Compositions containing neisseria meningitidis serogroup b and c antigens, and additional antigen

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discloses an immunogenic composition having an immunogenic activity on serogroup B and C Neisseria meningitidis containing (a) N. meningitidis serogroup C (NmC) oligosaccharide, (b) proteoliposome vesicles of the outer membrane of N.meningitidis (NmB) serogroup B and (c) NmB protein containing and an amino acid sequence presented in the description, or an immunogenic fragment of the above sequence, or a sequence min. 80% identical to the above sequence. The ingredient (a) may be conjugated with a carrier, e.g. with a protein, CRM197, a diphtherial anatoxin or a tetanus anatoxin. The immunogenic composition can contain aluminium hydroxide or MF59 as an adjuvant. What is described is a N.meningitidis serogroup B and C vaccine containing the described immunogenic composition.

EFFECT: using the invention enables preparing the combined vaccine eliciting an immune response on both serogroups of the agent.

6 cl, 4 dwg, 5 tbl, 6 ex

 

All documents cited here in all its fullness is included here as reference. The REGION of Izobreteniya the invention is in the field of immunogenic compositions, in more detail, the compositions, including immunogenic molecules of Neisseria meningitidis serogroups b and C (NmB and NmC). PREREQUISITES Izobreteniyami serogroups b and C Neisseria meningitidis (Nm) cause the most invasive disease in Europe and the United States. Currently available vaccines against individual serogroups Nm. Vaccine NmB from the Norwegian National Institute of Public Health is safe, induces strain-specific immunity in children and adults, and is effective in the prevention of disease NmB in adolescents. This vaccine is usually combined with polysaccharide vaccine meningococcus C and was given with alum. However, a simple polysaccharide component is not effective in infants and young children. Conjugate (conj.) vaccine NmC Chiron also safe, induces high titers of serum bactericidal antibodies in infants vaccinated at the age of two and three months, and induces immunological memory b cells to unconjugated polysaccharide NmC. view of the combined vaccine for NmB and NmC, which causes the immune response to both serogroup, international patent application WO99/61053 describes immunogenic compositions that include (a) oligosacharide the NmC,conjugatively with the carrier, in combination with (b). protein outer membrane NmB. Combination vaccine causes the immune response to both serogroup, which is slightly different from the immune response caused by each serogroup alone. The aim of the present invention is to develop them into compositions that induce immune responses against a wider range of organisms. DESCRIPTION Izobretatelstvo, the invention relates to immunogenic compositions comprising (a) NmC oligosaccharide and (b) outer membrane protein NmB, characterized in that the composition also comprises (C) one or more of the following components:

proteins described in WO 99/57280, or immunogenic fragments;

proteins described in WO 099/36554, or immunogenic fragments;

proteins described in WO 99/24578, or immunogenic fragments;

proteins described in WO 97/28273, or immunogenic fragments;

proteins described in WO 96/29412, or immunogenic fragments;

proteins described in WO 95/03413, or immunogenic fragments;

proteins described in WO 99/31132, or immunogenic fragments;

- protective antigen against Neisseria meningitidis serogroup;

- protective antigen against Neisseria meningitidis serogroup Y;

- protective antigen against Neisseria meningitidis serogroup W;

- protective antigen against Haemophilus influenzae; protective antigen against pneumococcus;

- about indifferency protective antigen;

- tetanus protective antigen;

- whooping cough booster protective antigen;

- protective antigen against Helicobacter pylori;

- protective antigen against polio; and/or

- protective antigen against hepatitis C.

Also, causing the immune response to N. meningitidis In, and With, the immunogenic composition according to the invention can induce an immune response against other organisms. Component (a)Oligosaccharide component (a) is preferably the oligosaccharide Chiron., representing pregnancyrichard NmC preferably from about 12 to 22 repeating units. The NmC oligosaccharide component (a) preferably anywhereman with the carrier. The carrier preferably is a protein, but the alternative may be a polysaccharide, polylactic acid, polyglycolic acid, polymeric amino acids, copolymers of amino acids, a lipid Assembly or inactive viral particle. Most preferably, if the carrier is a protein. The most preferable if the carrier is CRM197, a nontoxic diphtheria toxin. Each dose preferably contains 10 μg of oligosaccharide 12.5-33 μg CRM197 (i.e. to maintain the ratio of oligo/protein level from approximately 0.3 to approximately 0.8). Most preferably, can be used for approximately 20 μg CRM197. D. serowka NmC conjugate or polysaccharide is expressed in μg of sialic acid. Can also be used vaccine NmC containing unconjugated polysaccharide (referred to here as "NmC polysaccharide" or "MenC Ps"). MenC Ps is untreated isolates, including polysaccharides, preferably from about 60 to about 80 repetitive units. For other details on conjugation NmC-CRM197 see Costantino et al. (1992) Vaccine 10:691-698. Component (b)Protein NmB outer membrane component (b) preferably includes a partially purified outer membrane proteins from strain 44/76 (B15:R, 16:L3,7,9)Belok outer membrane preferably is present in the form proteoliposome vesicles obtained, for example, as a result by way of extraction with the use of deoxycholate. Dosage NmB is expressed in μg of protein. Preferably, the components of the immune composition/vaccine NmB can be obtained from the National Institute of Public Health Norway. Vaccine NmB/alum includes 0.05 mg/ml protein NmB, of 3.33 mg/ml Al(Oh)3(alum) and 0.10 mg/ml of thiomersal sodium. Component (C)Preferably, component (C) includes one or more of the following:

protein comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 80, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 39 In, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, 592, 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880, 882, 884, 886, 888, 890 and 892 described in WO 99/24578 (or a protein comprising immunogenic fragment of one or more data SEQ ID, or a protein comprising a sequence having sequence identity (preferably greater than 50%, for example,. 60%, 70%, 80%, 90%, 95%, 99% or more) with one of the data SEQ ID);

protein comprising the amino acid sequence, select the ing group, consisting of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88 and 90 described in W099/36544 (or a protein comprising immunogenic fragment of one or more data SEQ ID, or a protein comprising a sequence having sequence identity (preferably greater than 50%, for example, 60%, 70%, 80%, 90%, 95%, 99% or more) with one of the data SEQ ID);

protein comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286 288, 290, 292,. 294, 296, 298,.300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, 592, 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880, 882, 884, 886, 888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908, 910, 912, 914, 916, 918, 920, 922, 924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944, 946, 948, 950, 952, 954, 956, 958, 960, 962, 964, 966, 968, 970, 972, 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000, 1002, 1004, 1006, 1008, 1010, 1012, 1014, 1016, 1018, 1020, 1022, 1024, 1026, 1028, 1030, 1032, 1034, 1036, 1038, 1040, 1042, 1044, 1046, 1048, 1050, 1052, 1054, 1056, 1058, 1060, 1062, 1064, 1066, 1068, 1070, 1072, 1074, 1076, 1078, 1080, 1082, 1084, 1086, 1088, 1090, 1092, 1094, 1096, 1098, 1100, 1102, 1104, 1106, 1108, 1110, 1112, 1114, 1116, 1118, 1120, 1122, 1124, 1126, 1128, FROM, 1132, 1134, 1136, 1138, 1140, 1142, 1144, 1146, 1148, 1150, 1152, 1154, 1156, 1158, 1160, 1162, 1164, 1166, 1168, 1170, 1172, 1174, 1176, 1178, 1180, 1182, 1184, 1186, 1188, 1190, 1192, 1194, 1196, 1198, 1200, 1202, 1204, 1206, 1208, 1210, 1212, 1214, 1216, 1218, 1220, 1222, 1224, 1226, 1228, 1230, 1232, 1234, 1236, 1238, 1240, 1242, 1244, 1246, 1248, 1250, 1252, 1254, 1256, 1258, 1260, 1262, 1264, 1266, 1268, 1270, 1272, 1274, 1276, 1278, 1280, 1282, 1284, 1286, 1288, 1290, 1292, 1294, 1296, 1298, 1300, 1302, 1304, 1306, 1308, 1310, 1312, 1314, 1316, 1318, 1320, 1322, 1324, 1326, 1328, 1330, 1332, 1334, 1336, 1338, 1340, 1342, 1344, 1346, 1348, 1350, 1352, 1354, 1356, 1358, 1360, 1362, 1364, 1366, 1368, 1370, 1372, 1374, 1376, 1378, 1380, 1382, 1384, 1386, 1388, 1390, 1392, 1394,.1396, 1398, 1400, 1402, 1404, 1406, 1408, 1410, 1412, 1414, 1416, 1418, 1420, 1422, 1424, 1426, 1428, 1430, 1432, 1434, 1436, 1438, 1440, 1442, 1444, 1446, 1448, 1450, 1452, 1454, 1456, 1458, 1460, 1462, 1464, 1466, 1468, 1470, 1472, 1474, 1476, 1478, 1480, 1482, 1484, 1486, 1488, 1490, 142, 1494, 1496, 1498, 1500, 1502, 1504, 1506, 1508, 1510, 1512, 1514, 1516, 1518, 1520, 1522, 1524, 1526, 1528, 1530, 1532, 1534, 1536, 1538, 1540, 1542, 1544, 1546, 1548, 1550, 1552, 1554, 1556, 1558, 1560, 1562, 1564, 1566, 1568, 1570, 1572, 1574, 1576, 1578, 1580, 1582, 1584, 1586, 1588, 1590, 1592, 1594, 1596, 1598, 1600, 1602, 1604, 1606, 1608, 1610, 1612, 1614, 1616, 1618, 1620, 1622, 1624, 1626, 1628, 1630, 1632, 1634, 1636, 1638, 1640, 1642, 1644, 1646, 1648, 1650, 1652, 1654, 1656, 1658, 1660, 1662, 1664, 1666, 1668, 1670, 1672, 1674, 1676, 1678, 1680, 1682, 1684, 1686, 1688, 1690, 1692, 1694, 1696, 1698, 1700, 1702, 1704, 1706, 1708, 1710, 1712, 1714, 1716, 1718, 1720, 1722, 1724, 1726, 1728, 1730, 1732, 1734, 1736, 1738, 1740, 1742, 1744, 1746, 1748, 1750, 1752, 1754, 1756, 1758, 1760, 1762, 1764, 1766, 1768, 1770, 1772, 1774, 1776, 1778, 1780, 1782,1784, 1786, 1788, 1790, 1792, 1794, 1796, 1798, 1800,1802, 1804, 1806, 1808, 1810, 1812, 1814, 1816, 1818,1820, 1822, 1824, 1826, 1828, 1830, 1832, 1834, 1836, 1838, 1840, 1842, 1844, 1846, 1848, 1850, 1852, 1854, 1856, 1858, 1860, 1862, 1864, 1866, 1868, 1870, 1872, 1874, 1876, 1878, 1880, 1882, 1884, 1886, 1888, 1890,1892, 1894, 1896, 1898, 1900, 1902, 1904, 1906, 1908, 1910, 1912, 1914, 1916, 1918, 1920, 1922, 1924, 1926, 1928, 1930, 1932, 1934, 1936, 1938, 1940, 1942, 1944, 1946, 1948, 1950, 1952, 1954, 1956, 1958, 1960, 1962, 1964, 1966, 1968, 1970, 1972, 1974, 1976, 1978, 1980, 1982, 1984, 1986, 1988, 1990, 1992, 1994, 1996, 1998,2000, 2002, 2004, 2006, 2008, 2010, 2012, 2014, 2016, 2018, 2020, 2022, 2024, 2026, 2028, 2030, 2032, 2034, 2036, 2038, 2040, 2042, 2044, 2046, 2048, 2050, 2052, 2054, 2056, 2058, 2060, 2062, 2064, 2066, 2068, 2070, 2072, 2074, 2076, 2078, 2080, 2082, 2084, 2086, 2088, 2090, 2092, 2094, 2096, 2098, 2100, 2102, 2104, 2106, 2108, 2110, 2112, 2114, 2116, 2118, 2120, 2122, 2124, 2126, 2128, 2130, 2132, 2134, 2136, 2138, 2140, 2142, 2144, 2146, 2148, 2150, 2152, 2154, 2156, 2158, 2160, 2162, 2164, 2166, 2168, 2170, 2172, 2174, 2176, 2178, 2180, 2182, 2184, 2186, 2188, 2190, 2192, 2194, 2196, 2198, 2200, 2202, 2204, 2206, 2208, 2210, 2212, 2214,2216, 2218, 2220, 2222, 2224, 2226, 2228, 2230, 2232, 2234, 2236, 2238, 2240, 2242, 2244, 2246, 2248, 2250, 2252, 2254, 2256, 2258, 2260, 2262, 2264, 2266, 2268, 2270, 2272, 2274, 2276, 2278, 2280, 2282, 2284, 2286, 2288, 2290, 2292, 2294, 296, 2298, 2300, 2302, 2304, 2306, 2308, 2310, 2312, 2314, 2316, 2318, 2320, 2322, 2324, 2326, 2328, 2330, 2332, 2334, 2336, 2338, 2340, 2342, 2344, 2346, 2348, 2350, 2352, 2354, 2356, 2358, 2360, 2362, 2364, 2366, 2368, 2370, 2372, 2374, 2376, 2378, 2380, 2382, 2384, 2386, 2388, 2390, 2392, 2394, 2396, 2398, 2400, 2402, 2404, 2406, 2408, 2410, 2412, 2414, 2416, 2418, 2420, 2422, 2424, 2426, 2428, 2430, 2432, 2434, 2436, 2438, 2440, 2442, 2444, 2446, 2448, 2450, 2452, 2454, 2456, 2458, 2460, 2462, 2464, 2466, 2468, 2470, 2472, 2474, 2476, 2478, 2480, 2482, 2484, 2486, 2488, 2490, 2492, 2494, 2496, 2498, 2500, 2502, 2504, 2506, 2508, 2510, 2512, 2514, 2516, 2518, 2520, 2522, 2524, 2526, 2528, 2530, 2532, 2534, 2536, 2538, 2540, 2542, 2544, 2546, 2548, 2550, 2552, 2554, 2556, 2558, 2560, 2562, 2564, 2566, 2568, 2570, 2572, 2574, 2576, 2578, 2580, 2582, 2584, 2586, 2588, 2590, 2592, 2594, 2596, 2598, 2600, 2602, 2604, 2606, 2608, 2610, 2612, 2614, 2616, 2618, 2620, 2622, 2624, 2626, 2628, 2630, 2632, 2634, 2636, 2638, 2640, 2642, 2644, 2646, 2648, 2650, 2652, 2654, 2656, 2658, 2660, 2662, 2664, 2666, 2668, 2670, 2672, 2674, 2676, 2678, 2680, 2682, 2684, 2686, 2688, 2690, 2692, 2694, 2696, 2698, 2700, 2702, 2704, 2706, 2708, 2710, 2712, 2714, 2716, 2718, 2720, 2722, 2724, 2726, 2728, 2730, 2732, 2734, 2736, 2738, 2740, 2742, 2744, 2746, 2748, 2750, 2752, 2754, 2756, 2758, 2760, 2762, 2764, 2766, 2768, 2770, 2772, 2774, 2776, 2778, 2780, 2782, 2784, 2786, 2788,,2790, 2792, 2794, 2796, 2798, 2800, 2802, 2804, 2806, 2808, 2810, 2812, 2814, 2816, 2818, 2820, 2822, 2824, 2826, 2828, 2830, 2832, 2834, 2836, 2838, 2840, 2842, 2844, 2846, 2848, 2850, 2852, 2854, 2856, 2858, 2860, 2862, 2864, 2866, 2868, 2870, 2872, 2874, 2876, 2878, 2880, 2882, 2884, 2886, 2888, 2890, 2892, 2894, 2896, 2898, 2900, 2902, 2904, 2906, 2908, 2910, 2912, 2914, 2916, 2918, 2920, 2922, 2924, 2926, 2928, 2930, 2932, 2934, 2936, 2938, 2940, 2942, 2944, 2946, 2948, 2950, 2952, 2954, 2956, 2958, 2960, 2962, 2964, 2966, 2968, 2970, 2972, 2974, 2976, 2978, 2980, 2982, 2984, 2986, 2988, 2990 2992, 2994, 2996, 2998, 3000, 3002, 3004, 3006, 3008, 3010, 3012, 3014, 3016, 3018 and, 3020, described in WO 99/57280, (or a protein comprising immunogenic fragment of one or more of data,SEQ ID, or a protein, including, for sledovatelnot, having sequence identity (preferably greater than 50%, for example, 60%, 70%, 80%, 90%, 95%, 99% or more) with one of the data SEQ ID); protein described in figure 4 or figure 13 WO 97/28273; a protein comprising amino acid sequence selected from the group consisting of SEQ ID nos: 1-8, described in WO 96/29412 (or a protein comprising immunogenic fragment of one or more data SEQID, or a protein comprising a sequence having sequence identity (preferably above 50%, for example, 60%, 70%, 80%, 90%, 95%, 99% or more) with one of the data SEQ ID);

protein comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 1-23, described in WO 95/03413 (or a protein comprising immunogenic fragment of one or more data SEQ ID, or a protein comprising a sequence having sequence identity (preferably greater than 50%, for example, 60%, 70%, 80%, 90%, 95%, 99% or more) with one of the data SEQ ID);

protein comprising the amino acid sequence consisting of SEQ ID NO:2 described in WO 99/31132 (or a protein comprising immunogenic fragment of SEQ ID NO:2, or a protein comprising a sequence having sequence identity (preferably greater than 50%, for example, 60%, 70%, 80%, 90%, 95%, 99% or more) to SEQ ID NO:2);

- polysaccharide antigen against Neisseria meningitidis serogroup;

- policy is charigny antigen against Neisseria meningitidis serogroup Y;

- polysaccharide antigen against Neisseria meningitidis serogroup W;

- polysaccharide antigen against Haemophilus influenzae;

- polysaccharide antigen against pneumococcus;

- diphtheria protective antigen, consisting of diphtheria toxoid, such as a mutant CRM197 [e.g., Del Guidice et al. (1998) Molecular Aspects of Medicine 19:1-70].

- Tetanus protective antigen, consisting of tetanus toxoid [e.g. Wassilak & Orenstein, Chapter 4 of Vaccines (eds. Plotkin &Mortimer), 1988].

- Whooping cough booster protective antigen, including the pertussis holotoxin (PT) and filamentous hemagglutinin (FHA); optional extras including pertactin and/or agglutinogens 2 and 3 [e.g., Gustafsson et al. (1996) N. Engl. J. Med. 334:349-355; Rappuoli et al. (1991) TIBTECH 9:232-238].

- Protective antigen against H. pylori, including one or more of the Grounds (for example, WO 93/18150), VacA (for example, WO 93/18150), NAP (for example, WO 99/53310), Nor (for example, WO 98/04702), Hole (for example, WO 98/04702), urease.

- Protective antigen against hepatitis b virus, consisting of a surface antigen of HBV and/or crustal antigen of HBV.

Where component (C) includes a diphtheria antigen, it preferably also includes antigens against tetanus and polio. Where component (C) includes tetanus antigen, it preferably includes takeanother against diphtheria and polio. Where component (C) on the antigen comprises polio, it preferably also includes antigens against diphtheria and tetanus. Pertussis toxin is toxic protein, and when his presence in the component (C), it is preferably subjected to detoxification. Detoxification can be carried out chemical and/or genetic means. Preferred methoxycarbonyl mutant is a double mutant 9K/129G [for example, Rappuoli et al. (1997) Nature Medicine 3:374-376]. Where component (C) includes a protein that exists in different immature and Mature forms, preferably applies a Mature form of the protein. For example, including NspA (WO 96/29412; see also Martin et al. (1997) J. Exp.Med. 185 1173-1183) preferably applies a Mature form of the protein that does not contain a signal peptide. Where component (C) includes polysaccharide antigen, a polysaccharide, preferably conjugated to a protein carrier. Component (C) must not reduce the immune response that occurs in response to components (a) and (b). Pharmaceutically acceptable medium of the Composition according to the invention may also include pharmaceutically acceptable carrier. The media can be organic, inorganic or both. Suitable carrier materials well known to specialists in this field and include, without limitation, large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic the slots, polymeric amino acids, copolymers of amino acids, lipid aggregates (such as oil droplets or liposomes), and inactive virus particles. Pharmaceutically acceptable salts can also be used, for example, mineral acid salts such as hydrochloride, hydrobromide, phosphates, sulfates and the like; and organic acid salts such as acetates, propionate, malonate, benzoate and the like. A detailed discussion of pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991). Pharmaceutically acceptable carriers in the composition may contain such liquid as water, saline, glycerol and ethanol. Additionally, these vectors may be present such excipients as moisturizing agents or emulsifying agents, pH buffers, and the like. Usually, therapeutic compositions are prepared as ready for the introduction, either as liquid solutions or suspensions; solid forms suitable for cultivation in solution or in suspension prior to injection can also be prepared with liquid carriers. Liposomes are included in the definition of a pharmaceutically acceptable carrier. The media can also function as immunostimulating agent, for example, the adjuvant. Suitable adjuvants are well known to specialists in this field. Predpochtite lname carriers are aluminum hydroxide (alum) and MF59. Alum can be obtained from Superfos, Bedbaek, Denmark and are a 3% solution. If present, then ispolzuyutsya ~1 mg to ~1.67 mg of alum on the dose. When the component (C) comprises the antigen hepatitis b, the aluminum hydroxide is preferably not used as the carrier (for example, EP-A-0642355). Similarly, when the component (C) includes polysaccharide conjugate N. influenzae, the aluminum hydroxide is preferably not used as the carrier (for example, EP-A-0833662). Instead, it can be used phosphate .MF59 is microorgani emulsion of squalene in water, which has been shown to be safe and increases the responses of serum antibodies to various vaccines. MF59 includes approximately 5% squalene, 0.5% of Tween 80 and about 0.5% Span 85. Adjuvant MF59 described in WO 90/14837. MF59 can be obtained according to the method described, for example, Ott et al. in Vaccine Design: The Subunit And Adjuvant Approach (1995, Powell and Newman, Eds., Plenum Press, New York, p. 277-296); Singh et al. (1998) Vaccine 16, 1822-1827; Ott et al. (1995) Vaccine 13, 1557-1562; Valensi et al. (1994) J. Immunol. 153, 4029-39. Other media adjuvants that can be used include the formulation of an emulsion of oil in water (with or without other specific immunostimulating agents, as morelove peptides or components of the walls of the bacterial cells), as for example (a) MF59, as described above (optionally containing various amounts of MTP-PE, although it does not require the tsya) (b) SAF, containing 10% squalene, 0.4% of Tween 80, 5% blocked puranam polymer L121, and thr-MDP(see below) or microorganic to submicron emulsion or centrifuged to obtain the emulsion particles of large size, and (C) adjuvant system Ribi™ (RAS), (Ribi Immunochem, Hamilton, MT)containing 2% squalene, 0.2% of Tween 80, and one or more components of the walls of the bacterial cells from the group consisting of monophosphoric A (MPL), dimycolate trehalose (TDM), and the skeleton of the cell- walls (CWS), preferably MPL+CWS (Detox™); (3) can be used saponine adjuvants, such as Stimulon™ (Cambridge Bioscience, Worcester, MA) or derivatives particle type ISCOM (immunostimulating complexes); (4) complete adjuvant's adjuvant (CFA) and incomplete adjuvant's adjuvant (IFA); (5) cytokines such as interleukins (such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, etc), interferons (e.g. gamma interferon), colony stimulating factor, macrophage (M-CSF), tumor necrosis factor (TNF), etc; and (b) other substances that act as immunostimulating agents to enhance the effectiveness compositiion mentioned above, morelove peptides include as non-limiting examples of N-acetylmuramyl-L-threonyl - D-isoglutamine (thr-MDP), N-acetylmuramyl-L-alanyl-D-isoglutamine (nor-MDP), N-acetylmuramyl-L-alanyl-O-isoglutamine-L-alanine-2-(1'-2'-dipalmitoyl-ot-glycero-3-hydroxyrisperidone)ethylamine (MTP-PE), and so what.

Immunogenicity

When used herein, the term "immunogenic" refers to a substance that, when introduced vertebrate, kluchanovich, induces the production of antibodies.

The composition of the invention typically involve immunologically effective amount of components (a), (b) and (C). That is, enables the quantity of the component (a), (b) or (C), which in combination with any audience adjuvant is the subject of producing specific and sufficient immunological response, preferably T or lymphocytic response in such a way as to provide protection against subsequent exposure to Neisseria the subject."Immunologically effective amount" is effective either in a single dose or as part of a series of doses for the induction of the production of antibodies for the treatment or prevention of disease. This number varies depending on various factors, including the physical condition of the subject, and can be easily determined by the person skilled in the art. For a single dose could not be determined no signage, which will provide specific guidance for every antigen, which can be used in this invention. An effective amount of antigen is a function of its inherent activity, and of purity and empirically determined by customary SPE is eelistame in this area through routine experimentation. Immunogenic compositions of the present invention typically include an immunostimulatory amount of antigen of Neisseria. Immunostimulatory amount is an amount that is sufficient to cause a measurable humoral or cellular immune response. For example, immunogenic compositions of the present invention include from about 1 nanogram to about 1000 micrograms of antigen, or from about 10 nanograms to about 800 micrograms of antigen. In some preferred implementations immunological compositions contain from about 0.1 to about 500 micrograms of antigen. In some preferred implementations immunological compositions contain from about 1 to about 350 micrograms of antigen. In some preferred implementations immunological compositions contain from about 25 to about 250 micrograms of antigen. In some preferred implementations immunological compositions contain about 100 micrograms of antigen. Specialists in this field can easily be immunogenic composition comprising any desired quantity of the antigen, which can be determined empirically ordinary person skilled in the art by PN the other experimentation. Immunogenic compositions can be conveniently introduced in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical industry, for example, as described in (Mack Pub. Co., Easton, PA, 1980). Vaccines the Present invention is also directed to vaccines comprising any of the immunogenic compositions described above.

As used herein, the term "vaccine" means immunogenic composition, which can cause antimicrobial immune response. Preferably, the vaccine of the present invention cause antibacterial humoral response.

Vaccines of the present invention may either be prophylactic (i.e. to prevent infection)or therapeutic (i.e. to treat disease after infection). The invention also relates to a method of inducing an immune response to at least NmB and NmC or vaccination, including the introduction of immunologically effective amount of the immunogenic composition according to the invention. The introduction can be done to a person and may be using any of the methods known to experts in this field, including parenteral, rectal, intraperitoneal, intramuscular or subcutaneous route. Immediate shipping in General is performed by injecting either subcutaneously, intraperitoneally, intravenously or GNC is remisen, or delivery to the interstitial space of a tissue. The composition may also be in damage. Other routes of administration include oral and pulmonary introduction, suppositories, and transdermal or transcutaneous introduction (for example, WO 98/20734), needles, and gene guns" or needleless syringe. The dosage regimen can be a single dose or multiple doses.

The invention also relates to compositions according to the invention for use as medicaments. Additionally anoutside to the use of compositions according to the invention in the manufacture of medicaments for the treatment or prevention of infection by the bacteria Neisseria.

Alternatively, based on protein vaccines may be involved vaccination of nucleic acids [e.g., Robinson & Torres (1997) Seminars in Immunology 9:271-283; Donnelly et al. (1997) Annu Rev Immunol 15:617-648]. One or more protein components of the compositions according to the invention can thus be replaced by nucleic acid (preferably DNA)that encode a protein.

The method of production

The invention relates to a method of manufacturing the composition according to the invention, comprising mixing components (a), (b) and (C).

Total

For the implementation of the present invention, except where noted otherwise, will be zadeistvovannye methods in molecular biology, Microbiology, d is abinanti DNA and immunology, which lie within the practical experience in this field. Such methods are fully explained in the literature, for example, Sambrook Molecular Cloning; A Laboratory Manual, Second Edition (1989); DNA Cloning, Volumes I and ii (D.N Glover ed. 1985); Oligonucleotide Synthesis (M.J. Gait, ed, 1984); Nucleic Acid Hybridization (B.D. Hames &S.J. Higgias eds. 1984); and reduced Translation (B.D. Hames &S.J. Higgins, eds. 1984); Animal Cell Culture (R.I. Freshney ed. 1986); Immobilized Cells and Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide to Molecular Cloning (1984); the Methods in Enzymobgy series (Academic Press, Inc.), especially volumes 154 & 155; Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds. 1987, Cold Spring Harbor Laboratory); Mayer and Walker, eds. (1987), Immunochemical Methods in Celland Molecular Biology (Academic Press, London); Scopes, (1987) Protein Purification: Principles and Practice, Second Edition (Springer-Verlag, N.Y.), Handbook of Experimental Immunology, Volumes I-IV (DM. Weir and S. Blackwell eds 1986).

Definition

In this description uses standard abbreviations for nucleotides and amino acids. The term "including" means "comprising"as "comprising", for example, a composition "comprising" X may consist exclusively of X or may include something additional to X, such as X+Y.

The identity between proteins preferably determined by the search algorithm homology Smith-Waterman (Smith-Waterman) as implemented in the MPSRCH program (Oxford Molecular) using search related inserts with the parameters of the penalty for opening insert =12 and penalty for continuing inserts =1.

BRIEF DESCRIPTION of DRAWINGS

In all figures, the group which represents the data for 28 days after 1st injection and group b represents data for 18 days after the 2nd injection. The figure 1 shows the geometric average titers of IgG antibodies (KE (KU/ml) against (1A) OMV NmB and (1) capsule NmC, as determined by TYPHUS. * specified (1A) R≤0,03 for groups 5 groups 2 and 3 (1B) P≤0.02 for group 5 to group 1 and 4.

The figure 2 shows the titers of serum bactericidal antibodies (1/geometric mean titer) to (2A) NmB and (2B)NmC. * indicated P≤0,003 for group 5 to group 2.

WAYS of carrying out the INVENTION

The invention is further illustrated by the following examples, which are intended to explain the invention. The examples are intended to illustrate the invention and not to limit. Specialists in this field will be able to determine the modifications that are within the capabilities and scope of the invention.

Example 1: the Result of TYPHOID

Groups of Guinea pigs (n=15 animals) received one of the vaccines listed in the following table 1:

Table 1
GroupComponentsAmount per dose
Group1NmC conj./alum10 mcg/1 mg
Group 2NmB/alum25 mcg/1 mg
Group3NmC polysaccharide/NmB/alum10 mcg/25 mcg/1 mg
Group4NmC conj./NmB/alum10 mcg/25 mcg/1 mg
Group5NmC conj./NmB/MF5910 mcg/25 mcg/0.5 ml
Group 6(n=5) including control animals, which received talakvadze

Eighty Guinea pigs were randomly distributed into the ranks of the groups listed above, and received one of the six combinations of vaccines. As for the data presented in table 2, each animal received two injections,/m, separated by 28 days. Serum samples were obtained before each injection and 18 days after the second injection. That for the data shown in Fig. 1A and 1B, each was iwatayama two immunization, separated by six weeks. Each dose contained two I/m injection of 0.25 ml serum Samples were obtained immediately before each injection and after 14 or 18 days after the second iny the work. Serum samples were studied using concentrations anticapsular of IgG antibodies to NmC (table 2 and figa) and concentrations of IgG antibodies against outer membrane vesicles (0MV) to NmB with TYPHOID fever (figure 1). Data TYPHOID were obtained in a representative study of individual sera of animals (table 2), and expressed as average arithmetic values for a variety of studies (figa and 1B). Therefore, the total data of TYPHUS in table 2 are expressed as the geometric average. For TYPHOID conjugate MCPS-ADH (dehydrated polysaccharide-adipic acid NmC) or OMV components were superimposed on polystyrene tablets for micrometrology over night at 4°C With 1 µg/ml, 100 μl/cell. Each layered tablet 100 μl/cell of each of the standard of comparison (i.e., pooled serum of the Guinea pig), positive control, negative control and serum samples are periodically twice dissolved in buffer containing 75 μm of ammonium thiocyanate, and within two hours were incubated at room temperature Conjugated with peroxidase rabbit IgG antibody against Guinea pigs were added to the cells (100 μl/cell). After 2 hours was added colorimetric substrate 3,3',5,5 tetramethylbenzidine (TMB) (100 μl/cell), and staining was evident in techenie minutes. Antibody levels for MCPS and for OMV present in to what the trolls and samples received on standard curves using comparison standards, which have a fixed value of 100 TYPHOID units/ml the Results are shown in table 2 and figures 1A and verzeletti, are summarized in table 2, figures 1A and 1B show that the combination vaccine was immunogenic, which was measured by antibody titers of IgG NmB and NmC, respectively.

Table 2:
Humoral IgG response NmC (GMT)
The study SCN
VaccineAdjuvantAfter 1 injectionAfter 2 injections
NmC Conj.Alum20,3155
MenBAlum<1<1
NmC Ps+MenBAlum<11,5
NmC Conj.+MenBAlum9,5 71
NmC Conj.+MenBMF5915,2426
NoAlum<1<1

Figure 1A shows that the specific humoral response against meningococcal disease was induced by combinations of vaccines, including NmB. The figure 1 shows that the specific humoral response against meningococcus C was induced by combinations of vaccines, including NmC. In particular, the humoral response induced by the combination conjugate NmC and NmB in the presence of MF59 adjuvant (group 5) was significantly higher than the humoral response induced only by the NmC conjugate (group 1), or a combination of conjugate NmC and the NmB prisutstvie alum (group 4). When I attended adjuvant MF59, the titer of antibodies for combination vaccines has increased by about six times. Example 2: Bactericidal terriorists serum was tested for complement-mediated captions strain 60S MenC and strain 44/76 Mepv. Bactericidal titers were investigated by combined serum from each group. Bactericidal data were obtained using human complement. Components of the study (i.e., buffer, antibody, complement and bacteria) was added to the camping in sterile 96-well tablets with covers for tissue culture (Nunc # 167008). During the study, the tablets were stored at room temperature. In each cell sequentially added 50 μl of buffer Jay (Gey) (Gibco)containing 1% RIA Grade BSA (Sigma), 25 μl of diluted test antibodies, 25 µl of the bacteria, diluted in a ratio of 1:8000 in the buffer Jay (Gey)/1% BSA. Control cells included 1) buffer Jay (Gey)/1% BSA and only bacterium (in order to determine viable if the organisms only in solvent); 2) control time 0, containing 75 ál of buffer, 25 μl of inactivated by heat (56°C, 30 minutes) of human complement and 25 µl of bacteria; 3) monitoring for toxicity testing in the presence of complement at 20% and 40% buffer and bacteria, in order to verify that the source of complement is non-toxic to the tested strain. To show that the increase in colony forming units (CFU (cfu)), prisutstvie antibodies is dependent on complement, all samples antibodies (at the highest investigated concentration) was also tested with inaktivirovannye heating complement. After all reagents were added 22 μl was taken from each test cell was placed in a Cup with agar Mueller-Hinton (Mueller-Hinton), allowing the sample to flow from top to bottom, to determine SOME of the cell at 0 minutes. Tablets for micrometrology then covered and sealed with wax is gently rotated for 1 hour at 37°C in an incubator with 4% CO 2. Then the tablets were removed, and 22 μl of sample from each cell were transferred to agar Mueller-Hinton (Mueller-Hinton). Tablets with the culture was incubated for approximately 18 hours at 37°C With 4% CO2- Colonies were recalculated, and percent survival was determined for each tested cell: % survival=([CFU in the cell with the sample for 60 minutes] /[CFU in the control cell with inaktivirovannye heating complement at 0 minutes]) x 100. Here is bactericidal titers are titles that were obtained with 50% survival rate. The results of one experiment are presented in table 3. The results are also shown in figures 2A and 2 B, and figure 2 presents the average arithmetic value of the titles of many experiments. As shown by the results summarized in table 3, the combination vaccine induces high titers of serum bactericidal antibodies for NmB and NmC. The bactericidal titer antibody NmC was slightly higher decompencirovannah vaccine using MF59 as a carrier, but no significant effect on the bactericidal titer NmB using MF59. Interestingly, two to five times higher bactericidal titers NmB were obtained for the combination vaccine than one vaccine NmB. Figure 2A shows that are aimed at the meningococcus In the antibodies induced by the use of combination vaccines including NmB, were bactericidal. In figure 2 demonstrated that focused on meningococcal disease With antibodies induced using a combination vaccine comprising the conjugate NmC, were also bactericidal.

Table 3
NmC (1/titer)NmB (Ptar)
The vaccine groupBefore injectionsAfter 1 injectionAfter 2 injectionsBefore injectionsAfter 1 inyenziAfter 2 injections
NmC conj.+alum<580>3375<5<5<5
NmB+alum<5<515<515800
NmC Ps+NmB+alum<5<5 30<5251500
NmC Conj.+NmB+alum<5252000<5255000
NmC Conj.+NmB+MF59<550>3375<5254000
Alum<5<5<5<5<5<5

Example 3: Comparison of alum and adjuvants MF59. serum of animals described above in figures 1A and 1 B, and determined humoral responses MenC and Mepv caused when using NmB/NmC conj. or with alum or MF59 adjuvant, as described above in examples 1 and 2. The results are shown in table 4.

Table 4
The ratio of humoral responses in animals treated with the combination of OMV NmB + NmC conjugate or with Al(OH)3or hell the Vantomme MF59
ResearchThe ratio of GMT MF59: GMT AL(OH)3
28 days after 1 injection18 days after 2 injections
NmC
IgG1,66,0**
Bactericidal1,01,2*
NmB
IgG0,71,4
Bactericidal0,91,4
* tested only combined serum **p≤0,001

These data suggest that the humoral response to meningococcal disease was approximately six times greater than for vaccines, including adjuvant MF59.

Example 4: Comparison of responses invoked by using the combination to monovalent vaccines

Compared the serum of the animals described above in figures 1A and 1 B, and humoral responses of the MISP and MenB caused when using NmB/NmC conj., compared with the humoral responses induced or only vaccine NmB, or only NmC conj. with alum, to the described above in examples 1 and 2. The results are shown in table 5:

Table 5
The ratio of humoral responses in animals treated with a combination of Al(OH)3to monovalent vaccine Al(OH)3
ResearchThe ratio of GMT MF59: GMT AL(OH)3
28 days after 1 injection18 days after 2 injections
NmC
IgG0,50,5
Bactericidal0,2*0,7*
NmB
IgG1,31,2
Bactericidal1,62,9**
*tested only combined serum **p≤0,05

These data demonstrate that there is no significant difference in humoral responses to the vaccine components NmB/NmC conj. compared to the responses induced when using MANOVA entih vaccines (or NmB, or NmC conj.).

Example 5: Adding more antigens

The combination of NmB/NmC conj. further expanded by the addition of antigens against other pathogenic organisms (e.g., NspA, HBsAg). Good immune response was observed against NmB/NmC and against additional antigens.

Example 6: a Mixture of antigens NmB and NmC

For immunization of mice was used trivalent mixture of proteins of strain 2996 Mepv "919" (for example, figure 23 of WO 99/57280 and SEQ ID NO: 3069-3074 here), "287" (for example, figure 21 of WO 99/57280; SEQ ID NO: 3103-3108 here) and "ORF1" (for example, example 77 from WO 99/24578; see also W099/55873). This experiment was repeated with the addition of conjugate NmC. The aluminum hydroxide was used as adjuvant. Measured in bactericidal study titers against the homologous strain and heterologous strains of MenB were as follows:

2996BZ133BZ2321000MSNGH38
Trivalent mixture204820484<4644
+mC 2048>3200041281024128

Obviously, this application describes an invention only by way of example, and may be made of modifications, still in the limits and scope of the invention.

1. Immunogenic composition having immunogenic activity against Neisseria meningitidis from serogroups b and C, containing (a) oligosaccharide Neisseria meningitidis serogroup C (NmC), (b) proteoliposome of outer membrane vesicles of Neisseria meningitidis serogroup B (NmB) and (C) NmB protein containing
(i) an amino acid sequence selected from SEQ ID NO: 2534, 2536 2538 or,
(ii) an immunogenic fragment of the sequence, or
(iii) a sequence at least 80% identical to the sequence SEQ ID NO: 2534, 2536 2538 or.

2. Immunogenic composition according to claim 1, where component (a) anywhereman with the media.

3. Immunogenic composition according to claim 2, where the carrier is a protein.

4. Immunogenic composition according to claim 3, where the carrier is CRM197, diphtheria toxoid or toxoid tetanus.

5. Immunogenic composition according to any one of claims 1 to 4, in addition, containing aluminium hydroxide as adjuvant or MF59 adjuvant.

6. Vaccine Neiseria meningitidis from serogroups b and C, containing immunogenic composition according to any one of claims 1 to 5.



 

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SUBSTANCE: invention refers to a number of bicyclic nitroimidazole-replaced phenyloxazolydinones of the following structural formula (I):

,

containing nitroimidazole circle, or to its pharmaceutically acceptable salt; where R1 represents hydrogen, (C1-C6)alkyl or aryl; n is equal to 0, 1 or 2; X1 and X2 independently represent H, CF3, CI, OCF3 or F; G represents -OH, triazole or -NHCOR2; R2 represents (C1-C6)alkyl, cycloalkyl or aryl; and L represents a bond or a linker group chosen from any combination 2-3 of the following groups: 1) (C1-C6)alkylene, 2) (C3-C8)cycloalkylene, 3) arylene, arylene-replaced CN, ore arylene-replaced F, 4) group chosen from the group consisting of

,

where R10 represents H, CF3, hydroxyl, amino, alkyl, alkylamino, alkoxy or aryl, and R13 represents H, hydroxyl, amino, alkyl, alkyl amino, alkoxy or aryl, or R13 in combination with nitroimidazole circle can form spiral-shaped structure, 5) -C(=O)-, 6) -O-, 7) -S(O)n-, in which n is equal to 0.1 or 2, 8) -N(R3)-, 9) -C(R4)=C(R5)-, R3 represents hydrogen, (C1-C6) alkyl or aryl, and R4 and R5 represent hydrogen, (C1-C6) alkyl or aryl, or R4 and R5 can be combined together so that they can form a bond. Besides, the invention refers to pharmaceutical composition for treatment of bacterial infection based on compounds of formula I, as well as to a bacterial infection treatment method.

EFFECT: invention describes new compounds that have antibacterial activity against a line of wild type and stable lines of pathogenic microorganisms, and as a result, are suitable for prevention, control and treatment of a number of human and mammal bacterial infections caused by these pathogenic microorganisms such as bacillus Kochii.

15 cl, 93 ex, 1 tbl, 22 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, more specifically, to using a chimeric somatostatin-containing protein for improving the reproductive properties of male farm animals and cocks, and may be used in veterinary science. The injection preparation is used in the form of a chimeric protein suspension with water-insoluble enzyme-inactive chloramphenicol acetyltransferase with no 10 C-terminal amino acids, amino acid spacer (Sp)n, wherein n=1, 2, 4, 8 and somatostatin-14 with AGCFWKTFTSC amino acid sequence in the refined vegetable oil with bee wax added at 250-1000 mg of the above chimeric protein per 100 ml of the refined vegetable oil containing 0.9-1.1 wt % of bee wax. The injection preparation is used in cocks and farm animals after achieving the physiological maturity at 50-200 mcg of the protein per 1 kg of a live body weight.

EFFECT: invention enables increasing sperm production: increasing the ejaculate volume and reducing the biologically damaged sperm in farm animals and cocks by using the preparation for injections with a low-reactogenicity adjuvant.

2 cl, 13 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a composition for nicotinic immunonanotherapy containing synthetic nanocarriers having a polymeric surface conjugated with a variety of nicotine residues with the variety of the nicotinic residues on the nanocarrier form an immunogenic surface providing a low affinity, a high-avidity binding of the nicotinic residues to the surfaces of an antigen presenting cell (APC) compared with an antibody binding, and a pharmaceutically acceptable excipient. The invention provides the nanocarriers capable to stimulate an immune response in T-cells and/or B cells and to produce the antinicotin antibodies with the humoral and cellular response to be achieved in the absence of an exogenous adjuvant.

EFFECT: invention provides the absence of the non-specific response on an inflammation caused by an adjuvant.

17 cl, 37 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely biopharmaceutics and may be used for preparing an immunogenic conjugate. That is ensured by: (a) a reaction of serotype 1 purified polysaccharide with an alkaline buffer to prepare serotype 1 partially des-O-acetylated polysaccharide; (b) a reaction of serotype 1 partially des-O-acetylated polysaccharide and a weak acid to produce serotype 1 neutralised partially des-O-acetylated polysaccharide; (c) a reaction of serotype 1 neutralised partially des-O-acetylated polysaccharide and an oxidising agent to prepare serotype 1 activated polysaccharide; (d) mixing of serotype 1 activated polysaccharide and a carrier protein; (d') combined lyophilisation of mixed serotype 1 activated polysaccharide and the carrier protein before a reaction with a reducing agent; (e) reaction of mixed serotype 1 activated polysaccharide and the carrier protein with the reducing agent to prepare a serotype 1 activated polysaccharide/carrier protein conjugate; and (f) capping of unreacted aldehydes in the serotype 1 activated polysaccharide/carrier protein conjugate. What is also presented is a method for preparing a multivalent immunogenic composition.

EFFECT: group of inventions enables preparing the composition presented in the form of vaccines that decreases a number of severe pneumococcal diseases.

27 cl, 17 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is presented is a lyophilised preparation containing at least one nicotine - virus-like particle conjugate, and a stabiliser composition containing at least one nonreducing disaccharide and at least one non-ionic surfactant wherein the pre-lyophilisation pH value of the stabiliser composition makes 5.8 to 6.6, preferentially 6.0 to 6.4.

EFFECT: invention provides producing the effective lyophilised vaccinal preparation able to keep stability for a long period of time.

14 cl, 3 dwg, 4 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discloses compositions for inducing an immune response in a patient, containing a combination of two or more monovalent conjugates wherein each of the monovalent conjugates contains a carrier protein N19 conjugated with a saccharide antigen of the serogroups A, C, W135 or Y Neissera meningitides. A molecule of the carrier protein in the monovalent conjugate is preferred to be conjugated with more than one molecule of the saccharide antigen. Besides, the invention discloses a multivalent conjugate for inducing an immune response in a patient, containing two or more antigen-different saccharide antigens of the serogroups A, C, W135 or Y Neissera meningitides conjugated with the carrier protein N19. The compositions may contain one or more said monovalent conjugates and one or more said multivalent conjugates. The invention shows applicability of the multivalent conjugate and compositions in preparing a medicine for enhancing the immune response in a patient.

EFFECT: compositions used under the invention elicit much stronger and fast immune response and exhibit lower reactogenicity for a patient.

16 cl, 33 dwg, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to molecular biology, virology, immunology and medicine. The invention presents a composition which contains a sequenced and repetitive antigen or antigen determinant array, and particularly a composition which contains an Aβ1-6-peptide-HPV conjugate. More specifically, the invention provides the composition which contains a virus-like particle and at least one coupled Aβ1-6-peptide. Also, the invention describes a method for preparing the conjugates and the sequenced and repetitive arrays respectively.

EFFECT: compositions presented in the invention may be applicable for producing vaccines intended for treating Alzheimer's disease, and as pharmaceutical agents intended for preventing or treating Alzheimer's disease and for effective immune response induction, particularly antibody responses; besides, the compositions presented in the invention are established to be applicable first of all for effective induction of autoantigenic responses.

45 cl, 35 dwg, 22 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns an influenza vaccine and method for preparing it. Substance of the invention involves the influenza vaccine containing the coupling of purified influenza virus antigens and a polymeric carrier representing 2-methyl-5-vinylpyridine and N-vinylpyrrolidone copolymer in proportions 1: 5-30, and a method for preparing the influenza vaccine involving the cultivation of influenza virus strain in chicken embryos to produce a purified viral concentrate that is followed by inactivating, splitting the viral concentrate to produce the purified influenza virus antigens and coupling with the polymer carrier representing 2-methyl-5-vinylpyridine and N-vinylpyrrolidone copolymer in proportions 1: 5-30.

EFFECT: preparation of the vaccine.

2 cl, 5 ex, 3 tbl

FIELD: medicine, immunology.

SUBSTANCE: group of inventions relates to medicine in particular to immunology and can be applied to enhance the immune response of animals and human to antigen consisting of one or a number of epitopes; for the above purpose the parenteral immunization of the patient is performed either with the mixture of the above antigen and adjuvant in the shape of spherical particles or with the above antigen fixed on the surface of the spherical particles; at that the spherical particles consist of thermo-denaturated coat protein of spiral plant viruses, predominantly tobacco mosaic virus.

EFFECT: invention secures the efficient stimulation of the immune response to the antigen upon pareneteral immunization of the patient with small doses of the antigen.

2 cl, 9 ex, 9 dwg

FIELD: biology, medicine, nanotechnology.

SUBSTANCE: group of inventions is referred to the area of biology, medicine, nanotechnology and involves processing of new platform carriers for formation of complexes with biologically active compounds. The proposed platform carriers are of spherical shape and are made by the way of thermal reconfiguration of structure of tobacco mosaic virus (TMV) or another tobamovirus or another plant virus with spiral structure or their fragments. The platform carriers are also produced by the way of thermal reconfiguration of coat protein of TMV group virus (tobamoviruses) or another phytovirus with spiral structure or their fragments. There were also proposed the compositions containing the platform-carrier of said spherical carrier connected with the alien protein or another biologically active compound. The advantages of new platform carriers include the simplicity and quickness of production, possibility to get spherical particles of regulated sizes, long term storage, absence of aggregation and preservation of spherical shape during its storage, centrifugation and resedimentation, the convenience of spherical particles shape for formation of complexes with target compound.

EFFECT: important feature of a new carrier platform is the capability to adsorb on the surface and to form compositions with different structurally and functionally alien proteins/antigens.

3 cl, 6 ex, 10 dwg

FIELD: medicine.

SUBSTANCE: what is described is a composition containing an ordered antigen pattern where antigen represents IL-1, mutein IL-1 or fragment IL-1. There is also offered a based vaccine. The compositions offered in the invention can be applied for producing vaccines for inflammatory diseases and chronic autoimmune diseases, transmittable diseases and cardiovascular diseases.

EFFECT: compositions effectively induce immune responses, particularly humoral immune responses; compositions are the most suitable for effective induction of autogenic immune responses.

46 cl, 2 dwg, 3 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary medicine, and concerns a method for producing an associated salmonellosis, escherichiosis and rabbit viral hemorrhagic disease vaccine. Implement the method involves sampling the affected organs from fallen rabbits on the local epidemical block to prepare a suspension that is followed by inoculation of differential diagnostic media. Pure cultures of pathogens are recovered. The culture Salmonella typhimurium, Escherichia coli is separately grown in meat infusion broth with adding glucose to the concentration of 0.2% with a titre of 4-5 bln. microbial cells in 1 cm3. Then the rabbits are infected with a hemorrhagic disease virus at min. activity 103 LD50/cm3 and the fallen rabbits' liver is used to prepare 10-15% suspension. The pathogen cultures are inactivated separately in formalin to the final concentration of no more than 0.4% at temperature 37°C for no more than 4 days; the inactivated culture mixture is added with an adjuvant which is presented by an aluminium hydroxide gel in the amount of 20% to the volume; the end product is thoroughly mixed before packaging.

EFFECT: presented invention enables producing the safe, storage-stable high-immunogenic associated salmonellosis, escherichiosis and rabbit viral hemorrhagic disease vaccine which may be used in biopreparation engineering.

1 tbl

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