CN1259960A - 含有幽门螺杆菌FlgE多肽的疫苗组合物 - Google Patents
含有幽门螺杆菌FlgE多肽的疫苗组合物 Download PDFInfo
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- CN1259960A CN1259960A CN98806101A CN98806101A CN1259960A CN 1259960 A CN1259960 A CN 1259960A CN 98806101 A CN98806101 A CN 98806101A CN 98806101 A CN98806101 A CN 98806101A CN 1259960 A CN1259960 A CN 1259960A
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Abstract
本发明涉及引发针对幽门螺杆菌的保护性免疫应答的多肽和疫苗。本发明还涉及幽门螺杆菌多肽在生产治疗或预防幽门螺杆菌感染的组合物中的用途。
Description
技术领域
本发明涉及引发针对幽门螺杆菌的保护性免疫应答的多肽和疫苗。本发明还涉及幽门螺杆菌多肽在生产治疗或预防幽门螺杆菌感染的组合物中的用途。
背景技术
幽门螺杆菌
革兰氏阴性细菌幽门螺杆菌(Helicobacter pylori)是一种重要的人类病原体，与几种胃十二指肠疾病有关。细菌对胃上皮的定居引起活动炎症和进行性慢性胃炎，使发展成消化道溃疡的风险大大增加。胃粘膜的终身炎症与胃癌的机率增加密切相关。
为了定居于胃粘膜，幽门螺杆菌使用多种毒力因子。这些毒力因子包括几种粘附素，脲酶和蛋白水解酶，粘附素使细菌与粘膜粘附或与上皮细胞结合，脲酶帮助中和酸性环境，蛋白水解酶使粘膜流质化。此外，幽门螺杆菌是高度运动性的，可在粘膜中游动并穿入腺管。运动性似乎是一种必须的毒力因子，因为在实验模型中非运动性幽门螺杆菌不能感染粘膜(Eaton et al.Infection & Immunity 64(7)，2445-2448，1996)。对此有多种可能的原因，最为明显的是无法游动到粘膜细胞并进行粘附，不能规避胃中的有毒成分。
尽管宿主对幽门螺杆菌会产生强烈的免疫应答，产生局部(粘膜)和全身抗体，但该病原体在宿主胃粘膜中持续存在，通常是终身存在。原因可能是自动引发的免疫应答不足或针对抗原的错误表位。或者，可能是免疫应答的类型错误，因为免疫系统可能把幽门螺杆菌作为共生对待(由终身宿主/细菌关系推测)。
为了理解幽门螺杆菌感染的发病机制和免疫学，阐明该细菌的抗原结构具有重要意义。具体而言，需要鉴定表面暴露的、表面结合的和分泌的蛋白，在许多细菌病原体中，这些蛋白已被证明构成主要的毒力因子，可用于对幽门螺杆菌的诊断和疫苗组合物的生产。如果这些蛋白除了是表面结合的蛋白之外，对细菌的存活和/或定居也是必须的，则其作为疫苗介导的免疫治疗靶标的用途增加。
当受到胁迫或威胁时，幽门螺杆菌细胞从杆状转变成球状。在球状形式下，幽门螺杆菌细胞对抗生素和其它抗细菌剂更不敏感。间接证据表明，球状的幽门螺杆菌可在个体之间传播，可能是通过水或间接接触(口-口，或粪-口)。因此有效的疫苗组合物应当针对球状和杆状形式的幽门螺杆菌均可引发免疫应答。由于全身免疫在对粘膜感染的保护中可能作用有限，疫苗组合物增加胃局部的保护性免疫应答机制也有重要意义。
鞭毛钩蛋白
来自幽门螺杆菌的鞭毛钩已被证明由78kDa的FlgE亚单位组成(O’Toole et al.Molecular Microbiology，14(4)，691-703，1994)。鞭毛钩的作用是连接鞭毛与膜下的鞭毛发动器。鞭毛钩伸出细胞膜外的部分较短，大约为60纳米(相形之下鞭毛大约为10微米)。象鞭毛一样，鞭毛钩可能也覆盖着鞘(Geis et al.(1993)J.Med.Microbiol.38(5)，371-377)。
FlgE多肽的氨基酸序列与其它已知的钩蛋白具有明显的类似性，包括与其它螺杆菌种类如鼹鼠螺杆菌的有限同源性(O’Toole etal.上文)。针对FlgE多肽的多克隆抗体显示针对鞭毛蛋白A和B的交叉反应性，表明可能存在共同的表位。FlgE敲除的幽门螺杆菌为无鞭毛的非运动性细菌，其中仍然产生FlgE多肽，但仅见于细胞质中。
附图简述
图1：用FlgE多肽免疫接种幽门螺杆菌感染小鼠的治疗作用。结果表示为窦内(＝A)、体内(＝B)或全部(A+C)(＝C)幽门螺杆菌数量的平均值±标准误。缩写含义为：CFU＝集落形成单位(细菌的数量)；空白柱体＝DOC+CT，每只小鼠给予含0.5％脱氧胆酸的磷酸缓冲盐水和10μg霍乱毒素；阴影柱体＝FlgE+CT，每只小鼠给予100μg FlgE和10μg霍乱毒素。在窦中的CFU和全胃的计算值下降明显。
**p＜0.01；*p＜0.05(Wilcoxon-Mann-Whittney秩和检验)
图2：ELISA测定的小鼠血清IgG：对感染的应答和对FlgE免疫接种的应答。数值表示为平均滴度±标准误。n＝每组9-10。ELISA用幽门螺杆菌244菌株包被：作为幽门螺杆菌感染的指标，在DOC+CT治疗(＝A对照/244)的动物血清中可见到特异抗体。用FlgE+霍乱毒素(＝B FlgE/244)免疫接种之后，该活性增加了4倍(**p＜0.01；Wilcoxon-Mann-Whittney秩和检验)。C＝FlgE特异的。在给予FlgE+CT的动物中特异性FlgE IgG增加，但在对照动物中检测不到。
发明内容
本发明的目的是提供抗原性幽门螺杆菌多肽，其可用于引发针对幽门螺杆菌感染的保护性免疫应答和对幽门螺杆菌感染进行诊断。通过编码保守的必需多肽的幽门螺杆菌基因的重组克隆实现了该目的。该基因的核酸序列类似于O’Toole等(Molecular Microbiology，14(4)，691-703，1994)报导的flgE基因序列。由于是运动必需的蛋白，flgE基因在所有的幽门螺杆菌菌株中均有表达。
尽管只有小部分钩蛋白存在于细菌外并且可能覆盖有鞘，我们出乎意料地发现，与佐剂霍乱毒素一起给药，幽门螺杆菌FlgE多肽在幽门螺杆菌感染小鼠中可作为治疗性抗原。因此以下实验数据显示，幽门螺杆菌FlgE多肽作为口服免疫原时，可刺激免疫应答，引起实验小鼠中幽门螺杆菌定居的显著下降，实验小鼠在免疫接种前1个月用幽门螺杆菌感染。
这些结果有力地支持在人用口服疫苗制剂中使用FlgE多肽来治疗和预防幽门螺杆菌感染。因此，FlgE多肽可用于检测幽门螺杆菌感染和生产疫苗组合物，该疫苗组合物在以合适的药物制剂形式给药时，可以引发针对这些感染的保护性或治疗性免疫应答。
因此，本发明一方面提供幽门螺杆菌FlgE多肽，用于引发对幽门螺杆菌感染的保护性免疫应答。“幽门螺杆菌FlgE多肽”指O’Toole等(Molecular Microbiology，14(4)，691-703，1994)公开的多肽，其编码基因的核苷酸序列示于SEQ ID NO：1，或可获自国家生物技术信息中心(入藏号U09549)，或者还包括抗原功能等价的所述多肽的基本类似的修饰形式。
“保护性免疫应答”应理解为使组合物适于治疗和/或预防目的的免疫应答。
“抗原功能等价”应理解为能引发全身性和粘膜免疫应答而降低胃粘膜中的幽门螺杆菌细胞数量。本领域技术人员通过已知方法如体内诱导抗体的表位作图可以鉴定抗原功能等价的FlgE多肽的修饰形式。
在本发明的优选实施方案中，用于引发针对幽门螺杆菌感染的保护性免疫应答的幽门螺杆菌FlgE多肽具有基本上如序列表中SEQ IDNO：2所示的氨基酸序列，或是抗原功能等价的其修饰形式。
因此，应当理解，幽门螺杆菌FlgE多肽的定义不仅限于氨基酸序列与序列表中SEQ ID NO：2完全相同的多肽。本发明还包括具有置换、小缺失、插入或倒转等修饰的多肽，但该多肽具有与幽门螺杆菌FlgE多肽基本相同的生物活性并且抗原功能等价。因此，幽门螺杆菌FlgE多肽的定义包括以下多肽：其氨基酸序列与序列表中SEQ IDNO：2所示氨基酸序列至少90％同源，优选至少95％同源。
另一方面，本发明提供了一种疫苗组合物，用于引发针对幽门螺杆菌感染的保护性免疫应答，该组合物包括免疫有效量的如上所述幽门螺杆菌FlgE多肽，还可任选包括可药用的载体或稀释剂。
在本文中，“免疫有效量”应理解为引发针对幽门螺杆菌的明显保护性免疫应答，在感染哺乳动物中根除幽门螺杆菌感染或在易感哺乳动物中预防感染的量。一般，口服时免疫有效量包括大约1μg到1000mg，优选大约10μg到100mg幽门螺杆菌抗原，胃肠外给药时包括大约少于100μg的幽门螺杆菌抗原。
疫苗组合物中除可药用载体或稀释剂外还可任选含有一种或几种其它预防或治疗用免疫活性抗原。生理相容的载体和稀释剂为本领域技术人员所熟知，包括例如磷酸缓冲盐水(PBS)或在口服疫苗时为基于碳酸氢盐的制剂或肠道包衣粉剂。
疫苗组合物还可任选含有或与酸分泌抑制剂一起给药，优选为奥美拉唑等质子泵抑制剂(PPI)。疫苗可配制在已知的运送系统中，如脂质体、ISCOM、匙形体(cochleate)等(见Rabinovich et al(1994)Science 265，1401-1404)，或者结合于或包含在降解性或非降解性聚合物微球中。抗原可以与活减毒细菌、病毒或噬菌体或其杀死的载体结合。抗原可以化学或遗传上与惰性或佐剂型(即霍乱B亚单位)载体蛋白偶联。因此，本发明另一方面提供了上述疫苗组合物，其中也包含霍乱毒素等佐剂。这些可药用形式的霍乱毒素在本领域是已知的，如可参见Rappuoliet al(1995)Int.Arch.Allergy & Immunol.108(4)，327-333；Dickinson et al(1995)Infection & Immunity63(5)，1617-1623。
本发明的疫苗组合物可用于治疗和预防目的。因此，本发明包括一种上述疫苗组合物，可用作感染了幽门螺杆菌的哺乳动物包括人的治疗或预防疫苗。在本文中“预防目的”是指诱导保护免于将来的幽门螺杆菌感染的免疫应答，而“治疗用途”是指诱导可根除现存的幽门螺杆菌感染的免疫应答。
本发明的疫苗组合物优选给予任何哺乳动物粘膜，例如颊、鼻、扁桃体、胃、肠(小肠和大肠)、直肠和阴道粘膜。为此目的粘膜疫苗可以与合适的佐剂一起给药。疫苗也可经口服、胃肠外、皮下、皮内或肌肉给药，任选与合适的佐剂一起给药。疫苗组合物也可任选与抗微生物治疗剂一起给药。
另一方面，本发明提供了上述幽门螺杆菌FlgE多肽在以下产品的生产中的用途：
(i)治疗、预防或诊断幽门螺杆菌感染的组合物；
(ii)用于引发针对幽门螺杆菌的保护性免疫应答的疫苗；
(iii)诊断幽门螺杆菌感染的诊断试剂盒。
另一方面，本发明提供了体外诊断幽门螺杆菌感染的方法，包括至少一个步骤，其中使用上述幽门螺杆菌FlgE多肽，可任选以固相载体标记或与其偶联。该方法可包括例如步骤(a)使幽门螺杆菌FlgE多肽与哺乳动物体液接触，所述多肽可任选与固相载体结合；和(b)检测与所述FlgE多肽结合的所述体液的抗体。检测抗体的优选方法是本领域熟知的ELISA(酶联免疫吸附试验)方法。
另一方面，本发明提供了检测哺乳动物包括人中的幽门螺杆菌感染的诊断试剂盒，其中包括可以进行上述体外诊断方法的成分。所述诊断试剂盒可包括例如：(a)幽门螺杆菌FlgE多肽；(b)检测与该FlgE多肽结合的抗体。所述检测抗体的试剂可以是例如酶标记的抗免疫球蛋白和该酶的显色底物。
再一方面，本发明提供了引发哺乳动物包括人的针对幽门螺杆菌感染的保护性免疫应答的方法，该方法包括向该哺乳动物给予免疫有效量的上述幽门螺杆菌FlgE多肽的步骤，或向该哺乳动物给予免疫有效量的上述疫苗组合物。
实验方法
在本说明书中，在涉及分子克隆技术时“标准方法”或“标准步骤”应理解为普通实验手册上的方法和步骤，实验手册如：《现代分子生物学方法》，F.Ausubel等编辑，John Wiley and Sons，Inc.1994，或Sambrook，J.，Fritsch，E.F.和Maniatis，T.，《分子克隆：实验室手册》，第2版，Cold Spring Harbor LaboratoryPress，Cold Spring Harbor，NY 1989。
重组幽门螺杆菌FlgE多肽的制备
DNA序列信息
编码FlgE多肽的基因的序列信息获自国家生物技术信息中心(入藏号U09549；SEQ ID NO：1)。
含有幽门螺杆菌J99菌株膜蛋白和分泌蛋白ORF的DNA序列的PCR扩增和克隆
所述序列使用聚合酶链反应(PCR)通过扩增克隆克隆自幽门螺杆菌J99菌株。基因的5’和3’末端特异的合成寡核苷酸引物(见下文)由厂家设计并购买(GibcoBRL Life Technologies，Gaithersburg，MD，USA)。FlgE的正向引物(特异针对序列的5’末端)被设计成在5’最末端包括一个NcoI克隆位点，而反向引物在最末端包括一个EcoRI位点，以便允许每一个幽门螺杆菌序列被克隆进pET28b载体的读框中。克隆到pET-28b载体的NcoI-EcoRI位点的插入片段与一段载体DNA序列融合，该载体序列编码包括6个组氨酸残基(在C端最末端)的20个羧基末端氨基酸。
正向引物(SEQ ID NO：3)
5’-TAT ACC ATG GTG CTT AGG TCT TTA T-3’
反向引物(SEQ ID NO：4)
5’-GCC AAT TCA ATT GCT TAA GAT TCA A-3’
由幽门螺杆菌J99菌株制备的基因组DNA用作PCR扩增反应的模板来源(《现代分子生物学方法》，F.Ausubel等编辑，John Wileyand Sons，Inc.1994)。为了扩增含有幽门螺杆菌ORF的DNA序列，将50ng基因组DNA加入反应管中，反应管中含有2mM氯化镁，1μM与幽门螺杆菌ORF互补并延伸至其侧翼的合成寡核苷酸引物(正向和反向引物)，dATP，dGTP，dCTP，cTTP各0.2mM，和2.5单位热稳定性DNA聚合酶(Amplitaq，Roche Molecular Systems，Inc.，Branchburg，NJ，USA)，终体积为100μl。使用以下热循环条件和Perkin Elmer Cetus/GeneAmp PCR System 9600热循环仪获得每种ORF的扩增DNA产物：
94℃变性2分钟；
94℃ 15秒，30℃ 15秒和72℃ 1.5分钟2个循环；
94℃ 15秒，58℃ 15秒和72℃ 1.5分钟23个循环；
72℃ 6分钟后反应结束。
热循环反应结束后，洗涤各扩增DNA样品并使用Qiaquick SpinPCR纯化试剂盒纯化(Qiagen，Gaithersburg，MD，USA)。扩增的DNA样品按标准方法使用限制性内切酶NdeI和EcoRI消化，然后在1.0％ NuSeive(FMC BioProducts，Rockland，ME USA)琼脂糖凝胶上电泳。DNA使用溴化乙锭和长波UV辐射观察。使用Bio 101GeneClean Kit方法(Bio 101 Vista，CA USA)纯化由凝胶胶条中分离的DNA。
将幽门螺杆菌DNA序列克隆进pET-28b原核表达载体
用于克隆的pET-28b载体按照标准步骤通过NcoI和EcoRI消化制备。消化后，DNA插入片段根据标准步骤克隆进事先消化的pET-28b表达载体。连接反应产物然后用于转化以下所述大肠杆菌BL21菌株。
用重组质粒转化感受态细菌
按照标准方法使用携带有克隆的幽门螺杆菌序列的重组pET表达质粒转化感受态细菌大肠杆菌BL21菌株或大肠杆菌BL21(DE53)菌株。简而言之，1μl连接反应物与50μl电感受态细胞混合，并施以高电压脉冲，然后，样品在0.45ml SOC培养基(0.5％酵母提取物，2.0％胰胨，10mM NaCl，2.5mM KCl，10mM MgCl2，10mM MgSO4以及20mM葡萄糖)中37℃振荡温育1小时。样品然后涂布在含25μg/ml硫酸卡那霉素的LB琼脂平板上生长过夜。然后挑取转化的BL21菌落并进行分析以便如下所述评价克隆的插入片段。
鉴定携带幽门螺杆菌序列的重组pET表达质粒
用重组pET-28b幽门螺杆菌基因转化的单独BL21克隆如下分析：使用与原来的PCR扩增克隆反应中相同的、各幽门螺杆菌序列特异的正向和反向引物对克隆的插入片段进行PCR扩增。根据标准步骤的成功扩增证实了幽门螺杆菌序列整合在表达载体中。
从BL21转化子中分离和制备质粒DNA
挑取携带有正确克隆的幽门螺杆菌ORF的重组pET-28b载体的单独克隆，在5ml添加了25μg/ml硫酸卡那霉素的LB培养液中温育过夜。次日使用Qiagen质粒纯化方法(Qiagen Inc.，Chatsworth，CA，USA)分离和纯化质粒DNA。
重组幽门螺杆菌序列在大肠杆菌中的表达
为克隆或制备质粒，pET载体可在任何大肠杆菌K-12菌株如HMS174，HB101，JM109，DH5α等中增殖。表达宿主包括含有T7 RNA聚合酶基因的染色体拷贝的大肠杆菌菌株。这些宿主是细菌噬菌体DE3的溶源菌、携带有lacI基因，lacUV5启动子和T7 RNA聚合酶的λ衍生物。T7 RNA聚合酶通过加入异丙基-β-D-硫代半乳糖苷(IPTG)诱导，T7 RNA聚合酶转录携带其目标基因的任何靶质粒如pET-28b。我们实验室中使用的菌株包括：BL21(DE3)(Studier，F.W.，Rosenberg，A.H.，Dunn，J.J.和Dubendorff，J.W.(1990)酶学方法，185，60-89)。
为了表达重组幽门螺杆菌序列，50ng上述分离的质粒DNA用来转化上述感受态BL21(DE3)细菌(由Novagen以pET表达系统试剂盒的一部分提供)。转化细胞在SOC培养基中培养1小时，然后培养物涂布含25μg/ml硫酸卡那霉素的LB平板。次日，合并细菌菌落，在含硫酸卡那霉素(25μg/ml)的LB培养基中生长至600纳米光密度为0.5到1.0 O.D.单位，此时向培养基中加入1mM IPTG 3小时，以诱导幽门螺杆菌重组DNA构建物的基因表达。
用IPTG诱导基因表达之后，用Sorvall RC-3B离心机在3500×g，4℃离心15分钟使细菌沉淀。沉淀重悬于50毫升冷的STE缓冲液(10mM Tris-HCl，pH8.0，0.1M NaCl和0.1mM EDTA)中。细胞然后在4℃，2000×g离心20分钟。湿沉淀称重并在-80℃冻存以备进行蛋白纯化。
分析方法
纯化蛋白制备物的浓度使用由氨基酸含量计算的吸收系数以分光光度法确定(Perkins，S.J.1986 Eur.J.Biochem.157，169-180)。蛋白浓度也使用牛血清白蛋白作为标准以另一种方法确定(Bradford，M.M.(1976)Anal.Biochem.72，248-254，Lowry，O.H.，Rosebrough，N.Farr，A.L.&Randall，R.J.(1951))。
十二烷基硫酸钠-聚丙烯酰胺(SDS-PAGE)凝胶(12％或4-25％的梯度丙烯酰胺)购自BioRad(Hercules，CA，USA)，并用考马斯亮蓝染色。分子量标记包括兔骨骼肌肌球蛋白(200kDa)、大肠杆菌β-半乳糖苷酶(116kDa)、兔肌肉磷酸酶B(97.4kDa)、牛血清白蛋白(66.2kDa)、卵清蛋白(45kDa)、牛碳酸酐酶(31kDa)、大豆胰蛋白酶抑制剂(21.5kDa)，卵白溶菌酶(14.4kDa)和牛抑酶肽(6.5kDa)。
由包涵体纯化FlgE
在4℃进行以下步骤。细胞沉淀重悬于裂解缓冲液中，缓冲液中含有10％甘油，100μg/ml溶菌酶，5mM EDTA，1mM PMSF和0.1％β-巯基乙醇。通过细胞破碎器后，所得的匀浆物加入0.2％DOC，搅拌10分钟，然后离心(10000g×30min)。沉淀首先用含有10％甘油，10mM EDTA，1％Triton X-100，1mM PMSF和0.1％β-巯基乙醇的裂解缓冲液洗涤，然后用含有1M尿素，1mM PMSF和0.1％β-巯基乙醇的裂解缓冲液洗涤。所得的白色沉淀主要由包涵体组成，不含未破碎的细胞和膜成分。
在室温进行以下步骤。包涵体溶解于20毫升含有1mM EDTA，1mMPMSF和0.1％β-巯基乙醇以及8M尿素的裂解缓冲液中，室温温育1小时。不溶的物质通过离心(100,000×g，30分钟)除去。过滤清亮的上清液，上样于用含8M尿素的裂解缓冲液平衡的Ni2+-NTA琼脂糖柱。用250毫升(5倍床体积)含1mM PMSF、0.1％β-巯基乙醇以及8M尿素的裂解缓冲液洗柱，依次用含8M尿素、1mM PMSF、0.1％β-巯基乙醇以及20，100，200和500mM咪唑的裂解缓冲液洗脱。通过OD280的吸收值监测各级分，峰值级分用SDS-PAGE分析。用考马斯亮蓝染色可见到两条带，主要带的分子量为78kDa，次要带的分子量为60kDa。经分析重组FlgE(78kDa)的纯度大于90％。同可溶性蛋白的纯化一样，含有重组蛋白的级分用100mM咪唑洗脱下来。
对含有0.5％DOC的TBS透析，按以下次序依次减少尿素浓度：6M，4M，3M，2M，1M，0.5M然后是0M，从FlgE多肽中慢慢除去尿素。每一个透析步骤至少在室温下进行4小时。
透析后，使用Amicon搅拌室通过加压过滤使样品浓缩。然后通过Perkins，Bradford和Lowry方法测定蛋白浓度。
实施例
实施例1：治疗性免疫接种
1.材料与方法
1.1动物
雌性SPF BALB/c小鼠购自Bomholt育种中心(丹麦)。在普通makrolon饲养笼中饲养，自由取食和饮水。抵达时动物为4到6周龄。
1.2感染
在驯化至少一周后，用幽门螺杆菌2型菌株(菌株244，最初分离自溃疡病人)感染动物。该菌株以前已被证实容易定居于小鼠胃内。-70℃保存的原种细菌在37℃于微需氧气氛下(10％ CO2，5％O2)在补加有10％胎牛血清的Brucella培养液中生长过夜。动物口服给予奥美拉唑(400μmol/kg)，3-5小时后口服接种幽门螺杆菌(每只动物大约107-108CFU)。接种2-3周后在对照动物中检查感染。
1.3免疫接种
感染1个月后，两组小鼠(每组10只)在34天内接种4次(第1、15、25、35天)。纯化重组FlgE溶解在添加有0.5％脱氧胆酸(DOC)的PBS中，给药剂量为每只小鼠100微克。
每次免疫接种时，对照组和FlgE组每只小鼠均给予10微克霍乱毒素作为佐剂。免疫接种前3-5小时，口服给予奥美拉唑(400μmol/kg)用来保护抗原免于酸降解。最后一次免疫后1-2周处死动物。
第1组：300μl PBS+0.5％ DOC+10μg CT
第2组：300μl PBS+0.5％ DOC+10μg CT+100μg FlgE
1.4感染分析
小鼠通过CO2和断颈处死。打开胸腔和腹腔，通过心脏穿刺取血样。然后取出胃。沿胃大弯切开胃，用盐水洗涤，然后切成相等的两片。用手术刀分别自胃窦和胃体刮下25mm2的粘膜。刮下的粘膜悬浮在Brucella培养液中，稀释并涂布在Blood Skirrow平板上。平板在微需氧条件下温育3-5天，计数集落数量。通过脲酶和触酶试验和直接镜检或革兰氏染色确认培养物为幽门螺杆菌。
1.5抗体测定
自血样中收集血清抗体。浓缩前，血样以等量PBS稀释。血清在-20℃保存以待分析。使用ELISA测定血清抗体，平板用幽门螺杆菌菌株244颗粒部分或FlgE覆盖，然后加入不同稀释度的血清。ELISA用碱性磷酸酶标记的抗小鼠Ig抗体显色。抗Ig抗体为抗重链/抗轻链型，应能检测各种类型的抗体。
2.结果
2.1治疗性免疫接种：对CFU的影响
本试验中的动物在免疫接种前1个月用幽门螺杆菌菌株244感染。每组10只小鼠然后用霍乱毒素(CT)或CT与重组FlgE多肽免疫接种。最后一次免疫接种后4周，处死动物，测定CFU(图1)。仅用CT处理的动物胃体和胃窦均大量感染。用重组FlgE多肽和CT免疫接种的动物与CT处理动物相比胃窦和全胃CFU值明显下降(分别为p＜0.01，p＜0.05；Wilcoxon-Mann-Whittney符号等级试验)。
2.2治疗性免疫接种：对抗体形成和分泌的影响
作为感染幽门螺杆菌的指示，在血清中可见到特异性抗体(对照/244)。在给予FlgE+CT的动物中，抗244菌株的滴度(作为膜蛋白)增加了4倍(p＜0.01)。仅在给予FlgE+CT的动物中可检测到抗FlgE的特异血清IgG滴度(图2)。
FlgE特异的IgG在给予FlgE+CT的动物中增加，但在对照动物中检测不到。
本文结果表明在口服给药并给予霍乱毒素作为佐剂时重组FlgE幽门螺杆菌多肽是高度免疫原性的，可检测到全身FlgE特异性Ig抗体的增加。用FlgE免疫接种也导致抗幽门螺杆菌颗粒组分的Ig滴度的显著增加。此外，在免疫接种FlgE和霍乱毒素后，感染小鼠胃粘膜定居幽门螺杆菌的数量显著下降。
序列表(1)一般资料：(i)申请人：
(A)收件人：Astra AB
(B)街道：Vastra Malarehamnen 9
(C)城市：Sodertalje
(E)国家：Sweden
(F)邮编：S-151 85
(G)电话：+46855326000
(H)传真：+46855328820(ii)发明名称：疫苗组合物V(iii)序列数：4(iv)计算机可读形式：
(A)媒体类型：软盘
(B)计算机：IBM PC兼容
(C)操作系统：PC-DOS/MS-DOS
(D)软件：PatentIn Release#1.0，Version#1.30(EPO)(2)SEQ ID NO：1资料：(i)序列特征：
(A)长度：2550个碱基对
(B)类型：核酸
(C)链型：双链
(D)拓扑结构：线形(ii)分子类型：cDNA(vi)原始来源
(A)有机体：幽门螺杆菌(ix)特征：
(A)名称/关键词：CDS
(B)位置：321..2477
(D)其它信息：/产物＝“FlgE鞭毛钩蛋白” (x)公开信息：
(A)作者：O’Toole，Paul W.
(B)名称：幽门螺杆菌非运动性突变体和鼹鼠螺杆菌
鞭毛钩生成缺陷体
(C)杂志：分子微生物学
(D)卷号：14
(E)期号：4
(F)页码：691-703
(G)日期：1994(xi)序列描述：SEQ ID NO：1：AACAAAGCGA TAACTCCTTT GTCTTATTAG CGACACAATT TAACCCATTG ACTTTAAATC 60GCGCTTCAGC CGAAGAGATT CAAGATCATG AATGCGCGAT TTTGCACTAA AGCGAGTTAG 120ATTCTTAAAT TTGAGCGATA ACCTTTAAAA AGCGTAATTA AGGGGTGGTG TTACAAAACC 180CCCTATCCCC TTATGAATTT GACCGATCTT TTTGATTAAC AAAACTTTAA AATCCGCAAT 240CAATCATTCT AAAAAGCTAT TTAGGAACAA CTTTTGCTTT ATTTTGCATA GATTGAATTT 300CTTTAAATTA AAGGATAACC ATG CTT AGG TCT TTA TGG TCT GGT GTC AAT 350
Met Leu Arg Ser Leu Trp Ser Gly Val Asn
1 5 10GGG ATG CAA GCC CAC CAA ATC GCT TTG GAT ATT GAG AGT AAC AAT ATT 398Gly Met Gln Ala His Gln Ile Ala Leu Asp Ile Glu Ser Asn Asn Ile
15 20 25GCG AAC GTG AAT ACC ACT GGT TTT AAG TAT TCT AGG GCT TCT TTT GTG 446Ala Asn Val Asn Thr Thr Gly Phe Lys Tyr Ser Arg Ala Ser Phe Val
30 35 40GAT ATG CTT TCT CAA GTC AAA CTC ATC GCT ACC GCA CCC TAT AAA AAC 494Asp Met Leu Ser Gln Val Lys Leu Ile Ala Thr Ala Pro Tyr Lys Asn
45 50 55GGG TTA GCA GGG CAG AAT GAT TTT TCT GTG GGG CTT GGG GTA GGC GTG 542Gly Leu Ala Gly Gln Asn Asp Phe Ser Val Gly Leu Gly Val Gly Val
60 65 70GAT GCG ACG ACT AAA ATC TTT TCA CAA GGC AAT ATC CAA AAC ACA GAT 590Asp Ala Thr Thr Lys Ile Phe Ser Gln Gly Asn Ile Gln Asn Thr Asp75 80 85 90GTC AAA ACC GAT CTA GCG ATT CAA GGC GAT GGC TTT TTT ATC ATT AAC 638Val Lys Thr Asp Leu Ala Ile Gln Gly Asp Gly Phe Phe Ile Ile Asn
95 100 105CCT GAT AGG GGG ATC ACG CGC AAT TTC ACT AGA GAT GGG GAG TTC CTT 686Pro Asp Arg Gly Ile Thr Arg Asn Phe Thr Arg Asp Gly Glu Phe Leu
110 115 120TTT GAC TCG CAA GGG AGT TTG GTT ACC ACC GGC GGG CTT GTG GTG CAA 734Phe Asp Ser Gln Gly Ser Leu Val Thr Thr Gly Gly Leu Val Val Gln
125 130 135GGG TGG GTG AGA AAT GGG AGC GAT ACC GGC AAT AAA GGG AGC GAT ACA 782Gly Trp Val Arg Asn Gly Ser Asp Thr Gly Asn Lys Gly Ser Asp Thr
140 145 150GAC GCT TTA AAA GTG GAT AAC ACC GGT CCT TTA GAA AAC ATT AGG ATT 830Asp Ala Leu Lys Val Asp Asn Thr Gly Pro Leu Glu Asn Ile Arg Ile155 160 165 170GAT CCT GGA ATG GTG ATG CCA GCC AGA GCG AGT AAC CGC ATT TCT ATG 878Asp Pro Gly Met Val Met Pro Ala Arg Ala Ser Asn Arg Ile Ser Met
175 180 185AGG GCG AAT TTA AAC GCT GGA AGG CAT GCC GAT CAA ACA GCG GCG ATA 926Arg Ala Asn Leu Asn Ala Gly Arg His Ala Asp Gln Thr Ala Ala Ile
190 195 200TTC GCT TTG GAT TCT TCA GCC AAA ACC CCT TCA GAT GGC ATT AAT CCG 974Phe Ala Leu Asp Ser Ser Ala Lys Thr Pro Ser Asp Gly Ile Asn Pro
205 210 215GTG TAT GAT TCA GGC ACG AAT CTT GCT CAA GTC GCC GAA GAC ATG GGA 1022Val Tyr Asp Ser Gly Thr Asn Leu Ala Gln Val Ala Glu Asp Met Gly
220 225 230TCT TTA TAC AAT GAA GAT GGC GAC GCT CTT TTG TTG AAT GAA AAT CAA 1070Ser Leu Tyr Asn Glu Asp Gly Asp Ala Leu Leu Leu Asn Glu Asn Gln235 240 245 250GGG ATT TGG GTG AGC TAT AAG AGT CCA AAA ATG GTC AAA GAC ATC CTC 1118Gly Ile Trp Val Ser Tyr Lys Ser Pro Lys Met Val Lys Asp Ile Leu
255 260 265CCT TCT GCA GAA AAC AGC ACG CTT GAA TTG AAT GGC GTT AAG ATT TCT 1166Pro Ser Ala Glu Asn Ser Thr Leu Glu Leu Asn Gly Val Lys Ile Ser
270 275 280TTC ACA AAC GAT TCA GCG GTG AGC CGG ACT TCA AGC TTA GTG GCG GCT 1214Phe Thr Asn Asp Ser Ala Val Ser Arg Thr Ser Ser Leu Val Ala Ala
285 290 295AAA AAT GCG ATC AAT GCA GTC AAA AGC CAA ACA GGC ATT GAA GCT TAT 1262Lys Asn Ala Ile Asn Ala Val Lys Ser Gln Thr Gly Ile Glu Ala Tyr
300 305 310TTA GAC GGC AAG CAA TTG CGT TTG GAA AAC ACC AAT GAA TTA GAC GGC 1310Leu Asp Gly Lys Gln Leu Arg Leu Glu Asn Thr Asn Glu Leu Asp Gly315 320 325 330GAT GAA AAG CTT AAA AAC ATT GTA GTT ACT CAA GCC GGA ACC GGA GCG 1358Asp Glu Lys Leu Lys Asn Ile Val Val Thr Gln Ala Gly Thr Gly Ala
335 - 340 345TTC GCT AAC TTT TTA GAC GGC GAT AAA GAT GTA ACG GCT TTC AAA TAC 1406Phe Ala Asn Phe Leu Asp Gly Asp Lys Asp Val Thr Ala Phe Lys Tyr
350 355 360AGC TAC ACG CAT TCT ATT AGC CCT AAC GCC AAT AGC GGG CAG TTT AGG 1454Ser Tyr Thr His Ser Ile Ser Pro Asn Ala Asn Ser Gly Gln Phe Arg
365 370 375ACC ACT GAA GAC TTG CGC GCC TTA ATC CAG CAT GAC GCT AAT ATC GTT 1502Thr Thr Glu Asp Leu Arg Ala Leu Ile Gln His Asp Ala Asn Ile Val
380 385 390AAA GAT CCT AGC CTA GCG GAC AAT TAC CAA GAC TCA GCC GCT TCT ATA 1550Lys Asp Pro Ser Leu Ala Asp Asn Tyr Gln Asp Ser Ala Ala Ser Ile395 400 405 410GGA GTT ACA ATC AAC CAA TAC GGC ATG TTT GAA ATC AAC AAT AAA GAC 1598Gly Val Thr Ile Asn Gln Tyr Gly Met Phe Glu Ile Asn Asn Lys Asp
415 420 425AAT AAA AAT GTC ATT AAA GAA AAT CTT AAT ATC TTT GTG AGC GGG TAT 1646Asn Lys Asn Val Ile Lys Glu Asn Leu Asn Ile Phe Val Ser Gly Tyr
430 435 440TCT TCA GAC AGC GTA ACG AAC AAT GTT TTG TTT AAA AAT GCG ATG AAA 1694Ser Ser Asp Ser Val Thr Asn Asn Val Leu Phe Lys Asn Ala Met Lys
445 450 455GGG CTT AAT ACC GCT TCT TTA ATT GAA GGG GGA GCG TCA GCG AGC AGT 1742Gly Leu Asn Thr Ala Ser Leu Ile Glu Gly Gly Ala Ser Ala Ser Ser
460 465 470TCT AAA TTC ACC CAC GCT ACG CAT GCG ACA AGC ATT GAT GTG ATA GAC 1790Ser Lys Phe Thr His Ala Thr His Ala Thr Ser Ile Asp Val Ile Asp475 480 485 490AGC TTA GGC ACT AAA CAC GCC ATG CGC ATT GAG TTT TAT AGG AGT GGG 1838Ser Leu Gly Thr Lys His Ala Met Arg Ile Glu Phe Tyr Arg Ser Gly
495 500 505GGA GCG GAT TGG AAT TTT AGA GTG ATC GTG CCT GAG CCT GGG GAA TTA 1886Gly Ala Asp Trp Asn Phe Arg Val Ile Val Pro Glu Pro Gly Glu Leu
510 515 520GTA GGG GGG TCA GCG GCT AGG CCT AAT GTG TTT GAA GGA GGC CGT TTG 1934Val Gly Gly Ser Ala Ala Arg Pro Asn Val Phe Glu Gly Gly Arg Leu
525 530 535CAC TTC AAT AAT GAC GGA TCG CTT GCA GGC ATG AAC CCG CCT CTT TTG 1982His Phe Asn Asn Asp Gly Ser Leu Ala Gly Met Asn Pro Pro Leu Leu
540 545 550CAA TTT GAC CCT AAA AAT GGT GCT GAT GCC CCC CAA CGC ATC AAT TTA -2030Gln Phe Asp Pro Lys Asn Gly Ala Asp Ala Pro Gln Arg Ile Asn Leu555 560 565 570GCT TTT GGT TCC TCA GGG AGT TTT GAC GGG CTA ACG AGC GTG GAT AAG 2078Ala Phe Gly Ser Ser Gly Ser Phe Asp Gly Leu Thr Ser Val Asp Lys
575 580 585ATT TCT GAA ACT TAT GCG ATT GAG CAA AAC GGC TAT CAA GCG GGC GAT 2126Ile Ser Glu Thr Tyr Ala Ile Glu Gln Asn Gly Tyr Gln Ala Gly Asp
590 595 600TTG ATG GAT GTC CGC TTT GAT TCA GAT GGG GTG CTT TTA GGA GCG TTC 2174Leu Met Asp Val Arg Phe Asp Ser Asp Gly Val Leu Leu Gly Ala Phe
605 610 615AGT AAT GGC AGG ACT TTA GCG CTC GCT CAA GTG GCT TTA GCG AAT TTC 2222Ser Asn Gly Arg Thr Leu Ala Leu Ala Gln Val Ala Leu Ala Asn Phe
620 625 630GCT AAC GAT GCG GGC TTG CAG GCT TTA GGC GGG AAT GTC TTT TCT CAA 2270Ala Asn Asp Ala Gly Leu Gln Ala Leu Gly Gly Asn Val Phe Ser Gln635 640 645 650ACC GGA AAC TCA GGG CAA GCC TTA ATC GGT GCG GCT AAT ACG GGG CGT 2318Thr Gly Asn Ser Gly Gln Ala Leu Ile Gly Ala Ala Asn Thr Gly Arg
655 660 665AGG GGT TCA ATT TCA GGA TCT AAA CTG GAG TCT AGT AAT GTG GAT TTG 2366Arg Gly Ser Ile Ser Gly Ser Lys Leu Glu Ser Ser Asn Val Asp Leu
670 675 680AGC CGG AGT TTA ACG AAT TTG ATT GTG GTT CAA AGG GGC TTT CAA GCA 2414Ser Arg Ser Leu Thr Asn Leu Ile Val Val Gln Arg Gly Phe Gln Ala
685 690 695AAC TCT AAA GCG GTA ACC ACA TCC GAT CAA ATC CTT AAT ACC CTA TTG 2462Asn Ser Lys Ala Val Thr Thr Ser Asp Gln Ile Leu Asn Thr Leu Leu
700 705 710AAT CTT AAG CAA TAA ACTAAAGGAT TACTCTAATA CAATATAATA GGGGCTAATT 2517Asn Leu Lys Gln *715TAAAGATTAA GGTTTAGTAT GCATGAATAC TCG 2550(2)SEQ ID NO：2资料：(i)序列特征：
(A)长度：719氨基酸
(B)类型：氨基酸
(D)拓扑结构：线形(ii)分子类型：蛋白(xi)序列描述：SEQ ID NO：2：Met Leu Arg Ser Leu Trp Ser Gly Val Asn Gly Met Gln Ala His Gln1 5 10 15Ile Ala Leu Asp Ile Glu Ser Asn Asn Ile Ala Asn Val Asn Thr Thr
20 25 30Gly Phe Lys Tyr Ser Arg Ala Ser Phe Val Asp Met Leu Ser Gln Val
35 40 45Lys Leu Ile Ala Thr Ala Pro Tyr Lys Asn Gly Leu Ala Gly Gln Asn
50 55 60Asp Phe Ser Val Gly Leu Gly Val Gly Val Asp Ala Thr Thr Lys Ile65 70 75 80Phe Ser Gln Gly Asn Ile Gln Asn Thr Asp Val Lys Thr Asp Leu Ala
85 90 95Ile Gln Gly Asp Gly Phe Phe Ile Ile Asn Pro Asp Arg Gly Ile Thr
100 105 110Arg Asn Phe Thr Arg Asp Gly Glu Phe Leu Phe Asp Ser Gln Gly Ser
115 120 125Leu Val Thr Thr Gly Gly Leu Val Val Gln Gly Trp Val Arg Asn Gly
130 135 140Ser Asp Thr Gly Asn Lys Gly Ser Asp Thr Asp Ala Leu Lys Val Asp145 150 155 160Asn Thr Gly Pro Leu Glu Asn Ile Arg Ile Asp Pro Gly Met Val Met
165 170 175Pro Ala Arg Ala Ser Asn Arg Ile Ser Met Arg Ala Asn Leu Asn Ala
180 185 190Gly Arg His Ala Asp Gln Thr Ala Ala Ile Phe Ala Leu Asp Ser Ser
195 200 205Ala Lys Thr Pro Ser Asp Gly Ile Asn Pro Val Tyr Asp Ser Gly Thr
210 215 220Asn Leu Ala Gln Val Ala Glu Asp Met Gly Ser Leu Tyr Asn Glu Asp225 230 235 240Gly Asp Ala Leu Leu Leu Asn Glu Asn Gln Gly Ile Trp Val Ser Tyr
245 250 255Lys Ser Pro Lys Met Val Lys Asp Ile Leu Pro Ser Ala Glu Asn Ser
260 265 270Thr Leu Glu Leu Asn Gly Val Lys Ile Ser Phe Thr Arg Asp Ser Ala
275 280 285Val Ser Arg Thr Ser Ser Leu Val Ala Ala Lys Asn Ala Ile Asn Ala
290 295 300Val Lys Ser Gln Thr Gly Ile Glu Ala Tyr Leu Asp Gly Lys Gln Leu305 310 315 320Arg Leu Glu Asn Thr Asn Glu Leu Asp Gly Asp Glu Lys Leu Lys Asn
325 330 335Ile Val Val Thr Gln Ala Gly Thr Gly Ala Phe Ala Asn Phe Leu Asp
340 345 350Gly Asp Lys Asp Val Thr Ala Phe Lys Tyr Ser Tyr Thr His Ser Ile
355 360 365Ser Pro Asn Ala Asn Ser Gly Gln Phe Arg Thr Thr Glu Asp Leu Arg
370 375 380Ala Leu Ile Gln His Asp Ala Asn Ile Val Lys Asp Pro Ser Leu Ala385 390 395 400Asp Asn Tyr Gln Asp Ser Ala Ala Ser Ile Gly Val Thr Ile Asn Gln
405 410 415Tyr Gly Met Phe Glu Ile Asn Asn Lys Asp Asn Lys Asn Val Ile Lys
420 425 430Glu Asn Leu Asn Ile Phe Val Ser Gly Tyr Ser Ser Asp Ser Val Thr
435 440 445Asn Asn Val Leu Phe Lys Asn Ala Met Lys Gly Leu Asn Thr Ala Ser
450 455 460Leu Ile Glu Gly Gly Ala Ser Ala Ser Ser Ser Lys Phe Thr His Ala465 470 475 480Thr His Ala Thr Ser Ile Asp Val Ile Asp Ser Leu Gly Thr Lys His
485 490 495Ala Met Arg Ile Glu Phe Tyr Arg Ser Gly Gly Ala Asp Trp Asn Phe
500 505 510Arg Val Ile Val Pro Glu Pro Gly Glu Leu Val Gly Gly Ser Ala Ala
515 520 525Arg Pro Asn Val Phe Glu Gly Gly Arg Leu His Phe Asn Asn Asp Gly
530 535 540Ser Leu Ala Gly Met Asn Pro Pro Leu Leu Gln Phe Asp Pro Lys Asn545 550 555 560Gly Ala Asp Ala Pro Gln Arg Ile Asn Leu Ala Phe Gly Ser Ser Gly
565 570 575Ser Phe Asp Gly Leu Thr Ser Val Asp Lys Ile Ser Glu Thr Tyr Ala
580 585 590Ile Glu Gln Asn Gly Tyr Gln Ala Gly Asp Leu Met Asp Val Arg Phe
595 600 605Asp Ser Asp Gly Val Leu Leu Gly Ala Phe Ser Asn Gly Arg Thr Leu
610 615 620Ala Leu Ala Gln Val Ala Leu Ala Asn Phe Ala Asn Asp Ala Gly Leu625 630 635 640Gln Ala Leu Gly Gly Asn Val Phe Ser Gln Thr Gly Asn Ser Gly Gln
645 650 655Ala Leu Ile Gly Ala Ala Asn Thr Gly Arg Arg Gly Ser Ile Ser Gly
660 665 670Ser Lys Leu Glu Ser Ser Asn Val Asp Leu Ser Arg Ser Leu Thr Asn
675 680 685Leu Ile Val Val Gln Arg Gly Phe Gln Ala Asn Ser Lys Ala Val Thr
690 695 700Thr Ser Asp Gln Ile Leu Asn Thr Leu Leu Asn Leu Lys Gln *705 710 715(2)SEQ ID NO：3资料：(i)序列特征：
(A)长度：25碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线形(ii)分子类型：其它核酸
(A)描述：/desc＝“PCR引物”(xi)序列描述：SEQ ID NO：3：TATACCATGG TGCTTAGGTC TTTAT 25(2)SEQ ID NO：4资料：(i)序列特征：
(A)长度：25碱基对
(B)类型：核酸
(C)链型：单链
(D)拓扑结构：线形(ii)分子类型：其它核酸
(A)描述：/desc＝“PCR引物”
(xi)序列描述：SEQ ID NO：4：GCGAATTCAA TTGCTTAAGA TTCAA 25
Claims (17)
1.幽门螺杆菌FlgE多肽或抗原功能等价的其修饰形式，用于引发针对幽门螺杆菌感染的保护性免疫应答。
2.权利要求1的幽门螺杆菌FlgE多肽，具有基本上如序列表中SEQ ID NO：2所示的氨基酸序列，用于引发针对幽门螺杆菌感染的保护性免疫应答。
3.引发针对幽门螺杆菌感染的保护性免疫应答的疫苗组合物，包括免疫有效量的权利要求1或2限定的幽门螺杆菌FlgE多肽，可任选包括可药用载体或稀释剂。
4.权利要求3的疫苗组合物，还包括佐剂。
5.权利要求4的疫苗组合物，其中佐剂为可药用形式的霍乱毒素。
6.权利要求3到5中任一项的疫苗组合物用作感染了幽门螺杆菌的哺乳动物包括人的治疗性疫苗。
7.权利要求3到5中任一项的疫苗组合物用作保护哺乳动物包括人免于幽门螺杆菌感染的预防性疫苗。
8.权利要求1或2的幽门螺杆菌FlgE多肽在生产治疗、预防或诊断幽门螺杆菌感染的组合物中的用途。
9.权利要求1或2的幽门螺杆菌FlgE多肽在生产引发针对幽门螺杆菌的保护性免疫应答的疫苗中的用途。
10.权利要求1或2的幽门螺杆菌FlgE多肽在生产诊断幽门螺杆菌感染的诊断试剂盒中的用途。
11.体外诊断幽门螺杆菌感染的方法，包括至少一个步骤，其中使用权利要求1或2限定的幽门螺杆菌FlgE多肽，该多肽可任选以固相载体标记或与其偶联。
12.权利要求11的方法，包括以下步骤：
(a)使所述幽门螺杆菌FlgE多肽与哺乳动物体液接触，所述多肽可任选与固相载体结合；和
(b)检测与所述FlgE多肽结合的所述体液的抗体。
13.在哺乳动物包括人中检测幽门螺杆菌感染的诊断试剂盒，包括使权利要求11或12的方法得以进行的成分。
14.权利要求13的诊断试剂盒，包括：
(a)幽门螺杆菌FlgE多肽：和
(b)检测与所述FlgE多肽结合的抗体的试剂。
15.在哺乳动物中引发针对幽门螺杆菌感染的保护性免疫应答的方法，该方法包括向所述哺乳动物给予免疫有效量的权利要求1或2限定的幽门螺杆菌FlgE多肽。
16.在哺乳动物中引发针对幽门螺杆菌感染的保护性免疫应答的方法，该方法包括向所述哺乳动物给予免疫有效量的权利要求3到7中任一项的疫苗组合物。
17.权利要求书15或16的方法，其中所述哺乳动物是人。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9702242A SE9702242D0 (sv) | 1997-06-12 | 1997-06-12 | Vaccine compositions V |
| SE97022420 | 1997-06-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1259960A true CN1259960A (zh) | 2000-07-12 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98806101A Pending CN1259960A (zh) | 1997-06-12 | 1998-06-08 | 含有幽门螺杆菌FlgE多肽的疫苗组合物 |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP1009764A1 (zh) |
| JP (1) | JP2002507118A (zh) |
| KR (1) | KR20010013699A (zh) |
| CN (1) | CN1259960A (zh) |
| AR (1) | AR012896A1 (zh) |
| AU (1) | AU8048798A (zh) |
| BR (1) | BR9810026A (zh) |
| CA (1) | CA2293293A1 (zh) |
| EE (1) | EE9900566A (zh) |
| HU (1) | HUP0003164A3 (zh) |
| ID (1) | ID23052A (zh) |
| IL (1) | IL133144A0 (zh) |
| IS (1) | IS5288A (zh) |
| NO (1) | NO996132L (zh) |
| NZ (1) | NZ501427A (zh) |
| PL (1) | PL337503A1 (zh) |
| SE (1) | SE9702242D0 (zh) |
| SK (1) | SK173099A3 (zh) |
| TR (1) | TR199903060T2 (zh) |
| WO (1) | WO1998056816A1 (zh) |
| ZA (1) | ZA984696B (zh) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784687A (zh) * | 2015-04-27 | 2015-07-22 | 苏州大学附属第一医院 | 重组绿脓杆菌鞭毛钩蛋白FlgE的用途 |
| CN113425717A (zh) * | 2021-04-22 | 2021-09-24 | 成都欧林生物科技股份有限公司 | 一种提高口服幽门螺杆菌疫苗效力的药剂及其应用 |
| CN116535472A (zh) * | 2023-05-31 | 2023-08-04 | 四川大学华西医院 | 一种幽门螺杆菌重组蛋白抗原FlgK及其制备方法与应用 |
| CN118105473A (zh) * | 2024-04-30 | 2024-05-31 | 成都欧林生物科技股份有限公司 | 一种预防或治疗Hp感染口服免疫原性组合物及其应用 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5459041A (en) * | 1988-02-18 | 1995-10-17 | Enteric Research Laboratories, Inc. | Campylobacter pylori antigens and uses thereof for detection of Campylobacter pylori infection |
| AR003125A1 (es) * | 1995-06-01 | 1998-07-08 | Astra Ab | Antigenos bacterianos para el diagnostico de infecciones con helicobacter pylori, una molecula de adn que lo codifica, un vector, una celula huesped,procedimiento para producir el polipeptido, composiciones para vacunas adecuadas para uso terapeutico y profilactico, el uso del polipeptido en la |
-
1997
- 1997-06-12 SE SE9702242A patent/SE9702242D0/xx unknown
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1998
- 1998-06-01 ZA ZA984696A patent/ZA984696B/xx unknown
- 1998-06-01 AR ARP980102558A patent/AR012896A1/es unknown
- 1998-06-08 HU HU0003164A patent/HUP0003164A3/hu unknown
- 1998-06-08 AU AU80487/98A patent/AU8048798A/en not_active Abandoned
- 1998-06-08 IL IL13314498A patent/IL133144A0/xx unknown
- 1998-06-08 PL PL98337503A patent/PL337503A1/xx unknown
- 1998-06-08 JP JP50228399A patent/JP2002507118A/ja active Pending
- 1998-06-08 EE EEP199900566A patent/EE9900566A/xx unknown
- 1998-06-08 WO PCT/SE1998/001093 patent/WO1998056816A1/en not_active Application Discontinuation
- 1998-06-08 ID IDW991542A patent/ID23052A/id unknown
- 1998-06-08 BR BR9810026-2A patent/BR9810026A/pt not_active IP Right Cessation
- 1998-06-08 CN CN98806101A patent/CN1259960A/zh active Pending
- 1998-06-08 EP EP98928772A patent/EP1009764A1/en not_active Withdrawn
- 1998-06-08 SK SK1730-99A patent/SK173099A3/sk unknown
- 1998-06-08 CA CA002293293A patent/CA2293293A1/en not_active Abandoned
- 1998-06-08 TR TR1999/03060T patent/TR199903060T2/xx unknown
- 1998-06-08 NZ NZ501427A patent/NZ501427A/xx unknown
- 1998-06-08 KR KR1019997011714A patent/KR20010013699A/ko not_active Application Discontinuation
-
1999
- 1999-12-08 IS IS5288A patent/IS5288A/is unknown
- 1999-12-10 NO NO996132A patent/NO996132L/no not_active Application Discontinuation
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784687A (zh) * | 2015-04-27 | 2015-07-22 | 苏州大学附属第一医院 | 重组绿脓杆菌鞭毛钩蛋白FlgE的用途 |
| CN113425717A (zh) * | 2021-04-22 | 2021-09-24 | 成都欧林生物科技股份有限公司 | 一种提高口服幽门螺杆菌疫苗效力的药剂及其应用 |
| CN116535472A (zh) * | 2023-05-31 | 2023-08-04 | 四川大学华西医院 | 一种幽门螺杆菌重组蛋白抗原FlgK及其制备方法与应用 |
| CN116535472B (zh) * | 2023-05-31 | 2024-04-30 | 四川大学华西医院 | 一种幽门螺杆菌重组蛋白抗原FlgK及其制备方法与应用 |
| CN118105473A (zh) * | 2024-04-30 | 2024-05-31 | 成都欧林生物科技股份有限公司 | 一种预防或治疗Hp感染口服免疫原性组合物及其应用 |
| CN118105473B (zh) * | 2024-04-30 | 2024-08-16 | 成都欧林生物科技股份有限公司 | 一种预防或治疗Hp感染口服免疫原性组合物及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002507118A (ja) | 2002-03-05 |
| SE9702242D0 (sv) | 1997-06-12 |
| AU8048798A (en) | 1998-12-30 |
| IL133144A0 (en) | 2001-03-19 |
| ID23052A (id) | 2000-01-20 |
| SK173099A3 (en) | 2000-06-12 |
| WO1998056816A1 (en) | 1998-12-17 |
| IS5288A (is) | 1999-12-08 |
| HUP0003164A2 (hu) | 2000-12-28 |
| TR199903060T2 (xx) | 2000-09-21 |
| NZ501427A (en) | 2000-09-29 |
| NO996132L (no) | 2000-01-28 |
| EE9900566A (xx) | 2000-06-15 |
| EP1009764A1 (en) | 2000-06-21 |
| BR9810026A (pt) | 2000-09-19 |
| AR012896A1 (es) | 2000-11-22 |
| KR20010013699A (ko) | 2001-02-26 |
| ZA984696B (en) | 1999-01-04 |
| CA2293293A1 (en) | 1998-12-17 |
| PL337503A1 (en) | 2000-08-28 |
| NO996132D0 (no) | 1999-12-10 |
| HUP0003164A3 (en) | 2001-10-29 |
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