CN1909924A - 含有细菌鞭毛蛋白作为活性成分的粘膜疫苗佐剂 - Google Patents
含有细菌鞭毛蛋白作为活性成分的粘膜疫苗佐剂 Download PDFInfo
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- CN1909924A CN1909924A CNA2005800023214A CN200580002321A CN1909924A CN 1909924 A CN1909924 A CN 1909924A CN A2005800023214 A CNA2005800023214 A CN A2005800023214A CN 200580002321 A CN200580002321 A CN 200580002321A CN 1909924 A CN1909924 A CN 1909924A
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Abstract
本发明涉及含有来自创伤弧菌(Vibriovulnificus)、鼠伤寒沙门氏菌(Salmonella typhimurium)和单核细胞增生利斯特氏菌(Listeriamonocytogenes)的鞭毛蛋白(鞭毛的结构成分)作为活性成分的粘膜疫苗佐剂。
Description
技术领域
本发明涉及含有鞭毛蛋白作为活性成分的粘膜疫苗佐剂,鞭毛蛋白是细菌鞭毛的结构成分,该细菌鞭毛蛋白源自创伤弧菌(Vibrio vulnificus)、鼠伤寒沙门氏菌(Salmonella typhimurium)和单核细胞增生利斯特氏菌(Listeriamonocytogenes)。
背景技术
创伤弧菌或其缩写“V.vulnificus”引起的传染病具有较短的历史,但世界范围内已经连续报道了其临床病例,而且这种疾病是新观察到的疾病之一。虽然该疾病临床病例的绝对数目比霍乱或沙门氏菌食物中毒的病例数目少,但由于其高死亡率和灾难性的临床表现而成为一个重要的社会问题。
美国疾病控制中心(Centers for Disease Control in USA,CDC)的hollis等人在对从人分离出的嗜盐致病弧菌的细菌学特性研究11年后,于1976年首次报道了创伤弧菌,并由于该菌的乳糖发酵特征而命名为乳糖发酵弧菌或Lac(+)。1979年,CDC的Blake等人根据通过流行病学分析的临床表现将CDC报道的39名患者分为初级败血症和创伤感染组(Blake,P.A.,MersonM.H.,Weaver,R.E.,Hollis,D.G.,Heublin,P.C.,N.Engl.J. Med.300:1-6,1979)。同年,Farmer将该菌作为新种类命名为创伤弧菌(vulnus=创伤,ficus=形成)(Farmer,J.J.III,lancet 2:903,1979)。
致病细菌和病毒的传染主要经由吸气、口服和性传播等通过粘膜途径进行。成人体内,呼吸系统、消化系统和泌尿生殖系统由粘膜表面覆盖的表面积约为400平方米。抵抗常规菌群和源于外部环境的病毒和细菌入侵的初级防御系统主要涉及粘膜免疫应答。与全身免疫相比,主要关于粘膜表面的粘膜免疫仍然没有得到深入研究,但无需怀疑其重要性。最近,日本东京大学(Tokyo University)的kiyono教授等人已经对此进行了集中研究。通常已知的是,在通过粘膜途径接种疫苗的情况下,与通过皮内或皮下途径接种疫苗相比,更有效地诱导粘膜免疫应答,而且粘膜免疫应答主要通过免疫球蛋白-A(IgA)来介导。
经由粘膜途径的接种疫苗的优点是不仅增强全身免疫应答而且同时还增强粘膜免疫应答。因此,扩大了对诱导粘膜组织内有效免疫应答的预防性疫苗开发研究的关注。然而,与经由全身途径的给药相比,经由粘膜途径的蛋白质抗原给药具有免疫原性降低的缺点。因此,粘膜疫苗开发中最重要的因素是开发可以与疫苗抗原一起安全给药的有效粘膜佐剂。
疫苗佐剂最重要的因素之一是具有免疫控制功能,如控制抗原递呈细胞的共刺激分子的表达和由抗原特异性T细胞诱导作用诱导的细胞因子分泌。目前使用的或相关的作为疫苗佐剂的物质是无机盐如氢氧化铝凝胶、表面活性剂、源自细菌的物质、细胞因子、激素、聚阴离子、聚丙烯(polyacryls)、利用载体(carrier)和病毒的活载体(living vector),以及诸如矿物油或脂质体的媒介物(vehicle)。其中,研究最积极和引人注意的疫苗佐剂是源自蛋白的粘膜疫苗佐剂,如来自霍乱弧菌(Vibrio cholerae)的霍乱毒素(choleratoxin,CT)和来自埃希氏菌属大肠杆菌(Escherichia coli)的热不稳定性毒素(heat-labile toxin,LT)。据报道,这些疫苗佐剂经由粘膜组织途径的给药诱导血清和粘膜组织中产生抗原特异性抗体,并促进由抗原递呈细胞表面上B7-2表达诱导的T-细胞的共刺激信号(Boyaka,P.N.,Jackson,R.J.,Kiyoni,H.,Yuki,Y.,McGhee,J.R.Immunol.170:454-462,2003;Kweon,M.N.,Yamamoto,M.,Watanabe,F.,Tamura,S.,Van Ginkel,F.W.,Miyauchi,A.,Takagi,H.,Takeda,Y.,Hamabata,T.,Fujihashi,K.,McGhee,J.R.,Kiyono,H.J.Infect.Dis.186:1261-1269,2002)。然而,这些佐剂是具有高肠毒素毒性的外毒素,因此不适于直接用于人类。现今世界范围内正在进行的研究的目的是制备毒性更低但佐剂活性更高的佐剂。
发明内容
在这些情况下,本发明的发明人发现创伤弧菌的鞭毛蛋白是TLR-5的激动剂,刺激上皮细胞、成熟人树突细胞产生白细胞介素-8(IL-8),在与破伤风类毒素混合,并用其经由鼻内途径对小鼠免疫3次的情况下,与只给予破伤风类毒素的情况相比,显示出显著增多的粘膜IgA,还发现这保护了小鼠使其完全免受破伤风类毒素致死量的影响。另外,本发明的发明人发现上述效果并不限于创伤弧菌的鞭毛蛋白,而且在鼠伤寒沙门氏菌的鞭毛蛋白和单核细胞增生利斯特氏菌的鞭毛蛋白中发现了相同的保护性免疫效果,所述鼠伤寒沙门氏菌为革兰氏阴性菌且在单个细菌中具有许多鞭毛,所述单核细胞增生利斯特氏菌为革兰氏阳性菌;并因此完成本发明。
因此,本发明的目的是提供含有鞭毛蛋白作为活性成分的粘膜疫苗佐剂,所述鞭毛蛋白为细菌鞭毛的成分,该佐剂对于开发多种有效疫苗如用于传染病、抗癌和避孕等的疫苗是必需的。
附图说明
图1显示了创伤弧菌鞭毛蛋白基因的两个操纵子结构之一的基因座1;
图2显示了创伤弧菌鞭毛蛋白基因的两个操纵子结构之一的基因座2;
图3显示了用与破伤风类毒素混合的1微克、5微克和15微克FlaB经鼠鼻途径免疫后,完全保护宿主免受破伤风类毒素致死量影响的结果;
图4显示了用与破伤风类毒素混合的1微克、5微克和15微克FlaB经鼠鼻途径免疫后,通过酶联免疫吸附测定(ELISA)方法,使用取样的鼠血清和各种粘液样品来测量抗原特异性免疫应答的结果;
图5显示了用与破伤风类毒素混合的利斯特氏菌FlaA、创伤弧菌FlaB、沙门氏菌FliC经鼠鼻途径免疫后,通过ELISA方法,使用鼠血清来测量抗原特异性免疫应答的结果;
图6显示了将重组FlaB给予上皮细胞后,白细胞介素-8(IL-8)以剂量依赖性方式从上皮细胞分泌;
图7显示了将重组FlaB给予表达人体TLR-5和IL-8转录报告基因(transcriptional reporter)的细胞,或给予表达人体TLR-5和核因子κB的细胞时,IL-8和核因子κB的转录激活;
图8显示了将谷胱甘肽-S-转移酶和6个鞭毛蛋白(创伤弧菌鞭毛的结构成分)的融合蛋白给予表达人TLR-5和IL-8转录报告基因的细胞时,IL-8的转录激活;
图9显示了将重组创伤弧菌FlaB与重组沙门氏菌FliC给予人树突细胞时,树突细胞成熟的诱导。
具体实施方式
本发明的发明人分离了鞭毛蛋白,并给小鼠皮下注射(自动免疫接种)来证实防御性免疫力,并观察皮下注射有鞭毛蛋白的小鼠皮肤组织中形成肉芽肿损害(granulomatous lesion)。结果,我们证实鞭毛蛋白起到了疫苗佐剂的作用。
鞭毛,决定细菌活动性的重要因素,一般由钩形鞘(hook)、基体和鞭毛丝(filament)构成。已知鞭毛具有多种功能,如细菌的泳动活动性或爬动活动性,决定细菌的趋向性,形成生物膜和决定细菌的粘附性(McCarter,L.L.,Microbiol Mol Biol Rev.65:445-62,2001;Kim,Y.K.,McCarter,L.L.,JBacteriol.182:3693-704,2000;McCarter,L. L.,J Bacteriol.177:1595-609,1995;Boles,B.R.,McCarter,L.L.J Bacteriol.182:1035-45,2000;Prouty,M.G.,Correa,N.E.,Klose,K.E.Mol Microbiol.2001 Mar;39(6):1595-609,2001)。创伤弧菌具有极性鞭毛(McCarter,L.L.,Microbiol Mol Biol Rev.65:445-62,2001)。鞭毛的结构成分称为鞭毛蛋白,且该鞭毛蛋白形成规则排列的鞭毛丝。根据最近的研究结果,已知哺乳动物钟样受体-5(Toll-likereceptor-5,TLR-5)识别革兰氏阴性和革兰氏阳性细菌的鞭毛蛋白,并随后激活宿主细胞的NF-kB途径(Hayashi,F.,Smith,K.D.,Ozinsky,A.,Hwan,T.R.,Yi,E.C.,Goodlett,D.R.,Eng,J.K.,Akira,S.,Underhill,D.M.,Aderem,A.,Nature 410:1099-1103,2001)。TLR,识别与病原体相关的分子模型的受体,作为抵抗各种传染病原体的第一防线天然免疫系统的主要成分,而且是与有效适应性免疫应答的刺激相关的细胞受体(Akira,S.,Hemmi,H.,Immunol.Lett.85:85-95,2003)。因此,TLR激动剂可以是开发各种疫苗佐剂的靶标。
根据本发明的发明人的研究,构成创伤弧菌鞭毛的基因包括DNA序列编号1表达的或氨基酸序列编号2的flaA,DNA序列编号3表达的或氨基酸序列编号4的flaB,DNA序列编号5表达的或氨基酸序列编号6的flaF,DNA序列编号7表达的或氨基酸序列编号8的flaC,DNA序列编号9表达的或氨基酸序列编号10的flaD,DNA序列编号11表达的或氨基酸序列编号12的flaE;每个基因的组成与副溶血弧菌(Vibrio parahemolyticus)的基因的组成相似,且它们的同源性也很高。
证明根据本发明的含有鞭毛蛋白(细菌鞭毛的结构成分)的疫苗佐剂效果的方法如下:
1)制备和分离重组鞭毛蛋白;
2)用混合的重组鞭毛蛋白和破伤风类毒素鼻内免疫后,测量抗原特异性免疫应答的水平;
3)用混合的重组鞭毛蛋白和破伤风类毒素鼻内免疫小鼠后,测量宿主对破伤风毒素的防御能力;
4)证实重组鞭毛蛋白提高了上皮细胞IL-8的产生;
5)证实重组鞭毛蛋白和TLR-5结合后诱导了胞内信号传导;
6)观察重组鞭毛蛋白诱导人树突状细胞(dendritic cell,DC)成熟。
因此,本发明涉及含有鞭毛蛋白(细菌鞭毛的结构成分)作为活性成分的疫苗佐剂。
另外,本发明涉及制备具有受鞭毛蛋白诱导的佐剂活性的重组免疫原的方法,该方法包括用编码各种免疫原抗原决定部位的基因来替代结合TLR-5的细菌鞭毛蛋白的结构基因的N-端和C-端之间存在的部分基因。
更具体地,可以通过用编码蛋白抗原决定部位的基因替代SEQ ID NO:1至SEQ ID NO:12中所示的创伤弧菌的结构成分中FlaA的氨基酸序列1-191、FlaB的氨基酸序列1-191、FlaF的氨基酸序列1-191、FlaC的氨基酸序列1-191、FlaD的氨基酸序列1-191和FlaE的氨基酸序列1-189的N-端区域与FlaA的氨基酸序列277-376、FlaB的氨基酸序列278-377、FlaF的氨基酸序列278-377、FlaC的氨基酸序列285-385、FlaD的氨基酸序列278-377和FlaE氨基酸序列276-375的C-端区域之间的碱基序列来制备具有通过鞭毛蛋白诱导的佐剂活性的重组免疫原。
本发明的蛋白抗原决定部位是破伤风类毒素、流感病毒的免疫原抗原决定部位(immunogenic epitope)、肺炎球菌表面蛋白A(pneumococcal surfaceproteinA,PspA)的特异性抗原和肺炎球菌的雄配子(sperm)等。
可以将本发明的疫苗佐剂配制成口服形式,如水溶剂或油溶剂的溶液、悬浮液、或者乳剂形式,或者使用前为无菌形态的干粉型,而使用时溶解于无热原的水中,或者可以配制成非口服给药(例如,皮下注射、静脉注射或肌肉注射)。
口服制剂中,可以通过常规方法使用载体或成形剂(forming agent)制成各种剂型,例如,片剂、锭剂、水乳剂或油乳剂、可以喷雾的粉剂或颗粒、乳剂、软胶囊或硬胶囊、糖浆或酏剂,可以根据单位剂量或剂型选择。
可以通过悬浮于无毒可用的稀释剂或溶剂如1,2-丁二醇中的无菌注射溶液或乳剂的形式注射非口服制剂。可以使用的稀释剂或溶剂的实例为水、林格氏液(Ringer solution)和等渗生理盐水,也可以使用常规的溶剂如乙醇、聚乙二醇(polyethileneglycol)和聚丙二醇。无菌挥发油可以用作溶剂或乳化性溶剂。栓剂形式中,将药物和无刺激性赋形剂混合后,通过直肠内途径给予药物,无刺激性赋形剂例如是常温下为固体而在直肠温度下为液体的可可脂或聚乙二醇。
本发明的疫苗佐剂的实例是对抗破伤风等的抗毒素疫苗,对抗霍乱,伤寒等的减毒活疫苗或灭活疫苗;对抗流感,非典型肺炎(Severe AcuteRespiratory Syndrome,SARS)等的抗病毒疫苗;对抗子宫宫颈癌等的抗癌疫苗;抗精子的避孕疫苗;以及用于重组疫苗的佐剂,然而,不受限于这些实例。
此外,本发明并不受限于创伤弧菌的鞭毛蛋白,适用于具有与创伤弧菌相似的由鞭毛蛋白基因编码的鞭毛蛋白的其他有鞭毛细菌。
以下更详细地充分解释了本发明,但本发明不受限于这些实施例。
表1中描述了本发明中所用菌株和质粒的特征。在相应的实施例和实验实施例中描述了每个菌株或质粒的详细特征和制造方法
表1
菌株或质粒 | 特征 | 来源 |
创伤弧菌 | ||
CMCP6 | 临床分离,高度致病 | 本发明的发明人 |
MO6-24/O | 临床分离,高度致病 | Glenn Morris Jr.(马里兰大学) |
ATCC29307 | 典型菌株 | 购自美国典型培养物保藏中心(ATCC) |
单核细胞增生利斯特氏菌 | ||
10403S | 典型菌株 | Lee,Hyun Chul(韩国国立全南大学) |
鼠伤寒沙门氏菌 | ||
14028S | 典型菌株 | Choy,Hyun E(韩国国立全南大学) |
埃希氏大肠杆菌 | ||
R2566 | F-λ-fhuA2[lon]ompT lacZ::T7基因1 gal sulA11(mcrC-mrr)I14::IS10R(mcr-73::miniTn10-TetS)2R(zgb-210::Tn10)(TetS)endA1[dcm] | 新英格兰生物实验室(New EnglandBiolab) |
质粒 | ||
pTYB | 用亲和性几丁质结合标记物纯化介导的蛋白内含子(InteinMediated Purification with anAffinity Chitin-binding Tag,IMPACT)表达载体,AmpR,7,417bp | 新英格兰生物实验室 |
<每种菌株的培养与保存>
以下实施例和实验中,LB(Luria Bertani)培养基(Difco Co.)用于大肠杆菌、沙门氏菌和利斯特氏菌的菌株,心脏浸出液(heart infusion,HI)培养基(Difco Co.)用于培养创伤弧菌。这些菌株培养后,加入甘油,成为50%的溶液并且在深冻冰箱中-80℃保存。
实施例1 转座子文库的构建
将创伤弧菌MO6-24/O型菌株(从美国马里兰大学医学院医院流行病学部的J.Glenn Morris处获得)和包括E.coli SM10λpir的mini-Tn5 lacZ1菌株(从德国Braunschweig,GBF National Research Center for Biotechnology,Kenneth N.Timmis处获得)在37℃,210转/分钟的摇床中培养,两种菌分别在10毫升的2.5HI(2.5%NaCl心脏浸出液)肉汤培养基和20毫升的LB(含有100微克/毫升的氨苄青霉素和100微克/毫升卡那霉素)肉汤培养基中接种单个菌落。
第二天将上述接种培养物离心,并用无抗生素的LB肉汤培养基清洗和离心两次,然后悬浮在100微升的新LB肉汤培养基中。将大肠杆菌和创伤弧菌的单一细菌悬浮液混合在一起并滴在LB琼脂平板上。37℃培养过夜后,将800微升新的2.5HI肉汤培养基加入到LB琼脂平板上生长的菌落中,使用灭菌的玻璃棒将生长的菌落小心刮下。将该细菌悬浮液转移至1.5毫升的塑料试管中并悬浮直至变成均质状态。将该悬浮液稀释至1/10和1/100,然后停止稀释,将稀释液滴至含有200微克/毫升卡那霉素的硫代硫酸盐柠檬酸盐胆盐蔗糖(thiosulfate citrate bile sucrose,TCBS)琼脂平板上,涂覆直到充分渗透,在37℃下培养过夜。
接下来一天只取在TCBS琼脂平板上生长的弧菌菌落,并用牙签将其接种于含有300微克/毫升卡那霉素的琼脂平板上,并在37℃下培养过夜。第二天将生长的弧菌菌落接种于含有200微克/毫升卡那霉素的100微升2.5HI的96孔培养板上,并在37℃下培养过夜,没有振荡。接下来一天,将80微升50%的甘油加入含有生长细菌的每个孔中,储存于-80℃的深度冷冻冰箱中。当用于实验时,将这些接种于2.5HI肉汤培养基并按需要培养。
实施例2 失去运动性的转座子突变菌落的筛选
将实施例1中制得的创伤弧菌MO6-24/O转座子文库的每个克隆(clone)在37℃下培养过夜,然后使用灭菌的牙签接种于含有0.3%琼脂的半固态HI(心脏浸出液)琼脂平板,并在37℃下培养6小时。然后通过测量细菌生长后的移动范围来测定细菌的运动性程度。
通过筛选步骤选择几乎完全失去运动性的3个转座子突变克隆,并进行鉴定插入转座子的突变基因的实验。
实施例3 鞭毛蛋白操纵子基因的鉴定
通过筛选粘粒基因文库来进行转座子插入区域附近的基因克隆,使用DNA片段作为随机聚合酶链反应(Polymerase Chain Reaction,PCR)方法扩增的引物。使用两步PCR扩增方法来扩增转座子插入位点附近的DNA片段。第一步PCR中,使用序列编号13的随机引物1(5-GGCCACGCGTCGACTAGTCANNNNNNNNNNACGCCC-3),和序列编号14的mini-Tn5 lacZ1特异性引物1(5-TTCTTCACGAGGCAGACCTCAGCGC-3)。第一步PCR设置如下:94℃变性30秒,30℃退火30秒,然后在72℃延伸1分30秒,5个循环;然后通过94℃变性30秒,45℃退火30秒,72℃延伸2分钟,30个循环,再进行30个循环的PCR反应。使用第一步PCR的产物作为模板进行第二步PCR反应。第二步PCR中,使用序列编号15的随机引物2(5-GGCCAAGAGTCGACTAGTCA-3)和序列编号16的mini-Tn5 lacZ1特异性引物2(5-CCGCACTTGTGTATAAGAGTCAG-3)。反应条件为:94℃变性30秒,72℃退火30秒,72℃延伸1分30秒,30个循环。将这些PCR产物在琼脂糖凝胶中电泳,从凝胶中分离出扩增的DNA片段,并确定它们的碱基序列。结果,上述的PCR反应扩增了3种特异性的DNA片段。
测定扩增的DNA片段、并用美国国家生物信息中心的GeneBank数据库中记录的基因进行的BLAST分析的结果,表明了与副溶血弧菌的bcr,cheR和flgG基因的同一性。根据本发明的发明人对创伤弧菌的基因组序列分析的完全译码的结果,所述的基因位于极性鞭毛的鞭毛蛋白操纵子中,如图1和2所示。
实施例4 重组鞭毛蛋白的制备和纯化
将分别含有创伤弧菌flaB基因、沙门氏菌fliC基因(序列编号18)和利斯特氏菌flaA基因(序列编号17)的开放读码框(Open Reading Frame,ORF)的DNA片段连接至为蛋白内含子(intein)融合表达载体的pTYB12载体中(New England Biolabs Inc.),来产生各自的质粒pCMM250、pCMM251、pCMM252。通过电穿孔将每种质粒转化至E.coli ER2566中,并通过加入0.5mM 5-溴-吲哚-3-氯-异丙基-β-D-半乳糖吡喃糖苷(5-bormo-indol-3-chloro-isopropyl-β-D-galactopyranoside,ITPG)来诱导表达。根据制造商(New England Biolabs Inc.)的说明,使用几丁质珠层析柱(Chitin bead column)和1,4-二硫苏糖醇(1,4-dithiothreiol)从蛋白内含子融合蛋白中纯化Flab、FliC和FlaA蛋白质。使用亲和性PakTM DetoxigelTM内毒素去除凝胶(Pirece Inc.Rockgord,IL)除去包含在分离的FlaB、FliC和FlaA蛋白质中的内毒素。
使用上述的方法将创伤弧菌flaA、flaB、flaF、flaC、flaD和flaE基因的ORF连接至pGEX4T-1载体中(pCMM244-flaB、pCMM245-flaA、pCMM247-flaD、pCMM248-flaE、pCMM249-flaF)。根据制造商(AmershamPharmacia)的说明,纯化谷胱甘肽-S-转移酶融合蛋白质。
实验实施例1 重组鞭毛蛋白的粘膜免疫佐剂活性的实验
每隔7天,用20微升的PBS(磷酸盐缓冲盐水)、单独3微克的破伤风类毒素、或者3微克的破伤风类毒素分别与1微克、5微克和15微克的创伤弧菌FlaB的组合,向7周大的雌性Balb/c小鼠鼻内免疫3次。最后一次免疫后7天,从免疫的小鼠中收集唾液、阴道洗出物和血清样品来测定破伤风类毒素(TT)-特异性全身免疫应答和粘膜免疫应答。通过酶联免疫吸附测试(Enzyme linked immuno sorbant assay,ELISA)方法测量这些应答,将之前接种3次疫苗的小鼠,在全身给药最少200倍破伤风类毒素致死量后,观察7天。结果显示于图3和图4中。
如图3所示的,仅用PBS免疫的对照组小鼠在24小时内全部死亡(100%),只用破伤风类毒素(TT)鼻内免疫的组中仅有17%存活。然而,用破伤风类毒素和1微克、5微克或15微克的创伤弧菌FlaB的组合(TT+Vv-FlaB)免疫的小鼠有100%的存活。TT组存活的小鼠显示了强直性麻痹,但TT+Vv-FlaB的组存活的小鼠显示出与正常小鼠同样的特征。
如图4所示,就抗原特异性全身免疫应答和粘膜免疫应答的程度而言,TT+Vv-FlaB组高于仅用PBS或TT的组。
为了证实这些疫苗的佐剂活性中哪些对于其它非-创伤弧菌鞭毛的鞭毛蛋白是普通的,用纯化的FlaA重组蛋白和FliC重组蛋白进行了相同的实验,所述FlaA重组蛋白是单核细胞增生利斯特氏菌的鞭毛蛋白结构成分,单核细胞增生利斯特氏菌是革兰氏(+)细菌,所述FliC重组蛋白是鼠伤寒沙门氏菌的鞭毛蛋白结构成分,鼠伤寒沙门氏菌是革兰氏(-)细菌。结果显示于表2和图5中。
表2
组 | 保护性免疫测试(抗破伤风类毒素) | 存活率(7天) |
天然的(n=5) | + | 0% |
仪有TT(破伤风类毒素)(n=15) | + | 17% |
TT+7微克Lm-FlaA (n=5) | + | 100% |
TT+9微克Vv-FlaB (n=5) | + | 100% |
TT+12微克St-FliC (n=5) | + | 100% |
表2的数据是用利斯特氏菌的FlaA、创伤弧菌的FlaB和沙门氏菌的FliC分别与破伤风类毒素组合进行鼻内免疫后,给药破伤风类毒素的结果。表明这些鞭毛蛋白结构成分蛋白质完全保护了宿主免受破伤风类毒素致死量的影响。
表2和图5的结果中,观察到上述3种类型菌株的鞭毛蛋白与疫苗佐剂具有相同的效用。
图3、图4、图5和表2的结果表明,重组鞭毛蛋白起着有效疫苗佐剂的作用。
实验实施例2 鞭毛蛋白对上皮细胞的应答
将Caco-2细胞以2.0×105/孔接种于24孔平板中,并在补充10%胎牛血清(FCS)的达尔伯克氏改良伊格尔氏培养基(DMEM)中维持过夜。第二天用无胎牛血清的DMEM清洗两次,并用没有补充FCS的不同浓度的重组Vv-FlaB处理3小时,使用ELISA试剂盒(R&D系统Co.)测量释放至上清液的IL-8水平。通过实时逆转录-PCR分析来分析由Vv-FlaB处理的Caco-2细胞中的IL-8表达。从由Vv-FlaB处理的细胞中分离总RNA。结果显示于图6中。图6中,显示了重组FlaB结合Caco-2细胞表面的受体和传导胞内信号,并以剂量依赖性的方式促进IL-8,所述IL-8诱导嗜中性粒细胞分泌重要的炎症介质。
实验实施例3 调控TLR-5介导的鞭毛蛋白的IL-8表达
用合适量的表达质粒、报告基因pIL-8-Luc或pNF-κB-Luc(从Hanyang大学医学院的Kim,Jeong Mok教授处获得)和编码TLR-5基因的p3Xflag-hTLR5(从美国Wake Forest大学医学院微生物和免疫系的Steven B.Mizel处获得)来转染以2.0×105/孔接种于24孔平板中的Caco-2细胞。使用对照表达质粒pCMV-β-ga(9BD Biosciences Clontech,Palo Alto,CA)将荧光素酶的活性水平规范成lacZsd表达。通过加入适量空白载体来保持表达载体总数的恒定。转染后24小时,用新鲜培养基来替代培养物,每种所述培养基含有创伤弧菌的重组FlaB、沙门氏菌的重组FliC和利斯特氏菌的重组FlaA,以及通过MPACT-CNTM系统纯化的创伤弧菌FlaA、FlaB、FlaF、FlaC、FlaD和FlaE之一,并且和谷胱甘肽-S-转移酶融合蛋白共同给药。给药后几小时,通过照度计(luminometer)(MicroLumatPlus LB 96V,Berthold,Wilbad,德国)测定荧光素酶的活性来测量IL-8的表达,结果显示于图7和图8中。
重组FlaB以剂量依赖性的方式激活了IL-8和pNF-κB的表达。还表明了创伤弧菌的其他鞭毛结构成分FlaA、FlaF、FlaC、FlaD和FlaE具有一定程度的不同。
实验实施例4 重组FlaB对人外周血树突细胞的应答
使用Ficoll Paque PLUS(Amersham Inc.)通过离心从人外周血分离外周血单核细胞(peripheral blood mononuclear cell,PBMC)。将识别PBMC中骨髓细胞上选择性表达的CD14的磁珠在6-12℃反应20分钟。通过磁性细胞分选器来分离CD14阳性细胞。将CD14阳性细胞加入含有10%FCS的RPMI培养基中,并共同给予50纳克/毫升粒-巨噬细胞集落刺激因子(granulocyte macrophage colony stimulating factor,GM-CSF)及50纳克/毫升白细胞介素-4(IL-4),培养6天以分化为不成熟的树突细胞。分化后,用实施例4中制得的重组FlaB和沙门氏菌鞭毛蛋白FliC以6nM浓度的剂量处理,并培养24小时。观察FlaB和FliC对人树突细胞分化的影响。给予FliC的原因是用来确定本发明是否可以广泛应用。
对识别树突细胞表面上选择性表达的CD80、CD83和CD86并结合异硫氰酸荧光素(fluorescein isothicyanate,FITC)或藻红蛋白(phycoerythrin,PE)的单克隆抗体进行处理。使用流式细胞计来测量显示阳性信号的细胞组的表达水平。图9显示了结果。
用创伤弧菌的重组FlaB来处理人树突细胞时,意味着树突细胞成熟的CD80、CD83和CD86阳性的百分比水平分别增长了67.3%、23.57%和43.29%。这些水平的增长速率比对照组中的15.29%、0.82%和1.5%高得多。然而,在骨髓细胞上选择地表达的CD14成熟水平降低更多。沙门氏菌的鞭毛蛋白FliC显示出相似的表现。
工业实用性
如以上结果所示,创伤弧菌鞭毛蛋白的结构成分FlaA、FlaB、FlaF、FlaC、FlaD和FlaE,以及沙门氏菌鞭毛蛋白的结构成分FliC和利斯特氏菌鞭毛蛋白的结构成分FlaA刺激上皮细胞的IL-8释放和树突细胞的成熟。还提高了宿主对用作疫苗的免疫刺激剂的抗原特异性免疫应答。
与没有给予鞭毛蛋白作为佐剂的对照组相比,用破伤风类毒素和提及的鞭毛蛋白通过鼻内途径将小鼠免疫时,显示出对抗抗原的IgA水平的显著提高。此外,宿主完全受到保护免受破伤风类毒素的影响。尤其是在阴道洗出物中,IgA水平极大增加,因此可以用作对精子选择性的避孕疫苗的佐剂。
本发明的重组细胞鞭毛蛋白还可以用作对抗其它传染病和抗癌治疗疫苗的有效佐剂。
序列表
<110>全南大学校
<120>含有细菌鞭毛蛋白作为活性成分的粘膜疫苗佐剂
<130>P6525YOL
<150>KR10-2004-0001974
<151>2004-01-12
<160>18
<170>PatentIn version 3.1
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gcgaaagatg atgctgcagg tctacaaatt tctaaccgtt tgaactcgca aagccgtggt 180
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gcaatgacag agaccaccaa catcctacaa cgtatgcgtg accttgcctt gcaatcgtct 300
aacggttcga actctcgttc tgaacgcgtg gcgattcaag aagaagtgtc agcgttgaac 360
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acgtacggtt ctcaatcttt ccaaatcggt gctgactctg gtgaagctgt gatgctttct 480
atgggtaacc ttcgttcaga tacagacgcg atgggcggct tgagctacaa atctgaagaa 540
ggcgtaggcg cagattggcg tgtaagcgac aacactgact tcacgatgtc ttatgtgaat 600
aagcaaggtg aagaaaaaga gatcacagtc aacgccaaag cgggtgacga tcttgaagaa 660
ctggcgactt acatcaacgg tcaaaacgat gatgtgaaag cgtcggtcgg tgaaggcggc 720
aaactgcagc tattcgcttc taaccaacgt gtagaaggtg aagtggaatt cggtggtggt 780
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acgacggttg ctggctctca agaagcagta gcgatcattg atggcgcatt gaaatcggta 900
gacagtgagc gtgcetctct aggtgcattc caaaaccgtt tcaaccatgc aatcagcaac 960
ctaagcaaca tcaatgagaa cgtaaacgct tcgagcagcc gtatcaagga taccgactac 1020
gcgaaagaaa cgactcagat gactaagacg caaattctgc agcaggcgag tacttctatc 1080
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355 360 365
Leu Ala Gln Ala Lys Gln Leu Pro Asn Ser Ala Met Ser Leu Leu
370 375 380
<210>9
<211>1134
<212>DNA
<213>创伤弧菌(Vibrio vulnificus)
<400>9
atggcagtga atgtaaatac aaacgtagca gcaatgacag cacagcgtta cctgaataac 60
gcaaacagcg cacaacaaac ttcgatggag cgtctgtctt caggtttcaa aatcaacagt 120
gcaaaagatg acgcagccgg tctgcaaatc tctaaccgct tgaacgtgca aagtcgcggt 180
ctagacgttg cggtacgtaa cgccaacgac ggtatctcaa tcgcacaaac cgcagaaggt 240
gcgatgaacg agaccaccaa catcctacaa cgtatgcgtg acctatctct gcaatcagcg 300
aacggctcaa actcaaaatc agagcgcgtg gcgattcaag aagagatcac cgcattgaac 360
gacgagctaa accgtatcgc agaaaccacg tcttttggtg gtaacaaact gctcaacggc 420
acttacggca cgaaagcaat gcaaattggt gcggataacg gtgaagcggt catgctgtca 480
ctcaaagaca tgcgctctga caacgtgatg atgggcggcg tgagctacca agctgaagaa 540
ggcaaagaca agaactggaa tgtggccgca ggcgacaacg acttgacgat tgcactgaca 600
gacagctttg gtaacgagca agagatcgaa atcaacgcga aagcgggcga tgacatcgaa 660
gagctagcga cgtacatcaa cggtcaaact gaccttgtaa aagcgtcagt gggtgaaggc 720
ggcaagctac agatctttgc tggtaacaac aaagttcaag gtgaaattgc tttctcaggt 780
agcctagctg gtgaacttgg cctaggcgaa ggcaaaaacg tcacggtaga cacgattgac 840
gtgacaaccg tacaaggtgc gcaagagtcg gtagcgattg tggatgcggc actgaaatac 900
gtagacagcc accgtgcaga gctgggtgca ttccagaacc gtttcaacca tgcaatcagc 960
aacttggaca acatcaacga gaacgtgaac gcgtcgaaga gccgaatcaa agataccgac 1020
ttcgcgaaag aaacgactca gttgaccaag acacaaattc tatcgcaagc atcaagttcc 1080
attcttgcgc aagcgaaaca agcgccaaac tcagcgctaa gtctactagg ctaa 1134
<210>10
<211>377
<212>PRT
<213>创伤弧菌(Vibrio vulnificus)
<400>10
Met Ala Val Asn Val Asn Thr Asn Val Ala Ala Met Thr Ala Gln Arg
1 5 10 15
Tyr Leu Asn Asn Ala Asn Ser Ala Gln Gln Thr Ser Met Glu Arg Leu
20 25 30
Ser Ser Gly Phe Lys Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Leu
35 40 45
Gln Ile Ser Asn Arg Leu Asn Val Gln Ser Arg Gly Leu Asp Val Ala
50 55 60
Val Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Ala Glu Gly
65 70 75 80
Ala Met Asn Glu Thr Thr Asn Ile Leu Gln Arg Met Arg Asp Leu Ser
85 90 95
Leu Gln Ser Ala Asn Gly Ser Asn Ser Lys Ser Glu Arg Val Ala Ile
100 105 110
Gln Glu Glu Ile Thr Ala Leu Asn Asp Glu Leu Asn Arg Ile Ala Glu
115 120 125
Thr Thr Ser Phe Gly Gly Asn Lys Leu Leu Asn Gly Thr Tyr Gly Thr
130 135 140
Lys Ala Met Gln Ile Gly Ala Asp Asn Gly Glu Ala Val Met Leu Ser
145 150 155 160
Leu Lys Asp Met Arg Ser Asp Asn Val Met Met Gly Gly Val Ser Tyr
165 170 175
Gln Ala Glu Glu Gly Lys Asp Lys Asn Trp Asn Val Ala Ala Gly Asp
180 185 190
Asn Asp Leu Thr Ile Ala Leu Thr Asp Ser Phe Gly Asn Glu Gln Glu
195 200 205
Ile Glu Ile Asn Ala Lys Ala Gly Asp Asp Ile Glu Glu Leu Ala Thr
210 215 220
Tyr Ile Asn Gly Gln Thr Asp Leu Val Lys Ala Ser Val Gly Glu Gly
225 230 235 240
Gly Lys Leu Gln Ile Phe Ala Gly Asn Asn Lys Val Gln Gly Glu Ile
245 250 255
Ala Phe Ser Gly Ser Leu Ala Gly Glu Leu Gly Leu Gly Glu Gly Lys
260 265 270
Asn Val Thr Val Asp Thr Ile Asp Val Thr Thr Val Gln Gly Ala Gln
275 280 285
Glu Ser Val Ala Ile Val Asp Ala Ala Leu Lys Tyr Val Asp Ser His
290 295 300
Arg Ala Glu Leu Gly Ala Phe Gln Asn Arg Phe Asn His Ala Ile Ser
305 310 315 320
Asn Leu Asp Asn Ile Asn Glu Asn Val Asn Ala Ser Lys Ser Arg Ile
325 330 335
Lys Asp Thr Asp Phe Ala Lys Glu Thr Thr Gln Leu Thr Lys Thr Gln
340 345 350
Ile Leu Ser Gln Ala Ser Ser Ser Ile Leu Ala Gln Ala Lys Gln Ala
355 360 365
Pro Asn Ser Ala Leu Ser Leu Leu Gly
370 375
<210>11
<211>1127
<212>DNA
<213>创伤弧菌(Vibrio vulnificus)
<400>11
atggtttcac tcaataccaa cgtgtctgcg atggtcgctc agaggcatct gagcacagcg 60
gcaagtcagg tagctgaaac ccaaaaaaat ctaagttccg gattccgaat taatagtgcc 120
agcgatgatg ccgctggaat gcagatagcg aatacgcttc acgtccaaac ccgtggtttg 180
gatgtggcat taactaacgc tcatagtgct tatgctgttg cagaaacagc ggaaggggcg 240
ttggaagagg gcagtgaaat actgcagaga ttgcgatctc tttctcttca agccgcaaac 300
ggatcgaatt ctgatgagga tcggcaaagt ttgcagttgg aagtggtggt attgaaagat 360
gaagtggaaa gaatagccag gacaaccaca tttgcgggta aaaatctgtt tgatggaagt 420
tatggttcaa aaagttttca tcttggggca aattctaatt ccatttcttt gcaactcaaa 480
aacatgcgga ctcacgttcc tgagatgggc gggtatcatt accttgcctc ggagccagcg 540
gatgaggatt ggcaagttga caaggaatca aggcaactta gctttacttt tcgagatagc 600
gaaggggatg atcaatccat taagatctcg cttaagcctg gagacagtct cgaagaagtc 660
gctacgtata tcaattcaca gcaaaatgtt gtggagtcct cggtgacgga tgatcggcga 720
ttgcagtttt atgtcgctaa tcgtcacgct cctgatggtt taaatatctc aggaagcttg 780
gagggagagc tagactttga accgcaagga caagtgacgc tcgatgaact cgatatcagt 840
agtgtgggtg gtgctcaatt ggcgattgct gttgttgata ctgcaattca atatctggat 900
tctcaccgaa gtgaaatcgg cagttttcaa aatcgggtag aggggacgat ggacaatttg 960
caaagtatca atcgcaatgt cactgaatca aaagggcgaa tatgggatac cgattttgcg 1020
aaagcatcaa ccgctttagt gaagtctcag gtattgcaac aggctacctc tgccttgctg 1080
gctcaagcca agcaagcccc aggcagtgca attggattgc tatctta 1127
<210>12
<211>375
<212>PRT
<213>创伤弧菌(Vibrio vulnificus)
<400>12
Met Val Ser Leu Asn Thr Asn Val Ser Ala Met Val Ala Gln Arg His
1 5 10 15
Leu Ser Thr Ala Ala Ser Gln Val Ala Glu Thr Gln Lys Asn Leu Ser
20 25 30
Ser Gly Phe Arg Ile Asn Ser Ala Ser Asp Asp Ala Ala Gly Met Gln
35 40 45
Ile Ala Asn Thr Leu His Val Gln Thr Arg Gly Leu Asp Val Ala Leu
50 55 60
Thr Asn Ala His Ser Ala Tyr Ala Val Ala Glu Thr Ala Glu Gly Ala
65 70 75 80
Leu Glu Glu Gly Ser Glu Ile Leu Gln Arg Leu Arg Ser Leu Ser Leu
85 90 95
Gln Ala Ala Asn Gly Ser Asn Ser Asp Glu Asp Arg Gln Ser Leu Gln
100 105 110
Leu Glu Val Val Val Leu Lys Asp Glu Val Glu Arg Ile Ala Arg Thr
115 120 125
Thr Thr Phe Ala Gly Lys Asn Leu Phe Asp Gly Ser Tyr Gly Ser Lys
130 135 140
Ser Phe His Leu Gly Ala Asn Ser Asn Ser Ile Ser Leu Gln Leu Lys
145 150 155 160
Asn Met Arg Thr His Val Pro Glu Met Gly Gly Tyr His Tyr Leu Ala
165 170 175
Ser Glu Pro Ala Asp Glu Asp Trp Gln Val Asp Lys Glu Ser Arg Gln
180 185 190
Leu Ser Phe Thr Phe Arg Asp Ser Glu Gly Asp Asp Gln Ser Ile Lys
195 200 205
Ile Ser Leu Lys Pro Gly Asp Ser Leu Glu Glu Val Ala Thr Tyr Ile
210 215 220
Asn Ser Gln Gln Asn Val Val Glu Ser Ser Val Thr Asp Asp Arg Arg
225 230 235 240
Leu Gln Phe Tyr Val Ala Asn Arg His Ala Pro Asp Gly Leu Asn Ile
245 250 255
Ser Gly Ser Leu Glu Gly Glu Leu Asp Phe Glu Pro Gln Gly Gln Val
260 265 270
Thr Leu Asp Glu Leu Asp Ile Ser Ser Val Gly Gly Ala Gln Leu Ala
275 280 285
Ile Ala Val Val Asp Thr Ala Ile Gln Tyr Leu Asp Ser His Arg Ser
290 295 300
Glu Ile Gly Ser Phe Gln Asn Arg Val Glu Gly Thr Met Asp Asn Leu
305 310 315 320
Gln Ser Ile Asn Arg Asn Val Thr Glu Ser Lys Gly Arg Ile Trp Asp
325 330 335
Thr Asp Phe Ala Lys Ala Ser Thr Ala Leu Val Lys Ser Gln Val Leu
340 345 350
Gln Gln Ala Thr Ser Ala Leu Leu Ala Gln Ala Lys Gln Ala Pro Gly
355 360 365
Ser Ala Ile Gly Leu Leu Ser
370 375
<210>13
<211>36
<212>DNA
<213>人工序列
<220>
<223>随机引物1(arbitrary primer 1)
<400>13
ggccacgcgt cgactagtca nnnnnnnnnn acgccc 36
<210>14
<211>25
<212>DNA
<213>人工序列
<220>
<223>特异性引物1(specific primer 1)
<400>14
ttcttcacga ggcagacctc agcgc 25
<210>15
<211>20
<212>DNA
<213>人工序列
<220>
<223>随机引物2(arbitrary primer 2)
<400>15
ggccaagagt cgactagtca 20
<210>16
<211>23
<212>DNA
<213>人工序列
<220>
<223>特异性引物2(specific primer 2)
<400>16
ccgcacttgt gtataagagt cag 23
<210>17
<211>864
<212>DNA
<213>单核细胞增生利斯特氏菌(Listeria monocytogenes)flaA
<400>17
atgaaagtaa atactaatat cattagcttg aaaacacaag aatatcttcg taaaaataac 60
gaaggcatga ctcaagcgca agaacgtttg gcatctggta aacgtattaa cagttctctt 120
gatgacgctg ctggtcttgc agttgttact cgtatgaacg ttaaatctac aggcttagat 180
gcagcaagca aaaactcatc catgggtatt gacttgttac aaacagcgga ttcagctctt 240
agctccatga gttcaatctt gcaacgtatg cgtcaattag cagtacaatc ttctaacggt 300
tcattcagtg acgaagatcg taaacaatac actgctgaat tcggtagctt gatcaaagaa 360
cttgatcacg ttgctgacac tactaactac aacaacatca aattactaga tcaaactgct 420
acaggtgctg ctactcaagt aagcatccaa gcgtctgata aagctaatga cttaatcaat 480
atcgatcttt tcaatgcgaa aggtctttct gctggaacaa tcactttagg tagtggttct 540
acagttgctg gttatagtgc attatctgtt gctgatgctg attcttctca agaagcaacg 600
gaagctattg atgaattaat caataacatc tctaacggtc gtgcacttct aggtgctggt 660
atgagtcgcc ttagctacaa tgtatctaac gtgaacaacc aatccatcgc aactaaagca 720
tctgcttcct ctattgaaga tgcagatatg gctgctgaaa tgtccgaaat gactaaatac 780
aaaattctta cacaaacatc tatcagcatg ctttctcaag caaaccaaac accgcaaatg 840
ttaactcaat taattaacag ctaa 864
<210>18
<211>1488
<212>DNA
<213>鼠伤寒沙门氏菌(Salmonella typhimurium)fliC
<400>18
atggcacaag tcattaatac aaacagcctg tcgctgttga cccagaataa cctgaacaaa 60
tcccagtccg ctctgggcac cgctatcgag cgtctgtctt ccggtctgcg tatcaacagc 120
gcgaaagacg atgcggcagg tcaggcgatt gctaaccgtt ttaccgcgaa catcaaaggt 180
ctgactcagg cttcccgtaa cgctaacgac ggtatctcca ttgcgcagac cactgaaggc 240
gcgctgaacg aaatcaacaa caacctgcag cgtgtgcgtg aactggcggt tcagtctgct 300
aacagcacca actcccagtc tgacctcgac tccatccagg ctgaaatcac ccagcgcctg 360
aacgaaatcg accgtgtatc cggccagact cagttcaacg gcgtgaaagt cctggcgcag 420
gacaacaccc tgaccatcca ggttggtgcc aacgacggtg aaactatcga tatcgatctg 480
aagcagatca actctcagac cctgggtctg gatacgctga atgtgcaaca aaaatataag 540
gtcagcgata cggctgcaac tgttacagga tatgccgata ctacgattgc tttagacaat 600
agtactttta aagcctcggc tactggtctt ggtggtactg accagaaaat tgatggcgat 660
ttaaaatttg atgatacgac tggaaaatat tacgccaaag ttaccgttac ggggggaact 720
ggtaaagatg gctattatga agtttccgtt gataagacga acggtgaggt gactcttgct 780
ggcggtgcga cttccccgct tacaggtgga ctacctgcga cagcaactga ggatgtgaaa 840
aatgtacaag ttgcaaatgc tgatttgaca gaggctaaag ccgcattgac agcagcaggt 900
gttaccggca cagcatctgt tgttaagatg tcttatactg ataataacgg taaaactatt 960
gatggtggtt tagcagttaa ggtaggcgat gattactatt ctgcaactca aaataaagat 1020
ggttccataa gtattaatac tacgaaatac actgcagatg acggtacatc caaaactgca 1080
ctaaacaaac tgggtggcgc agacggcaaa accgaagttg tttctattgg tggtaaaact 1140
tacgctgcaa gtaaagccga aggtcacaac tttaaagcac agcctgatct ggcggaagcg 1200
gctgctacaa ccaccgaaaa cccgctgcag aaaattgatg ctgctttggc acaggttgac 1260
acgttacgtt ctgacctggg tgcggtacag aaccgtttca actccgctat taccaacctg 1320
ggcaacaccg taaacaacct gacttctgcc cgtagccgta tcgaagattc cgactacgcg 1380
accgaagttt ccaacatgtc tcgcgcgcag attctgcagc aggccggtac ctccgttctg 1440
gcgcaggcga accaggttcc gcaaaacgtc ctctctttac tgcgttaa 1488
Claims (7)
1、一种粘膜疫苗佐剂,该佐剂含有作为活性成分的细菌鞭毛蛋白。
2.根据权利要求1所述的粘膜疫苗佐剂,其中,所述鞭毛蛋白来源于创伤弧菌、鼠伤寒沙门氏菌、单核细胞增生利斯特氏菌。
3.根据权利要求1所述的粘膜疫苗佐剂,其中,所述鞭毛蛋白是选自由以下序列编码的创伤弧菌鞭毛蛋白中的一种或多种:
DNA SEQ ID NO:1或氨基酸SEQ ID NO:2所示的flaA,
DNA SEQ ID NO:3或氨基酸SEQ ID NO:4所示的flaB,
DNA SEQ ID NO:5或氨基酸SEQ ID NO:6所示的flaF,
DNA SEQ ID NO:7或氨基酸SEQ ID NO:8所示的flaC,
DNA SEQ ID NO:9或氨基酸SEQ ID NO:10所示的flaD,和
DNA SEQ ID NO:11或氨基酸SEQ ID NO:12所示的flaE。
4.一种通过鞭毛蛋白制造具有佐剂活性的免疫原的方法,该方法包括用编码蛋白抗原决定部位的基因来替代SEQ ID NO:1至SEQ ID NO:12中所示的创伤弧菌的结构成分中FlaA的氨基酸序列1-191、FlaB的氨基酸序列1-191、FlaF的氨基酸序列1-191、FlaC的氨基酸序列1-191、FlaD的氨基酸序列1-191和FlaE的氨基酸序列1-189的N-端区域与FlaA的氨基酸序列277-376、FlaB的氨基酸序列278-377、FlaF的氨基酸序列278-377、FlaC的氨基酸序列285-385、FlaD的氨基酸序列278-377和FlaE的氨基酸序列276-375的C-端区域之间的基因。
5、根据权利要求4所述的方法,其中,所述蛋白抗原决定部位为破伤风类毒素、流感病毒的免疫原抗原决定部位、诱导子宫宫颈癌症的人乳头状瘤病毒的免疫原抗原决定部位、肺炎球菌抗原肺炎球菌表面蛋白A或精子。
6、一种粘膜疫苗佐剂,该佐剂含有由权利要求4的方法制得的免疫原作为活性成分。
7、根据权利要求1-3和6中任意一项所述的粘膜疫苗佐剂,其中,所述疫苗佐剂为下列疫苗的佐剂:对抗破伤风类毒素等的抗毒素疫苗;对抗霍乱、伤寒等的减毒活疫苗或灭活疫苗;抵抗流感、非典型肺炎等的抗病毒疫苗;抵抗子宫宫颈癌等的抗癌疫苗;抗精子的避孕疫苗;或重组蛋白或多肽疫苗。
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KR1020040001974A KR20050073865A (ko) | 2004-01-12 | 2004-01-12 | 비브리오 패혈증균 편모 구성인자 플라젤린을유효성분으로 함유하는 백신 보조제 |
KR1020040001974 | 2004-01-12 | ||
KR10-2004-0001974 | 2004-01-12 | ||
PCT/KR2005/000103 WO2005070455A1 (en) | 2004-01-12 | 2005-01-12 | Mucosal vaccine adjuvants containing bacterial flegellins as an active component |
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WO2002085933A1 (en) * | 2001-04-20 | 2002-10-31 | The Institute For Systems Biology | Toll-like receptor 5 ligands and methods of use |
US20060257415A1 (en) | 2002-09-03 | 2006-11-16 | Fondation Eurov Acc | Adjuvants |
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US7914802B2 (en) | 2011-03-29 |
CN1909924B (zh) | 2011-04-13 |
EP1708749B1 (en) | 2012-06-27 |
US20080069844A1 (en) | 2008-03-20 |
KR20050073865A (ko) | 2005-07-18 |
WO2005070455A1 (en) | 2005-08-04 |
EP1708749A4 (en) | 2009-08-05 |
EP1708749A1 (en) | 2006-10-11 |
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