. The alternating sequences are predicted amphiphilic β-strands; vertical segments correspond to transmembrane segments; the top of the figure corresponds to surface exposed segments, labelled as loops 1 to 4 .
According to Martin et al., the only significant homology between the deduced amino acid sequence of NspA and those of other proteins are weak homologies with the Neisseria opacity protein (Opa) family in two small segments (-20 amino acids) near the C-terminal end of the protein . However, separate comparisons of the N- and C-termini of NspA with GenBank reveals a high degree of homology (>40 % identity and >70%> similarity) between NspA and Opa proteins from N. meningitidis, N. gonorrhoeae, N. flavius, N. sicca, and H. influenzae. The Opa proteins are thought to be integral membrane proteins that have eight transmembrane segments and a β-barrel topology in the membrane similar to that of porin [Merker et al. (1997) Mol. Microbiol. 23:281-293]. The presence of NspA in detergent-insoluble membrane preparations indicate that NspA is located in the outer membrane, which would be consistent with the Opa-like membrane topology shown in the model. In addition, the segments of NspA that are most homologous to those of the Opa proteins are the putative transmembrane segments indicated in the shaded areas of Figure 32.
The opacity proteins of Neisseria can, under certain circumstances, elicit protective antibody. However, problems with limited antibody accessibility of the opacity proteins in encapsulated bacteria, variability of amino acid sequences in exposed loop segments, and phase variation of protein expression during clinical infection, have limited the ability of Opa to elicit protective antibody consistently [Malorny et al. (1998) J. Infect. Dis. 172:1279-89]. In contrast, there appears to be little or no sequence variation in the surface exposed loops of NspA in Figure 32. However, it was recently reported that a panel of anti-N. meningitidis ΝspA monoclonal antibodies that reacted with all meningococcal strains tested reacted with only a limited number
of N.gonorrhoeae strains, even though the respective amino acid sequences in the two species are 92%> identical. When the respective NspA sequences of the meningococcal and gonococcal strains are compared (Figure 29). all of the respective amino acid differences result in changes in hydrophobicity or charge, and are located in the putative surface exposed connecting loops (Figure 32). This finding suggests that the connecting loops in NspA, which are highly conserved in N. meningitidis, may be important epitopes for antibodies that bind to native NspA. These segments of the molecule, therefore, would appear to be of greatest interest with respect to interacting with protective antibody. However, the putative surface loops of NspA are relatively small (10-14 amino acids) compared to, for example, the highly immunogenic external loops of PorA and Ope (24 to 45 amino acids). The shorter length of the loops may limit the accessibility of NspA surface epitopes for binding interactions with serum antibody, especially in the presence of abundant capsular polysaccharide.
Accordingly, the invention provides the fragments of NspA that are exposed on the cell-surface in Figure 32, namely SSSLGSAKG , NYKAPSTDFKLY , NRASVDLGGSDSFSQT , and NYIGKV TVKNVRSG, and also provides corresponding fragments from allelic variants of NspA. In addition, the invention provides sub-sequences of these fragments, comprising 7 or more contiguous amino acids from the fragments. The invention further provides proteins comprising these fragments. Nucleic acid encoding these fragments and proteins is also provided.
These NspA fragments, proteins comprising the fragments, and nucleic acid, may be used in the compositions of the invention, in particular as substitutes for full-length NspA. In a further aspect, these fragments, proteins and nucleic acids may be used as products in isolation, that is to say they need not exclusively be used in combination with other biological molecules.
It will be appreciated that the invention has been described by means of example only, and that modifications may be made whilst remaining within the spirit and scope of the invention.
Reactivity of anti-rNspA polycional antisera with native NspA exposed on the surface of live, encapsulated, Neisseria meningitidis B bacteria in relation to susceptibility to bacteriolysis and capsular production.
Meningococcal B Strains NspA Cell Anti-rNspA Polysaccharide
Surface Bactericidal Capsule
Strain Country Year Serologic ET Complex Reactivity 1 Activit '' ( 1 /titer) Production Classification (1/titer + SE)
SWZ107" Switzerland 1980 4:P1.2 104 Positive >64 28±4
NG6/88 " Norway 1988 NT: Pl . l 173 Positive 4 1 15±23
CU385 * Cuba 1980 4: P1.15 5 Positive 4 1 I 6±1
IH5341 Finland 1985 15:P1.7, 16 ND Positive 16 176±6 I
BZ 198 Netherlands 1986 NT: P- 154 Positive >64 362±l
NMB US 1968 2b:P1.2,5 ND Positive 16 244±20
8047 US 1978 2b: PI .2 ND Positive 16 1 125±50
H44/76 Norway 1976 15: P1.7, 16 5 Positive 24 99-4-16
1000 " USSR 1989 NT:P1.5 61 Positive <4 287±12
S3446 '' US 1972 14: P 1.23, 14 1 1 (A 1 cluster) Positive <4 (static=16) 585±15 l
H355 " Norway 1973 15: PI .15 1 1 cluster Positive <4 (static=4) 6564= 141
BZ232 " Netherlands 1964 NT:P1.2 76 Negative <4 1493±18
NG3/88 " Norway 1988 8: Pl . l A4 cluster Negative <4 498±105
MC58 UK 1985 15:P1.7, 16b 5 Negative <4 627± I 21
M 136 Λ US 1968 1 1 : P1.15 Dl cluster Negative <4 1056±81
M986 Λ US 1963 2a: PI .5, 2 B2 cluster Negative <4 1442±206
NGP165 Norway 1974 NT:PI .2 37 Negative <4 138±6
" Denotes strains that have been characterized further by multilocus sequence typing [Maiden, 1998].
'' Denotes strains obtained from the Frasch collection, US FDA. 8047 was obtained from W. Zollinger, Walter Reed Aπny Institute of Research, Washington, D.C. MC58 is the strain selected by TIGR for genomic sequencing. J351 was obtained from M. Sarvas, National Public Health Institute, Helsinki, Finland. The remaining strains are from the collection described by Seiler et al. [Seiler, 1996]. ET data are from Caugnant et al. [/'. Infect. Dis. (1990) 162:867-874], and Seiler et al. c By indirect fluorescence flow cytometry with anti-rNspA antisera.
'' Dilution of anti-rNspA antisera that when incubated for 60 min. with bacterial cells and 20% human complement yielded >50% decrease in CFU/ml, compared to that at time 0. "Static" refers to strains that were inhibited but not killed in the assay (>50% but <100 % survival at 60 mins).
' Titre defined as dilution of capsule extract giving 50% inhibition of antibody binding to meningococcal B polysaccharide antigen in an ELISA.
Claims
1. A composition comprising a first biological molecule from a Neisseria bacterium and a second biological molecule from a Neisseria bacterium.
2. The composition of claim 1, wherein the first biological molecule is selected from the group consisting of SEQ IDs 1 -8376.
3. The composition of claim 2, wherein the first biological molecule is selected from the group consisting of SEQ IDs 1-4002.
4. The composition of any preceding claim, wherein the second biological molecule is selected from the group consisting of SEQ IDs 1 -8376.
5. The composition of claim 4, wherein the second biological molecule is selected from the group consisting of SEQ IDs 1-4002.
6. The composition of any one of claims 1 to 4, comprising two or more biological molecules selected from SEQ IDs 1-4002.
7. The composition of any one of claims 1 to 4, comprising one or more biological molecules selected from SEQ IDs 1-4002 combined with one or more biological molecules selected from SEQ IDs 4003-8376.
8. The composition of any one of claims 1 to 4, comprising one or more biological molecules selected from SEQ IDs 1-4002 & 4057-8376 combined with the NspA protein disclosed in WO96/29412, preferably in mature form.
9. The composition of any one of claims 1 to 4, comprising one or more biological molecules selected from SEQ IDs 1-8376 combined with 953 protein.
10. The composition of any preceding claim for use as a medicament
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| EP00935438A EP1179072A2 (en) | 1999-05-19 | 2000-05-19 | Combination neisserial compositions |
| JP2000620102A JP5622344B2 (en) | 1999-05-19 | 2000-05-19 | Neisseria combination composition |
| BR0010721-2A BR0010721A (en) | 1999-05-19 | 2000-05-19 | Compositions of combined neisseries |
| NZ515935A NZ515935A (en) | 1999-05-19 | 2000-05-19 | Combination Neisserial compositions and vaccines for the prevention of infections due to Neisseria bacteria such as meningococcal meningitis |
| MXPA01011867A MXPA01011867A (en) | 1999-05-19 | 2000-05-19 | Combination neisserial compositions. |
| CNB008106002A CN100338218C (en) | 1999-05-19 | 2000-05-19 | Combination neisserial compositions |
| CA2373236A CA2373236C (en) | 1999-05-19 | 2000-05-19 | Combination neisserial compositions |
| US10/982,703 US7862827B2 (en) | 1999-05-19 | 2004-11-05 | Combination neisserial compositions |
| US10/984,376 US20050244436A1 (en) | 1999-05-19 | 2004-11-09 | Combination Neisserial compositions |
| AU2006201153A AU2006201153B2 (en) | 1999-05-19 | 2006-03-20 | Combination Neisserial compositions |
| AU2009200865A AU2009200865B2 (en) | 1999-05-19 | 2009-02-27 | Combination Neisserial compositions |
| US12/979,239 US20110104193A1 (en) | 1999-05-19 | 2010-12-27 | Combination neisserial compositions |
| US13/366,226 US20120135026A1 (en) | 1999-05-19 | 2012-02-03 | Combination neisserial compositions |
| US13/921,087 US20140037668A1 (en) | 1999-05-19 | 2013-06-18 | Combination neisserial compositions |
| US14/284,326 US20150174231A1 (en) | 1999-05-19 | 2014-05-21 | Combination neisserial compositions |
| US15/015,041 US9364528B1 (en) | 1999-05-19 | 2016-02-03 | Combination neisserial compositions |
| US15/015,004 US9610342B2 (en) | 1999-05-19 | 2016-02-03 | Combination neisserial compositions |
| US15/438,584 US20170165346A1 (en) | 1999-05-19 | 2017-02-21 | Combination neisserial compositions |
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| GBGB9911692.3A GB9911692D0 (en) | 1999-05-19 | 1999-05-19 | Antigenic combinations |
| GB9911692.3 | 1999-05-19 | ||
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| GB0005730A GB0005730D0 (en) | 2000-03-09 | 2000-03-09 | Antigenic combinations |
| GB0005730.7 | 2000-03-09 |
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| US10/984,376 Continuation-In-Part US20050244436A1 (en) | 1999-05-19 | 2004-11-09 | Combination Neisserial compositions |
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| JP (3) | JP5622344B2 (en) |
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