CN1146444C - 含有吸附于磷酸铝上的多糖偶联抗原的疫苗组合物 - Google Patents
含有吸附于磷酸铝上的多糖偶联抗原的疫苗组合物 Download PDFInfo
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- CN1146444C CN1146444C CNB961949732A CN96194973A CN1146444C CN 1146444 C CN1146444 C CN 1146444C CN B961949732 A CNB961949732 A CN B961949732A CN 96194973 A CN96194973 A CN 96194973A CN 1146444 C CN1146444 C CN 1146444C
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- vaccine
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Abstract
本发明涉及预防流感嗜血菌B型(Hib)感染的疫苗制剂，其中抗原被吸附到磷酸铝上，本发明也涉及多价疫苗，此疫苗可改善或治疗一种以上的疾病，本发明也涉及这种疫苗的生产或在医药中的应用。
Description
本发明涉及含有与载体蛋白相连的偶联多糖抗原的新的疫苗制剂，本发明具体涉及抗原吸附于磷酸铝上的预防流感嗜血菌B型(Hib)感染的疫苗制剂，本发明也涉及多价疫苗，即用于改善或治疗一种以上疾病状态的疫苗，本发明也涉及这种疫苗的生产及其在医药上的应用。
现有技术中已知利用多糖的疫苗，例如用于预防流感嗜血菌B型(Hib)感染的疫苗是以与载体蛋白偶联的荚膜多糖(PRP)为基础的。该多糖是核糖、核糖醇和磷酸的聚合物，这些疫苗通常以简单的(即没有佐剂)制剂形式存在，尽管在一种情况下，(由Merek生产的Pedvax Hib)利用了含有氢氧化铝的稀释剂以重建冻干的偶联物。载体蛋白通常是白喉或破伤风类毒素或脑膜炎奈瑟氏球菌的外膜蛋白。这种偶联疫苗抗原的例子公开于US4 365 170，US4 673 574，EP208 375，EP477 508和EP161 188。
可以将这种偶联疫苗与其他抗原或疫苗同时施用，这可涉及到多次注射，与多次注射相关的问题包括更复杂的施用方法和大的总注射体积。当疫苗给婴儿使用时，这是一个十分严重的问题。
因此建议生产联合疫苗，一个众所周知的联合疫苗提供抗白喉、破伤风和百日咳杆菌(B.pertussis)感染的保护，此疫苗含有整个细胞或无细胞的百日咳成分，所述成分通常由两或三种抗原组成(去毒的PT，FHA，经常但不是全部为69KDa)，尽管在某些情况下，其他百日咳杆菌(B.pertussis)抗原也可存在并使白喉和破伤风毒素类毒素化。这种疫苗经常指的是DTPw或DTPa，也可以在这种联合疫苗中加入合乎需要的其他抗原以预防如乙型肝炎或脊髓灰质炎的疾病。
可以在此联合中加入多糖偶联疫苗，然而我们已发现各种成分的简单混合会导致降低对多糖成分的抗体滴度。
本发明人已发现如果将偶联抗原吸附于磷酸铝上即可抑制这种降低，相反，如果抗原被吸附于氢氧化铝上，对多糖成分的抗体滴度彻底降低。
因此本发明提供了含有吸附于磷酸铝上的多糖偶联抗原的疫苗组合物，此抗原优选为与载体蛋白偶联的得自Hib的荚膜多糖(PRP)。
载体蛋白优选为白喉或破伤风类毒素，白喉Crm197蛋白或如脑膜炎奈瑟氏球菌等细菌的外膜蛋白。
通过任何已知的偶联技术都可制备多糖偶联物，例如可通过硫醚键偶联多糖，此偶联法依靠用1-氰-4-二甲基氨基吡啶鎓四氟硼酸盐(CDAP)激活多糖以形成氰酸酯，因此被激活的多糖可直接或通过间隔基与载体蛋白上的氨基基团偶联，优选使氰酸酯与己烷二胺偶联，使用涉及硫醚键形成的异连接(heteroligation)化学使氨基-衍生化的多糖与载体蛋白偶联。这种偶联物描述于PCT公开申请WO93/15760 Uniformed Services University。
也可通过US 4365170(Jennings)和US 4673574(Anderson)中描述的直接还原胺化法制备偶联物，其他方法描述于EP-0-161-188，EP-208375和EP-0-477508中。
另一个方法涉及通过碳二亚胺缩合使被溴化氰激活又被己二酸酰肼(ADH)衍生化的多糖与蛋白载体偶联，这种偶联描述于Chu C.等感染免疫(Infec Immunity)，1983 245 256。
在本发明优选的实施方案中，PRP多糖与载体蛋白的比例由典型的1∶3降至1∶0.3-1∶2，这种低比例的偶联物是有利的，因为即使在没有佐剂的状态下，它们也不会遇到干扰的问题。
在本发明优选的实施方案中，该制剂优选含有至少一种其他成分，所述其它成分可提供抗一种或多种选自下列病原的保护作用的抗原：甲型肝炎病毒(HAV)，白喉，破伤风，百日咳，乙型肝炎和脊髓灰质炎。
在本发明范围内的具体联合疫苗包括DTPa(白喉-破伤风-无细胞的百日咳)-Hib联合疫苗制剂，Hib-乙型肝炎疫苗制剂，DTPa-Hib-乙型肝炎疫苗制剂和IPV(灭活的脊髓灰质炎疫苗)-DTPa-Hib-乙型肝炎疫苗制剂。
上述联合疫苗可任选包括具有抗甲型肝炎的保护作用的成分。
用于这种疫苗的适当成分已经可以商购，可从世界卫生组织得到详情。例如，IPV成分可以是Salk灭活型脊髓灰质炎疫苗。白喉、破伤风和百日咳疫苗可含有无细胞的产物，如Infanrix DTPa(SmithKline Beecham Bilolgicals)。提供抗甲型肝炎的保护作用的成分优选是已知为‘Havrix’(SmithKlineBeecham Bilolgicals)的产物，它是得自HAV的HM-175株的被杀死的减毒疫苗[见灭活甲肝候选疫苗(‘Inactivated Candidate Vaccines for Hepatitis A’)，F.E Andre，A Hepburn and E.D Hondt，医学病毒学进展(Prog.Med.Virol).Vol37，page 72-95(1990)and‘Havrix’产品专题(the product monograph‘Havrix’published by SmithKline Beecham Biolgicals(1991))。乙型肝炎病毒成分可含有‘S’抗原，如在‘Engerix-B’中的情况。
有利的是根据本发明的流感嗜血菌B型或联合疫苗可作为儿科疫苗。
疫苗的制备一般描述于疫苗设计-亚单元和佐剂方法(Vaccine Design-The Subunit and adjuvant approach)Ed Powell and Newman；Pellum Press。包入脂质体囊的方法描述于例如Fullerton的美国专利4,235,877。蛋白质与大分子的偶联公开于如Likhite的美国专利4,372,945和Armor等人的美国专利4,474,757。
每一疫苗剂量中偶联抗原的量选定为，在典型的疫苗接种者中可诱导免疫保护性应答而没有显著的，有害的副作用的量，这种量依据所用特殊免疫原的不同而有所不同，一般希望每一剂量含有1-1000ug总免疫原，优选2-100ug，最优选4-40ug。可通过涉及观察抗体滴度和受试者的其他反应的标准研究确定对于具体疫苗而言的最适量，受试者可以以约4周为间隔接受一或两次加强注射。
根据本发明的另一方面，提供了含有吸附于磷酸铝上的偶联抗原的疫苗的生产方法，所述吸附优选在pH5-6之间进行，优选在约5.4时进行。在一个实施方案中，将疫苗在放置超过24小时后冷冻干燥，另外本发明的疫苗可以液体形式与其他抗原联合。
本发明进一步提供了这种疫苗的首次医学应用。
本发明的另一个实施方案提供了预防或改善流感嗜血菌B型感染的方法，此方法包括施用无毒的有效量的本发明疫苗。
下列实施例将阐明本发明。
实施例1
含有吸附于磷酸铝上的与破伤风类毒素偶联的HiB多糖的疫苗制剂合成流感嗜血菌B型荚膜多糖(PRP)破伤风类毒素(TT)偶联物
1.a溴化氰偶联
通过由NIH开发的偶联化学(Chu C.et al(1983)，进一步研究流感嗜血菌B型和肺炎球菌6A型的多糖蛋白偶联物的免疫原性(further studies on theimmunogenicity of Haemophilus influenzae type b and pneumococcal type 6Apolysaccharide protein conjugates)，感染免疫(infec Immunity)，245-256)进行PRP和TT的共价偶联，在受控制的条件下，PRP用溴化氰激活并用己二酸酰肼间隔基衍生化。
衍生化后，通过渗滤纯化被激活的多糖(PRP-AH)，通过碳二亚胺缩合使两种纯化的成分(PRP-AH和TT)偶联，然后通过超滤和凝胶过滤纯化偶联物以除去试剂和未偶联的PRP和TT。
PRP-TT偶联物的合成
1.bCDAP偶联
将30mg天然Hib PRP溶于6ml 2M NaCl中，在多糖溶液(来自100mg/ml的于乙腈中的储存溶液)中加入225mcl的CDAP(1-氰-4-二甲基氨基-吡啶鎓四氟硼酸盐)，90秒后，加入450mcl 0.2M的三乙胺，激活在pH10.0下进行，冰上1分钟，室温下分钟。
在激活的多糖中加入90mg破伤风类毒类(最初的PS与蛋白质的比例为1比3)，偶联反应在室温下进行1小时，然后，在室温下用3ml 1M的甘氨酸溶液，pH5.0淬灭该反应30分钟，并在4℃下过夜。
通过在用0.2M NaCl平衡过的sephacryl HR 500柱上凝胶过滤纯化偶联物，测定每一级分中的糖类和蛋白质的含量，收集偶联物并过滤除菌(膜Minisart 0.222γm)。
吸附于磷酸铝上
1.c在0.15mg磷酸铝中加入12.5mcg实施例1(a)中的多糖偶联物，搅拌2小时，将pH调至5.1，将混合物在室温下放置一天，再将被吸附的偶联物在2至8℃下放置9天，为了制备冻干的产物，将被吸附的产物在乳糖(15.75mg)中稀释以得到25mcg多糖/ml和0.4mg Al/ml的最终组合物，将所得最终组合物装入0.5ml小瓶中冻干。
为了制备液体产物，将被吸附的偶联物与150mM NaCl和5mg/ml苯氧基乙醇在用于注射的水中稀释以得到20mcg多糖/ml和0.32mg Al/ml的最终组合物。
1.d根据WO93/24148(SmithKline Beecham Bilolgicals)的方法配制含和不含乙型肝炎病毒的白喉破伤风和百日咳(无细胞的)疫苗。
1.e制备‘低比例’PRP-TT磷酸铝预-吸附偶联物。
用与实施例1.a相似，但是所用的破伤风类毒素的量(30mcg，60mcg)有所降低的方法制备偶联物，得到多糖：蛋白质的比例为1∶1或1∶2的产物，然后根据实施例1c的方法，将偶联物吸附于磷酸铝上，最终的冻干制品含有12.5μg偶联物，0.15mg ALPO4，15.75mg乳糖，使用前在0.5ml注射用水，pH0.1+/-0.1中重建。
实施例2：预吸附于磷酸铝上并与DTPa或DTPa-HB联合的PRP-TT偶联物的免疫原性
在注射前的1小时内，将简单型或预吸附于ALPO4上的实施例1a)中的Hib偶联物(两种疫苗都被冻干)与DTPa或DTPaHB混合，将此联合疫苗以相当于1/20人剂量的剂量(0.5μg PRP)通过皮下途径注射幼龄大鼠(1周龄)，2周和4周后对大鼠加强免疫，每次免疫接种后收集血清以测量抗-PRP抗体，对照包括在盐水中重建的Hib疫苗(吸附或未吸附于ALPO4上)。
在0-14-28天用1/20人剂量的Hib疫苗，单独或与DTPa或DTPaHB(1/20th人剂量)联合将随机抽取的每组10只幼龄大鼠(1周的ago-OFA株)皮下免疫3次，在免疫接种前的1小时内，用盐水或联合(DTPa或DTPaHB)重建冻干的Hib疫苗。
在14-28-56天，麻醉下取鼠血，通过对单份血清的ELISA测量抗-PRP的抗体，使用校正参比以γ/ml表示滴度，计算每一组和每一时间点的GMT，计算第三次免疫接种后所得滴度的95％置信限。
如表1所示，Hib偶联物吸附于ALPO4没有改变其免疫原性：如在婴儿中见到的，第二次剂量后产生了一些抗-PS，第三次剂量后显示出良好的加强免疫效果。将Hib疫苗与DTPa或DTPaHB混合使抗-PRP反应降低了3至8倍，在DTPaHB情况下，这一降低更加明显。相反，Hib疫苗预吸附至ALPO4使抗-PRP反应恢复到至少与简单型疫苗所能获得的相等的水平。
结论：
因而，该Hib/磷酸铝制剂具有解决当将Hib与其他小儿科联合疫苗混合时所遇到的相容性问题的潜力。
表1 预吸附于ALPO4上的以及与DTPa或DTPa-HB联合的
PRP-TT偶联物在幼龄大鼠模型中的免疫原性
| 疫苗 | 抗PRP滴度(γ/ml)(天) | |||
| 14天(第一剂量后) | 28天(第二剂量后) | 42天(第三剂量后) | 56天(第三剂量30天后) | |
| 无(Nacl 0.9％) | ＜0.05 | ＜0.05 | ＜0.05 | ＜0.05 |
| Hib-001Hib/AlPO4(Dhib-024) | ＜0.05＜0.05 | 0.061.3 | 12.9(4-37)11.8(5-29) | 10.9(4-31)15.4(7-35) |
| Hib-001+DTPa(119)Hib/AlPO4+DTPa(119) | ＜0.05＜0.05 | 0.161.9 | 3.4(0-28)20.9(7-59) | 1.4(0.1-1.7)19.7(9.42) |
| Hib-001+DTPaHB(16705)Hib/AlPO4+DTPaHB(16705) | ＜0.05＜0.05 | 0.140.47 | 2.8(1-6)11.4(5-27) | 3.9(2-9)18.1(9-38) |
| Hib/Al(OH3) | ＜0.05 | ＜0.05 | ＜0.05 | ＜0.14 |
Claims (19)
1.一种组合疫苗，其包括偶联于载体蛋白上的并和至少一种其它抗原混合的B型流感嗜血菌荚膜多糖，该其它抗原选自：甲肝病毒，白喉，破伤风，百日咳，乙肝病毒以及脊髓灰质炎；特征是该偶联物吸附于磷酸铝上。
2.根据权利要求1所述的组合疫苗，其中的载体蛋白选自：白喉类毒素，白喉CRM197蛋白，脑膜炎球菌外膜蛋白和破伤风类毒素。
3.根据权利要求1所述的组合疫苗，其中偶联B型流感嗜血菌荚膜多糖的载体蛋白是破伤风类毒素。
4.根据权利要求1所述的组合疫苗，其中B型流感嗜血菌荚膜多糖对载体蛋白的重量比例为1∶0.3到1∶2。
5.根据权利要求1所述的疫苗，其中与磷酸铝吸附后的偶联物被冻干。
6.根据权利要求5所述的疫苗，其中与磷酸铝吸附后的偶联物悬浮于水中以供注射。
7.一种试剂盒，含有第一和第二容器，所述第一容器中含有经冻干的吸附至磷酸铝上的偶联物，所述偶联物包含与载体蛋白偶联的B型流感嗜血菌荚膜多糖，所述第二容器中含有抗第二种病原体的疫苗，所述第二种病原体选自甲型肝炎病毒、白喉、破伤风、百日咳、乙型肝炎病毒或脊髓灰质炎病毒。
8.一种生产根据权利要求1所述的疫苗的方法，包括：将B型流感嗜血菌荚膜多糖抗原偶联到蛋白载体上；在pH5-6将所述荚膜多糖偶联物吸附至磷酸铝上；与一种或多种其它抗原混合，所述其它抗原选自：甲肝病毒，白喉，破伤风，百日咳，乙肝病毒或脊髓灰质炎。
9.一种生产根据权利要求2所述的疫苗的方法，包括：将B型流感嗜血菌荚膜多糖抗原偶联到蛋白载体上；在pH5-6将所述荚膜多糖偶联物吸附至磷酸铝上；与一种或多种其它抗原混合，所述其它抗原选自：甲肝病毒，白喉，破伤风，百日咳，乙肝病毒或脊髓灰质炎。
10.一种生产根据权利要求3所述的疫苗的方法，包括：将B型流感嗜血菌荚膜多糖抗原偶联到蛋白载体上；在pH5-6将所述荚膜多糖偶联物吸附至磷酸铝上；与一种或多种其它抗原混合，所述其它抗原选自：甲肝病毒，白喉，破伤风，百日咳，乙肝病毒或脊髓灰质炎。
11.一种生产根据权利要求4所述的疫苗的方法，包括：将B型流感嗜血菌荚膜多糖抗原偶联到蛋白载体上；在pH5-6将所述荚膜多糖偶联物吸附至磷酸铝上；与一种或多种其它抗原混合，所述其它抗原选自：甲肝病毒，白喉，破伤风，百日咳，乙肝病毒或脊髓灰质炎。
12.一种生产根据权利要求5所述的疫苗的方法，包括：将B型流感嗜血菌荚膜多糖抗原偶联到蛋白载体上；在pH5-6将所述荚膜多糖偶联物吸附至磷酸铝上；与一种或多种其它抗原混合，所述其它抗原选自：甲肝病毒，白喉，破伤风，百日咳，乙肝病毒或脊髓灰质炎。
13.一种生产根据权利要求6所述的疫苗的方法，包括：将B型流感嗜血菌荚膜多糖抗原偶联到蛋白载体上；在pH5-6将所述荚膜多糖偶联物吸附至磷酸铝上；与一种或多种其它抗原混合，所述其它抗原选自：甲肝病毒，白喉，破伤风，百日咳，乙肝病毒或脊髓灰质炎。
14.根据权利要求1所述的疫苗组合物在制备药物中的用途。
15.根据权利要求2所述的疫苗组合物在制备药物中的用途。
16.根据权利要求3所述的疫苗组合物在制备药物中的用途。
17.根据权利要求4所述的疫苗组合物在制备药物中的用途。
18.根据权利要求5所述的疫苗组合物在制备药物中的用途。
19.根据权利要求6所述的疫苗组合物在制备药物中的用途。
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9512827.8A GB9512827D0 (en) | 1995-06-23 | 1995-06-23 | Vaccines |
| GB9512827.8 | 1995-06-23 | ||
| GBGB9513443.3A GB9513443D0 (en) | 1995-07-01 | 1995-07-01 | Vaccines |
| GB9513443.3 | 1995-07-01 | ||
| GB9525657.4 | 1995-12-15 | ||
| GBGB9525657.4A GB9525657D0 (en) | 1995-12-15 | 1995-12-15 | Vaccines |
| GB9606032.2 | 1996-03-22 | ||
| GBGB9606032.2A GB9606032D0 (en) | 1996-03-22 | 1996-03-22 | Vaccines |
Publications (2)
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| CN1188418A CN1188418A (zh) | 1998-07-22 |
| CN1146444C true CN1146444C (zh) | 2004-04-21 |
Family
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Family Applications (1)
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| CNB961949732A Expired - Lifetime CN1146444C (zh) | 1995-06-23 | 1996-06-19 | 含有吸附于磷酸铝上的多糖偶联抗原的疫苗组合物 |
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| JP (2) | JP4850987B2 (zh) |
| KR (1) | KR100425929B1 (zh) |
| CN (1) | CN1146444C (zh) |
| AP (1) | AP812A (zh) |
| AR (1) | AR003006A1 (zh) |
| AT (2) | ATE199831T1 (zh) |
| AU (1) | AU696338B2 (zh) |
| BG (1) | BG62720B1 (zh) |
| BR (1) | BRPI9609414B8 (zh) |
| CA (1) | CA2222455C (zh) |
| CY (1) | CY2297B1 (zh) |
| CZ (1) | CZ288908B6 (zh) |
| DE (2) | DE69637950D1 (zh) |
| DK (2) | DK0833662T4 (zh) |
| DZ (1) | DZ2055A1 (zh) |
| EA (1) | EA199700413A1 (zh) |
| EG (1) | EG25924A (zh) |
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| HU (1) | HU224514B1 (zh) |
| IL (1) | IL122588A (zh) |
| MA (1) | MA23918A1 (zh) |
| MY (1) | MY114786A (zh) |
| NO (1) | NO325169B1 (zh) |
| NZ (1) | NZ312132A (zh) |
| OA (1) | OA10646A (zh) |
| PE (1) | PE11298A1 (zh) |
| PL (1) | PL184872B1 (zh) |
| PT (2) | PT1082965E (zh) |
| SI (2) | SI0833662T2 (zh) |
| SK (1) | SK176197A3 (zh) |
| TR (1) | TR199701682T1 (zh) |
| TW (1) | TW467746B (zh) |
| WO (1) | WO1997000697A1 (zh) |
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| CZ283910B6 (cs) | 1992-05-23 | 1998-07-15 | Smithkline Beecham Biologicals (S.A.) | Kombinovaný očkovací prostředek, způsob jeho výroby a použití fosforečnanu hlinitého jako pomocného prostředku |
| US6355450B1 (en) | 1995-04-21 | 2002-03-12 | Human Genome Sciences, Inc. | Computer readable genomic sequence of Haemophilus influenzae Rd, fragments thereof, and uses thereof |
| US6468765B1 (en) | 1995-04-21 | 2002-10-22 | Human Genome Sciences, Inc. | Selected Haemophilus influenzae Rd polynucleotides and polypeptides |
| US6696065B1 (en) | 1995-05-04 | 2004-02-24 | Aventis Pastuer Limited | Acellular pertussis vaccines and methods of preparation thereof |
| EP0833662B2 (en) * | 1995-06-23 | 2011-01-26 | SmithKline Beecham Biologicals S.A. | A vaccine composition comprsing a Haemophilus influenzae B polysaccharide conjugate antigen adsorbed onto aluminium phosphate |
| BRPI9710460B8 (pt) * | 1996-07-02 | 2021-05-25 | Aventis Pasteur | composição imunogênica multi-valente e composição de vacina |
| GB9806456D0 (en) * | 1998-03-25 | 1998-05-27 | Smithkline Beecham Biolog | Vaccine composition |
| EP1126876B1 (en) | 1998-10-16 | 2007-03-21 | GlaxoSmithKline Biologicals S.A. | Adjuvant systems and vaccines |
| US6585973B1 (en) | 1998-10-29 | 2003-07-01 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Method for preparing solid phase conjugated vaccine |
| GB9928196D0 (en) | 1999-11-29 | 2000-01-26 | Chiron Spa | Combinations of B, C and other antigens |
| JP4870895B2 (ja) * | 2000-06-29 | 2012-02-08 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | ワクチン組成物 |
| GB0108364D0 (en) | 2001-04-03 | 2001-05-23 | Glaxosmithkline Biolog Sa | Vaccine composition |
| JP2005504718A (ja) | 2001-01-23 | 2005-02-17 | アヴェンティス パストゥール | 多価髄膜炎菌多糖−タンパク質複合ワクチン |
| GB0115176D0 (en) | 2001-06-20 | 2001-08-15 | Chiron Spa | Capular polysaccharide solubilisation and combination vaccines |
| GB0118249D0 (en) | 2001-07-26 | 2001-09-19 | Chiron Spa | Histidine vaccines |
| AU2003274511B2 (en) | 2002-10-11 | 2009-06-04 | Glaxosmithkline Biologicals S.A. | Polypeptide-vaccines for broad protection against hypervirulent meningococcal lineages |
| US8409587B2 (en) | 2002-11-01 | 2013-04-02 | Glaxosmithkline Biologicals S.A. | Immunogenic composition |
| GB0227346D0 (en) | 2002-11-22 | 2002-12-31 | Chiron Spa | 741 |
| CN102302776B (zh) | 2003-01-30 | 2014-06-18 | 诺华疫苗和诊断有限公司 | 抗多种脑膜炎球菌血清组的可注射性疫苗 |
| GB0313916D0 (en) | 2003-06-16 | 2003-07-23 | Glaxosmithkline Biolog Sa | Vaccine composition |
| EP1667712B1 (en) * | 2003-10-02 | 2010-07-21 | GlaxoSmithKline Biologicals S.A. | B. pertussis antigens and use thereof in vaccination |
| GB0323103D0 (en) | 2003-10-02 | 2003-11-05 | Chiron Srl | De-acetylated saccharides |
| BRPI0415025A (pt) | 2003-10-02 | 2006-12-12 | Chiron Srl | vacinas lìquidas para sorogrupos meningocócicos múltiplos |
| GB0405787D0 (en) * | 2004-03-15 | 2004-04-21 | Chiron Srl | Low dose vaccines |
| GB0500787D0 (en) | 2005-01-14 | 2005-02-23 | Chiron Srl | Integration of meningococcal conjugate vaccination |
| GB0409745D0 (en) | 2004-04-30 | 2004-06-09 | Chiron Srl | Compositions including unconjugated carrier proteins |
| RU2379052C2 (ru) | 2004-04-30 | 2010-01-20 | Чирон С.Р.Л. | Вакцинация менингококковыми конъюгатами |
| GB0505518D0 (en) | 2005-03-17 | 2005-04-27 | Chiron Srl | Combination vaccines with whole cell pertussis antigen |
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| SG175456A1 (en) | 2005-04-18 | 2011-11-28 | Novartis Vaccines & Diagnostic | Expressing hepatitis b virus surface antigen for vaccine preparation |
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| GB0522765D0 (en) | 2005-11-08 | 2005-12-14 | Chiron Srl | Combination vaccine manufacture |
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| FR2918671B1 (fr) * | 2007-07-10 | 2010-10-15 | Sanofi Pasteur | Milieu de culture d'haemophilus influenzae type b. |
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| TW201043267A (en) * | 2009-03-19 | 2010-12-16 | Intervet Int Bv | In situ constituting a vaccine for administration to a predetermined herd of animals |
| PL2411048T3 (pl) * | 2009-03-24 | 2020-11-16 | Glaxosmithkline Biologicals Sa | Adjuwantowe meningokokowe białko wiążące czynnik h |
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| GB2495341B (en) | 2011-11-11 | 2013-09-18 | Novartis Ag | Fermentation methods and their products |
| DE102011122891B4 (de) | 2011-11-11 | 2014-12-24 | Novartis Ag | Fermentationsmedium, das frei von tierischen Bestandteilen ist, zur Herstellung von Diphtherie-Toxoiden zur Verwendung bei der Impfung von Menschen |
| DE102011118371B4 (de) | 2011-11-11 | 2014-02-13 | Novartis Ag | Zur Impfung von Menschen geeignete Zusammensetzung, die ein Diphtherie-Toxoid umfasst, sowie Verfahren zu deren Herstellung |
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1996
- 1996-06-19 EP EP96922871A patent/EP0833662B2/en not_active Expired - Lifetime
- 1996-06-19 SI SI9630310T patent/SI0833662T2/sl unknown
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- 1996-06-19 DK DK96922871.7T patent/DK0833662T4/da active
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- 1996-06-19 CZ CZ19974189A patent/CZ288908B6/cs not_active IP Right Cessation
- 1996-06-19 DK DK00203874T patent/DK1082965T3/da active
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- 1996-06-19 PT PT96922871T patent/PT833662E/pt unknown
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- 1996-06-19 KR KR1019970709651A patent/KR100425929B1/ko not_active IP Right Cessation
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- 1996-06-19 DE DE69637950T patent/DE69637950D1/de not_active Expired - Lifetime
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