CN1170594C - 弯曲菌疫苗 - Google Patents
弯曲菌疫苗 Download PDFInfo
- Publication number
- CN1170594C CN1170594C CNB001049828A CN00104982A CN1170594C CN 1170594 C CN1170594 C CN 1170594C CN B001049828 A CNB001049828 A CN B001049828A CN 00104982 A CN00104982 A CN 00104982A CN 1170594 C CN1170594 C CN 1170594C
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- Prior art keywords
- vaccine
- campylobacter jejuni
- campylobacter
- antibody
- ala
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Abstract
本发明涉及含有抗无鞭毛弯曲菌菌株之抗血清、可用于预防动物体内弯曲菌定居的疫苗,在空肠弯曲菌蛋白印迹中所述蛋白印迹膜与抗空肠弯曲菌无鞭毛突变体抗体温育后可见、而与抗野生型空肠弯曲菌抗体温育后不可见的弯曲菌抗原性蛋白,并涉及它们在疫苗及其生产中的用途。本发明还涉及包含这些蛋白和抗这些蛋白之抗体的疫苗,这些弯曲菌蛋白的用途,抗弯曲菌抗原之抗血清和抗体在疫苗制备中的用途,以及制备这些疫苗的方法。
Description
技术领域
本发明涉及抗弯曲菌定居的疫苗、弯曲菌蛋白和弯曲菌抗体在制备这种疫苗中的用途以及制备这种疫苗的方法。
背景技术
弯曲菌属的细菌为革兰氏阴性螺旋形致病菌,具有较强的运动能力并在其细胞的一端或两端带有鞭毛。目前已发现好几种弯曲菌。空肠弯曲菌常见于家禽。猪群中常见大肠弯曲菌,最近还(在较小范围内)发现猪肠弯曲菌。
空肠弯曲菌是这些弯曲菌中最常分离到的与人类腹泻有关的弯曲菌。越来越多的证据表明人体中弯曲菌的感染比沙门菌的感染更多见。(Griffiths等,用途细菌学杂志(Journ.of Applied Bacteriology)1990,69:281-301,Walker等,微生物学评论1986,50:81-94,Butzler,J-P.,ISBN 0-8493-5446-3,RIVM报告号216852002,Bilthoven,荷兰)。人的弯曲菌感染难以避免,因为首先弯曲菌是来自食物的人畜互传细菌,很多动物,不管是野生的还是家养的,也不管是健康的还是患病的,其体内都可能大量带菌。此外,该细菌有多种不同的传播途径。它们可在诸如屠宰后的畜体表面及水中以球形休眠形式存活好几星期。因而该细菌极易通过直接与动物接触或经污染的水源或食物如牛奶或肉类而传染至人类。空肠弯曲菌可见于很多健康动物,如火鸡或小鸡之类的禽类、牛、绵羊、马和啮齿动物。鸡肉,作为全世界很多国家的重要营养来源,已知经常受到弯曲菌的污染(Shane(1992),S.M.,鸟类病理学21:189-213)。不仅发展中国家如此,欧洲也不例外。弯曲菌定居在家禽肠道中。在屠宰场中将常常严重污染了弯曲菌的肠道从动物体内除去时常发生肉类的污染。屠宰过程中的污染很难避免。在荷兰,尽管肉类行业采用了较高的卫生标准,仍有50%的鸡肉被污染。C.M.Karssen的论文(ISBN 90-71463-72-9)对家禽中弯曲菌的流行病学作了最新回顾。由于污染的情况如此严重,仅在荷兰(总人口15,000,000)每年就有约300,000人因接触或吃了未煮透的禽肉而感染弯曲菌。其它欧洲国家的这类数据也大同小异。据估计全世界每年发生超过400,000,000例的感染(Pace等,疫苗1998,16:1563-1574)。弯曲菌引起人体肠道的感染,偶尔还导致更为严重的疾病如流产、脑膜炎、盲肠炎及尿路感染。(Blaser等,新英格兰医学杂志1981,305:1444-1452,Butzler等,临床肠胃病学1979,8:737-765)。有时还引起严重的神经性并发症如急性热病性多神经炎和Miller-Fisher综合征(Schwerer等,1995,内毒素研究杂志2:395-403和Salloway等,1996,感染与免疫64:2945-2949)。弯曲菌所致腹泻常为自限性感染,病程约2-7天。在幼龄儿童、老人和免疫受损患者中,此病不是自限性的,必需抗生素治疗。很显然,若有了抗弯曲菌的有效人用疫苗,就可阻止弯曲菌感染人。但这将要求类似抗腮腺炎和麻疹之免疫接种的标准接种程序。显然这是不现实的。更合理方法是避免动物向人,特别是家禽向人的传播。最简易的方法是免疫接种家禽以抵抗弯曲菌感染。然而家禽的免疫接种(就象人类免疫接种一样)实施起来比最初预料的要复杂得多。原因是弯曲菌尽管定居于家禽的肠道却对家禽不致病。已检验的大多数疫苗是灭活的全细胞制品,经全身给药或口服,有时与佐剂联合使用。部分情况下肠道的定居在一定程度上可减少,但无一例疫苗可避免定居。这些疫苗无一例可阻止弯曲菌的排出。全细胞灭活疫苗若与亚单位疫苗比较,则是疫苗的首选,因为原则上它们仍具有全部潜在的免疫原性决定簇。继全细胞疫苗的开发之后,很多努力集中在基于鞭毛的亚单位疫苗的开发上。鞭毛是感染期间被识别的免疫显性抗原,多项研究均显示此蛋白有保护作用(Martin等,感染和免疫1989,57:2542-2546,Wenman等,临床微生物学杂志1985,21:108-112)。已知无鞭毛的突变体不定居肠道,而且它们在一或两周后从感染动物体内消失,而此时野生型细菌仍留在肠道中。因此鞭毛是制备疫苗的最佳选择,尤其因为在肠道定居方面它们所起的作用即使不是唯一的也是关键的。如果能阻止定居,将迈出消除家禽污染的第一步。尽管如此,基于弯曲菌鞭毛的潜在疫苗尚不能提供足够的保护。
继上述主动免疫接种之后,被动免疫接种作为减少弯曲菌感染的一个方法也受到检验。Tsubokura等(1997,临床实验免疫学108:451-455)施行口服抗空肠弯曲菌全细胞的抗体,然后用空肠弯曲菌攻击。他们声称经此免疫的小鸡粪便中发现的细菌数减少了1-2个对数级。迄今所作的所有努力尚未能找到一种能明显减少定居水平及粪便中排出的细菌量的活性、灭活或基于亚单位的疫苗。显然仍有必要寻找可靠而安全的疫苗或其它治疗方法。
原则上,无需在家禽的一生中保护它不受弯曲菌感染。如上所述它们并无感染的痛苦。所以,能减少细菌量并因此减少屠宰前的感染机率的治疗方法将能有效抑制屠宰时的后继肉类污染。而这就能预防由肉类传播的人弯曲菌感染。
本发明的目标之一是提供能减少定居水平及排出量、或甚至能从家禽的盲肠清除弯曲菌的疫苗。这可避免屠宰时发生肉类的弯曲菌污染并因此避免随后的人类污染。
发明内容
现已惊讶地发现,具有这些特征的疫苗可基于抗弯曲菌之无鞭毛突变体的抗体。这是大大出乎人们预料之外的,因为如上所述,鞭毛已被认为是与粘附和定居有关的关键蛋白。更令人惊讶的是,这种疫苗确实减少了野生型有鞭毛弯曲菌的定居和排出。这是首次报道疫苗甚至能将盲肠中的弯曲菌清除至检测水平以下。
附图说明
图1.包含野生型弯曲菌81116株总抗原的蛋白印迹(左),和包含无鞭毛弯曲菌81116-R2株之抗原的蛋白印迹。泳道1和7、2和8、3和9分别与20倍、200倍、400倍稀释的抗野生型弯曲菌81116株之抗血清温育。泳道4和10、5和11、6和12分别与20倍、200倍、400倍稀释的抗无鞭毛弯曲菌81116-R2株之抗血清温育。
图2.野生型弯曲菌81116株总抗原的双向电泳凝胶。
图3a.与抗无鞭毛弯曲菌81116-R2株之抗血清温育的双向电泳凝胶的蛋白印迹。60KD蛋白用箭头1指示,13KD蛋白用箭头2指示。
图3b.与抗野生型弯曲菌81116株之抗血清温育的蛋白印迹。
具体实施方式
因此,本发明的一个实施方案涉及预防弯曲菌在动物体内定居的疫苗,该疫苗包含抗弯曲菌无鞭毛菌株的抗血清。
这样的疫苗可以非常简单地包含新分离的抗弯曲菌抗血清,或许还有稀释剂。可加入这样的稀释剂以使效价过高的抗血清得到稀释。稀释剂可以简单地采用蒸馏水或生理盐水溶液。事实上任何药学可接受的稀释剂均可使用。
本发明在猪和其它动物的弯曲菌感染中与在家禽的感染中同等适用。
由于鸡肉污染率极高,该实施方案的一个优选形式涉及无鞭毛的空肠弯曲菌菌株,并涉及家禽。
任何无鞭毛弯曲菌菌株均可用于制备抗血清。尤其优选那些生长率与野生型菌株相当的无鞭毛弯曲菌菌株。制备抗体的无鞭毛弯曲菌最佳菌株之一已由Wassenaar,T.M.,Bleumink-Pluym,N.M.C.和van derZeijst,B.A.M.于1991年述于EMBO杂志10:2055-2061。
因此,在一个优选形式中,用来生成抗体的无鞭毛空肠弯曲菌菌株为R2。
适于本发明疫苗的抗体可得自多克隆血清、单特异性血清或单克隆抗体培养物。多克隆血清的优势在于可按常规技术简便制备。生产和加工多克隆血清的技术最为领域内熟知(如Mayer和Walter,编,细胞和分子生物学中的免疫化学方法,Academic出版社,伦敦,1987)。适于制备抗体的动物包括如牛、兔子、小鼠和小鸡。获得抗弯曲菌之牛抗体的有效方法已由Hilpert等1987年述于传染病杂志156:158-166。生产大量抗体的另一个有效方法即在卵黄囊中的生产已述于Hatta等,1993,生命科学、生物技术及生物化学57:450-454。
本发明的另一实施方案涉及针对空肠弯曲菌无鞭毛菌株的抗体在制备抗空肠弯曲菌定居之疫苗中的用途。
更惊讶的发现是:针对空肠弯曲菌无鞭毛突变体产生的抗血清在空肠弯曲菌总蛋白之蛋白印迹上可识别三条主要蛋白带,97KD(+/-5KD)、60KD(+/-5KD)带和13KD(+/-3KD)带,而用抗野生型空肠弯曲菌的抗血清则不能显示这些带。该现象亦见于野生型弯曲菌和无鞭毛弯曲菌的蛋白印迹中。故,这三种蛋白在弯曲菌的野生型和无鞭毛菌株中都存在。由此得出结论:免疫系统对这三种特异性蛋白的识别只发生于鞭毛缺乏时。
如上述,抗弯曲菌无鞭毛突变体的抗血清能自盲肠中将弯曲菌清除至检测水平以下。这种抗血清与针对野生型弯曲菌的抗血清(不能清除弯曲菌)的区别是它还包含抗97KD、60KD和13KD蛋白的抗体。这三种蛋白显然只在缺乏鞭毛时诱导抗体的产生,从而可得出结论:这三种蛋白能诱导在盲肠的弯曲菌清除中起主要作用的抗体。因此,针对97KD、60KD或13KD蛋白产生的抗体或者它们的混合物均能自盲肠中清除弯曲菌。
因而本发明的另一个实施方案涉及分子量为97KD、60KD或13KD的抗原性蛋白,在空肠弯曲菌蛋白印迹中,将蛋白印迹与抗空肠弯曲菌无鞭毛突变体之抗体温育后可见这些蛋白质,而与抗野生型空肠弯曲菌抗体温育后不可见。
对60KD蛋白和13KD蛋白作了进一步分析,已测定它们的氨基酸序列。
60KD蛋白的氨基酸序列如下,亦示于SEQ ID NO 2。
60KD蛋白的氨基酸序列是:
“MAKEIIFSDEARNK-
LYEGVKKLNDAVKVTMGPRGRNVLIQKSFGAPSITKDGVSVAKEVELKD-
SLENMGASLVREVASKTADQAGDGTTTATVLAHAIFKEGLRNITAGANPIEVK-
RGMDKACEAIVAELKKLSREVKDKKEIAQVATISANSDEKIGNLIADA-
MEKVGKDGVITVEEPKSINDELNVVEGMQFDRGYLSPYFITNAEKMTVEL-
SSPYILLFDKKITNLKDLLPVLEQIQKTGKPLLIIAEDIEGEALATLVVNKLRGV-
LNISAVKAPGFGDRRKAMLEDIAILTGGEVISEELGRTLESATIQDLGQASS-
VIIDKDNTTIVNGAGEKANIDARVNQIKAQIAETTSDYDREKLQERLAKLSG-
GVAVIKVGATTETEMKEKKDRVDDALSATKAAVEEGIVIGGGAALIKA-
KAKIKLDLQGDEAIGAAIVERALRAPLRQIAENAGFDAGVVVNSVENAK-
DENTGFDAAKGEYVNMLESGIIDPVKVERVALLNAVSVASMLLT-
TEATISEIKEDKPTMPDMSGMGGMGGMGGMM”
13KD蛋白的氨基酸序列如下,并见SEQ ID NO 1。
13KD蛋白的氨基酸序列是:“MAISKEDVLEYISNLSVLELSELVKE-
FEEKFGVSAAPVMVAGGAVAGGAVAAAEEKTEFDIVLTDGGAKKIEVI-
KIVRALTGLGLKEAKDAVEQTPSTLKEGVAKAEAEEAKKQLEEAGAKVELK”
60KD和13KD蛋白的氨基酸序列可能略有变动。氨基酸序列的变异可能是一或多个氨基酸被相同功能的其它氨基酸替换的结果。同功替换十分常见。Neurath等(蛋白质,Academic出版社,纽约(1979),第14页,图6)所述实例尤其是丙氨酸被丝氨酸替换;Ala/Ser、或Val/Ile、Asp/Glu等。除了上述导致被相同功能的其它氨基酸替换的变异外,也有变异是氨基酸被功能不同的另一个氨基酸替换。这种变异与同功替换的区别仅在于可能产生空间折叠稍有改变的蛋白。两类变异均常见于蛋白中,它们被称为生物学变异。
毋庸置疑,60KD和13KD蛋白的氨基酸序列中能保留多肽之免疫原活性的变异方式也包括在本发明的范围内。
97KD、60KD或13KD蛋白可用于产生多克隆、单特异性或单克隆抗体(或其衍生物)。97KD、60KD和13KD蛋白可按本领域内已知的多种标准的蛋白分离方案进行分离。一个十分简易的方法是从制备胶上切下这些蛋白。若要多克隆抗体,生产和加工多克隆抗血清的技术为本领域内已知(如Mayer和Walter,编,见上)。对本发明之97KD、60KD或13KD蛋白(或其变异体或片段)有反应性的单克隆抗体,可用本领域内已知技术免疫近交小鼠而制备(Kohler和Milstein,自然,256,495-497,1975)。
用抗这三种蛋白中任一种的抗体而不用抗完整无鞭毛弯曲菌抗血清的好处之一是,抗这三种蛋白的特异性单克隆抗体可自发酵罐中生长的大量杂交瘤中很容易地获得。从而能低成本/低消耗地生产大量抗体,且无需使用动物。
因此,本发明的另一个实施方案涉及含有抗弯曲菌97KD、60KD或13KD蛋白之抗体的疫苗。
本发明还有一个实施方案涉及抗本发明之97KD和/或60KD和/或13KD蛋白的抗体在制备抗空肠弯曲菌定居的疫苗中的用途。
制备本发明之疫苗的方法不必很复杂。原则上只需在如某种动物体内产生抗无鞭毛突变体或抗97KD和/或60KD和/或13KD蛋白的抗体,然后按常规技术收集血液并分离抗血清。适于用来产生这类抗体的动物有兔子和小鸡。若用小鸡,则抗体也可从系统性免疫的小鸡的卵黄囊获得。原则上抗体无需稀释。它们可以是、或必需是浓缩的形式。另外,如果抗体浓度很高,如此获得的抗血清可以在施用前稀释。
因此,本发明的另一实施方案涉及制备本发明之疫苗的方法。这些方法包括在宿主动物体内产生抗空肠弯曲菌无鞭毛菌株之抗原物质的抗体,然后分离抗体。原则上,这种方法通常包括从宿主动物体内采集血液再通过如离心或过滤纯化抗血清。
亦有可能获得生产所需针对97KD、60KD和13KD蛋白之抗体的细胞并在如发酵罐中进行培养。然后收集抗体,若有必要,可将其与某种药学可接受的载体混合。这类方法的好处是无需使用动物来制备抗体。
本发明还十分适于处理宰杀前的肉仔鸡。这些肉仔鸡通常在六周龄被宰杀。因而,用本发明的疫苗在宰杀前约一周处理这些动物,可显著降低弯曲菌污染水平。显然疫苗用量主要取决于疫苗中抗体的浓度。据说0.1-1ml粗抗血清中的抗体含量就十分合适。
象卵黄囊制备物中的抗体效价可用本领域内熟知的标准技术如ELISA轻易测得。
抗体可以十分粗制的制备物给予。可能的用药途径有给小鸡喂食粗制抗血清。其它用药途径有将血清与饮用水混合。或者,可将抗体直接与小鸡饲料混合。为此,还可采用冻干抗体,从而提高它们在与食物或水混合前的长期稳定性。抗体还可先包入胶囊再加入小鸡的食物中。
本发明另有一实施方案提供了用本发明之抗血清或抗体作疫苗的方法。或者,可直接用本发明的97KD、60KD或13KD蛋白作疫苗。当直接给家禽施用97KD、60KD或13KD蛋白时,它们直接诱导抗97KD、60KD或13KD蛋白的抗体产生。动物随后产生它们自己的抗弯曲菌保护性抗体。这再次让人惊讶:施用完整野生型弯曲菌不能自盲肠清除弯曲菌,因为野生型弯曲菌抑制了抗97KD、60KD和13KD蛋白之抗体的诱导产生。因此,当97KD、60KD和13KD蛋白不是以分离形式给予,而是作为完整野生型弯曲菌细胞的部分给予时,它们无效。因此,另一实施方案涉及含有特异性抗原性的97KD、60KD或13KD蛋白的疫苗,所述蛋白在空肠弯曲菌蛋白印迹中与抗空肠弯曲菌无鞭毛突变体之抗体温育后可见而与抗野生型空肠弯曲菌抗体温育后不可见。
这样的疫苗易与药学可接受载体混合制成。药学可接受载体当然是对接种动物的健康无不利影响、至少有不利影响时也不至于比未接种动物中所见影响更差的化合物。药学可接受载体有无菌水或无菌生理盐水等。更复杂一点,载体可以是如某种缓冲液。
本发明另有一实施方案涉及本发明之97KD、60KD或13KD抗原性蛋白在疫苗中的用途。
该实施方案的优选形式涉及本发明之97KD、60KD或13KD抗原性蛋白在制备抗空肠弯曲菌定居的药物组合物中的用途。
制备疫苗所用蛋白的最适量按给药途径的不同而不同。若是系统性给药,最适用量为1-1000μg。口服疫苗的用量也可在此范围内。若想通过饮用水口服给药,由于喂食时水的溢出,或许用量更大。
本发明之疫苗优选还包括某种佐剂。通常佐剂包含可非特异性增强宿主免疫应答的物质。多种佐剂为本领域内已知,如完全弗氏佐剂和不完全弗氏佐剂、维生素E、非离子型嵌段聚合物和聚胺如硫酸葡聚糖、聚羰乙烯和吡喃。表面活性物质如Span、吐温、十六胺(hexadecylamine)、溶血卵磷脂、甲氧基十六烷基甘油和皂角苷(尤其是Quil A)也很合适。此外,肽如胞壁酰二肽、二甲基甘氨酸、吞噬细胞增强激素均为常用。除了这些佐剂,免疫刺激复合物(ISCOMS)、矿物油如Bayol或Markol、植物油或它们的乳液以及DiluvacForte均可方便地使用。疫苗还可包含所谓的“载体”。载体是无需共价结合而能粘附多肽的化合物。常用的载体化合物有例如氢氧化铝、磷酸铝、硫酸铝或氧化铝、硅胶、高岭土和斑脱土。这样的载体的一种特殊形式(即抗原部分包埋于载体中)称为ISCOM(EP 109,942,EP 180,564,EP 242,380)。
疫苗常与稳定剂混合,以便如保护易降解多肽不被降解、延长疫苗的有效期、或提高冻干效率。有效稳定剂尤其有SPGA(Bovarnik等;细菌学杂志59:509(1950))、脱脂乳、明胶、牛血清白蛋白、碳水化合物如山梨醇、甘露醇、海藻糖、淀粉、蔗糖、右旋糖酐或葡萄糖,蛋白如白蛋白或酪蛋白或它们的降解产物,以及缓冲液如碱金属磷酸盐。冻干是有效的保藏法。冻干物质可稳定保藏多年。冻干物质的贮存温度可在零度以上,而对物质无损。
冻干可按众所周知的标准冻干过程进行。
含有97KD、60KD或13KD蛋白的疫苗优选经粘膜给药。如将疫苗与饮用水混合后口服。尤其对家禽免疫时,其它诸如眼内免疫和鼻内免疫也都是很好的粘膜免疫方法。
97KD、60KD和13KD蛋白的检测
细菌菌株:
野生型81116:空肠弯曲菌,野生型,人类分离物,鞭毛表型A+B+,体外有运动能力和侵袭力(Wassenaar,T.M.,Bleumink-Pluym,N.M.C.和van der Zeijst,B.A.M.1991,EMBO杂志10:2055-2061)。
突变型81116-R2:FlaA和FlaB缺失突变体(+卡那霉素插入子),鞭毛表型A-B-,体外无运动能力也无侵袭力(Wassenaar,T.M.,Bleumink-Pluym,N.M.C.和van der Zeijst,B.A.M.1991,EMBO杂志10:2055-2061)。
细胞培养:空肠弯曲菌81116株接种于Blaser弯曲菌琼脂上,空肠弯曲菌81116-R2株接种于补加了40μg/ml卡那霉素的Blaser弯曲菌琼脂上。将平板置于微需氧条件下41℃温育48小时。将琼脂平板上的小部分81116菌落接种于加有1%酵母提取物的Brucella培养液中,而将小部分的81116-R2菌落接种于加有1%酵母提取物并补加了40μg/ml卡那霉素的Brucella培养液中。41℃微需氧温育24小时后,检查培养物中的细菌总数并加入0.2%福尔马林灭活(室温24小时)。灭活细菌经离心收集。细胞沉淀重新悬浮于0.01M Tris pH7.4中,使蛋白质浓度调至1.0mg/ml。
然后在4-12%Bis-Tris的NuPage凝胶上按每个样品槽20μl该悬浮液进行标准聚丙烯酰胺凝胶电泳(PAAGE)。用NuPage转移缓冲液/甲醇进行蛋白印迹。采用Adessi,C.(电泳1997,18 127-135)和Gorg,A.(电泳1995,16,1079-1086)所述标准方法以及Pharmacia 18-1038-63的说明书进行双向(2-D)电泳。
小鸡抗血清的制备
4周龄小鸡肌肉内注射81116菌株或81116-R2菌株的全细胞疫苗(见下)1ml。剩下一组小鸡不免疫。免疫4周后所有小鸡放血处死。合并每组的血清用于免疫4日龄小鸡。
将由此获得的血清稀释20、200或400倍,按标准方法与蛋白印迹膜温育。
结果:图1中左侧蛋白印迹膜包含野生型弯曲菌81116菌株的全部抗原,右侧蛋白印迹膜包含无鞭毛弯曲菌81116-R2菌株的抗原。泳道1和7、2和8、3和9分别与20倍、200倍或400倍稀释的野生型弯曲菌81116菌株抗血清进行温育。泳道4和10、5和11、6和12分别与20倍、200倍或400倍稀释的无鞭毛弯曲菌81116-R2菌株抗血清进行温育。
泳道4-6和泳道10-12均可清楚地看见两条分子量分别为97和60KD的带,这两条带在泳道1-3和7-9中看不到。(这些泳道之间略显模糊并较为扩散的带都是分子量标准物)。
图2显示了包含野生型弯曲菌81116菌株全部抗原的双向电泳凝胶。双向凝胶更适于检测较小分子蛋白,因而比常规单向聚丙烯酰胺凝胶电泳更适于检测13KD蛋白(相应抗体)的存在。图3显示了此凝胶的蛋白印迹结果。印迹/温育按图1所用的标准过程执行。图3a显示与无鞭毛弯曲菌81116-R2菌株的抗血清温育的双向凝胶蛋白印迹。图3b显示同一蛋白印迹与野生型弯曲菌81116菌株的抗血清温育的结果。图3a的蛋白印迹显示在针对无鞭毛弯曲菌的抗血清中存在抗60KD(箭头1)和13KD(箭头2)蛋白的抗体,而在针对野生型弯曲菌的抗血清中未发现这两种抗体(图3b)。
这些蛋白印迹清楚地显示,无鞭毛弯曲菌菌株能诱导针对97KD、60KD和13KD蛋白的免疫应答,而野生型弯曲菌菌株无这种现象。
疫苗的制备
细菌菌株:
野生型81116:见上。
突变型81116-R2:见上。
用于被动免疫的小鸡抗血清的制备
4周龄小鸡经肌肉内注射81116株或81116-R2株的全细胞疫苗(见下)1ml。剩下一组小鸡未免疫。免疫4周后,所有小鸡放血处死。收集每组的血清并用于免疫4日龄小鸡。
灭活的全细胞疫苗的制备
将空肠弯曲菌81116株接种于Blaser弯曲菌琼脂上,空肠弯曲菌81116-R2株接种于补加了40μg/ml卡那霉素的Blaser弯曲菌琼脂上。将平板置于微需氧条件下41℃温育48小时。将琼脂平板上的81116菌落接种于加有1%酵母提取物的Brucella培养液中,而将81116-R2菌落接种于加有1%酵母提取物并补加了40μg/ml卡那霉素的Brucella培养液中。41℃微需氧温育24小时后,检查培养物中的细菌总数并加入0.2%福尔马林灭活(室温24小时)。灭活细菌经离心收集,悬浮于PBS,将细胞与不完全弗氏佐剂的油包水乳液混合制成疫苗制品。疫苗乳液每ml约含细菌109个。
弯曲菌攻击菌株的制备
将空肠弯曲菌81116株在Blaser弯曲菌琼脂平板上于41℃微需氧培养48小时。将其中一个平板上的培养物悬浮于加有1%酵母提取物的Brucella培养液中,并在紧闭小瓶内41℃培养48小时。小鸡们口服给予0.2ml此培养物进行攻击。攻击培养物的活力计数通过平板计数测定。
免疫接种实验
在此实验中,比较了用野生型弯曲菌抗血清和无鞭毛弯曲菌抗血清进行的被动免疫,以及用灭活的野生型弯曲菌全细胞制品进行的主动免疫。
小鸡
4日龄或两周龄SPF小鸡。
实验1的实验设计
4组每组10只4日龄小鸡(每天一次)口服抗野生型弯曲菌81116株之小鸡抗血清0.8ml,或口服抗无鞭毛突变体81116-R2之小鸡抗血清0.8ml,或口服未灭活的小鸡抗血清对照0.8ml,或不作处理作为对照。第一天(即在4日龄时)各小鸡在临近3.2×107CFU/ml攻击之前、或在攻击的6小时后接受抗血清。口服处理持续至尸检。攻击后5或10天,每组处死5只小鸡,测定每克盲肠内容物的CFU(见下:尸检和细菌学)。
实验2的实验设计
4组每组10只4日龄小鸡(每天一次)口服抗野生型弯曲菌81116株之小鸡抗血清0.8ml,或口服抗无鞭毛突变体81116-R2之小鸡抗血清,或口服未灭活的小鸡抗血清对照,或不作处理作为对照。第一天(即在4日龄时)各小鸡在临近1.4×108CFU/ml攻击之前、或在攻击后6小时接受抗血清。口服处理持续至尸检。攻击的5天后每组处死5只小鸡,测定每克盲肠内容物的CFU。
实验3的实验设计
3组每组10只2周龄小鸡肌肉内注射与不完全弗氏佐剂的油包水乳液混合的全细胞疫苗(包含野生型弯曲菌81116株或无鞭毛突变株81116-R2的灭活细胞)1ml,或不免疫。在5周龄时所有小鸡都口服接受野生型弯曲菌81116株1.4×108CFU/ml的攻击。攻击的一周后处死小鸡,测定每克盲肠内容物的CFU。
尸检和细菌学
处死小鸡,轻柔地取出每段盲肠的内容物,称重,在0.04M PBS中稀释至0.1g/ml。经连续10倍稀释后铺板于Blaser弯曲菌选择琼脂平板上。41℃微需氧培养48小时后,测定每克盲肠内容物的CFU。
结果
实验1
从表1可得出结论:每天重复用野生型弯曲菌抗血清或用未免疫小鸡的对照血清进行的被动免疫,与未处理的对照小鸡相比(在攻击后5和10天),对野生型弯曲菌的盲肠定居没有影响。所有三个组均显示弯曲菌的高水平盲肠定居(每克盲肠内容物高达108CFU以上)。与之形成明显对比的是,用本发明之抗血清(即针对无鞭毛突变体刺激产生的抗血清)被动免疫导致了野生型弯曲菌从盲肠中清除(或阻止了定居)。每克盲肠内容物中CFU<3,这意味着在检测水平之下。
实验2
在本实验中重复了检验(见表2)。再次发现,用本发明之抗血清(即针对无鞭毛突变体刺激产生的抗血清)被动免疫导致了小鸡中盲肠定居的大大减少:6/10的小鸡完全无盲肠定居,显示平均减少3log以上。
实验3
因为文献指出,用野生型弯曲菌主动免疫最多可导致弯曲菌定居减少2log(Widders,P.R.,Perry,R.,Muir,W.I.,Husband,A.J.& Long,K.A.,1996,英国禽类科学37:765-778),我们检验并比较了主动保护模型中基于野生型和R2的疫苗。
从结果(表3)可看出:无一疫苗对盲肠定居有影响。
表1a
攻击后5天,空肠弯曲菌81116的再分离
Log CFU/克盲肠内容物 | ||||
抗血清 | 空肠弯曲菌81116株 | 空肠弯曲菌R2株 | 未免疫组 | 无抗血清组 |
小鸡12345 | 8.15.98.55.58.6 | <3.0<3.0<3.0<3.0<3.0 | 7.88.78.17.77.6 | 7.65.69.17.28.8 |
平均值标准误差 | 7.31.5 | <3.0 | 8.00.4 | 7.71.4 |
表1b
攻击后10天,空肠弯曲菌81116的再分离
Log CFU/克盲肠内容物 | ||||
抗血清 | 空肠弯曲菌8116株 | 空肠弯曲菌R2株 | 未免疫组 | 无抗血清组 |
小鸡12345 | 9.09.19.09.18.5 | 3.5<3.0<3.0<3.0<3.0 | 7.88.99.37.08.7 | 8.17.67.47.88.2 |
平均值标准误差 | 8.90.3 | <3.10.2 | 8.30.9 | 7.80.3 |
表2攻击后5天,空肠弯曲菌81116的再分离
Log CFU/克盲肠内容物 | ||||
抗血清 | 空肠弯曲菌81116株 | 空肠弯曲菌R2株 | 未免疫组 | 无抗血清组 |
小鸡12345678910 | 7.5<3.07.47.56.09.18.97.6<3.0<3.0 | 3.89.18.96.0<3.0<3.0<3.0<3.0<3.0<3.0 | 9.57.97.68.47.37.06.69.17.59.4 | <3.07.57.98.59.05.89.07.09.09.8 |
平均值标准误差 | <6.3a2.4 | <4.6b2.5 | 8.0L0 | <7.72.0 |
a与接受未免疫小鸡抗血清的小组比较p≤0.05(两样本t检验)
b与接受未免疫小鸡抗血清的小组比较p≤0.001(两样本t检验)
表3攻击后6天,空肠弯曲菌81116的再分离
Log CFU/克盲肠内容物 | |||
小鸡 | 用空肠弯曲菌81116株免疫 | 用空肠弯曲菌R2株免疫 | 未免疫 |
12345678910 | 8.38.77.18.18.47.78.59.17.5 | 5.28.08.78.57.87.88.88.37.4 | 8.38.77.18.18.47.78.59.17.5 |
平均值标准误差 | 8.20.6 | 7.81.1 | 8.20.6 |
结论:
基于针对无鞭毛弯曲菌产生的抗体的疫苗能从盲肠中清除野生型弯曲菌。这与其对应物,即含有针对野生型弯曲菌产生的抗体的疫苗的效果形成明显对照。亦与含有野生型弯曲菌细胞的疫苗形成明显对照。
序列表
<110>AKZO Nobel N.V.
<120>弯曲菌疫苗
<130>弯曲检验(campylotest)
<140>
<141>
<160>2
<170>PatentIn Ver.2.1
<210>1
<211>125
<212>PRT
<213>空肠弯曲菌
<400>1
Met Ala Ile Ser Lys Glu Asp Val Leu Glu Tyr Ile Ser Asn Leu Ser
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Val Leu Glu Leu Ser Glu Leu Val Lys Glu Phe Glu Glu Lys Phe Gly
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Val Ser Ala Ala Pro Val Met Val Ala Gly Gly Ala Val Ala Gly Gly
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Ala Val Ala Ala Ala Glu Glu Lys Thr Glu Phe Asp Ile Val Leu Thr
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Asp Gly Gly Ala Lys Lys Ile Glu Val Ile Lys Ile Val Arg Ala Leu
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Thr Gly Leu Gly Leu Lys Glu Ala Lys Asp Ala Val Glu Gln Thr Pro
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Ser Thr Leu Lys Glu Gly Val Ala Lys Ala Glu Ala Glu Glu Ala Lys
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Lys Gln Leu Glu Glu Ala Gly Ala Lys Val Glu Leu Lys
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<210>2
<211>545
<212>PRT
<213>空肠弯曲菌
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Met Ala Lys Glu Ile Ile Phe Ser Asp Glu Ala Arg Asn Lys Leu Tyr
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Glu Gly Val Lys Lys Leu Asn Asp Ala Val Lys Val Thr Met Gly Pro
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Arg Gly Arg Asn Val Leu Ile Gln Lys Ser Phe Gly Ala Pro Ser Ile
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Thr Lys Asp Gly Val Ser Val Ala Lys Glu Val Glu Leu Lys Asp Ser
50 55 60
Leu Glu Asn Met Gly Ala Ser Leu Val Arg Glu Val Ala Ser Lys Thr
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Ala Asp Gln Ala Gly Asp Gly Thr Thr Thr Ala Thr Val Leu Ala His
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Ala Ile Phe Lys Glu Gly Leu Arg Asn Ile Thr Ala Gly Ala Asn Pro
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Ile Glu Val Lys Arg Gly Met Asp Lys Ala Cys Glu Ala Ile Val Ala
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Glu Leu Lys Lys Leu Ser Arg Glu Val Lys Asp Lys Lys Glu Ile Ala
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Gln Val Ala Thr Ile Ser Ala Asn Ser Asp Glu Lys Ile Gly Asn Leu
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Ile Ala Asp Ala Met Glu Lys Val Gly Lys Asp Gly Val Ile Thr Val
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Glu Glu Pro Lys Ser Ile Asn Asp Glu Leu Asn Val Val Glu Gly Met
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Gln Phe Asp Arg Gly Tyr Leu Ser Pro Tyr Phe Ile Thr Asn Ala Glu
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Lys Met Thr Val Glu Leu Ser Ser Pro Tyr Ile Leu Leu Phe Asp Lys
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Lys Ile Thr Asn Leu Lys Asp Leu Leu Pro Val Leu Glu Gln Ile Gln
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Lys Thr Gly Lys Pro Leu Leu Ile Ile Ala Glu Asp Ile Glu Gly Glu
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Ala Leu Ala Thr Leu Val Val Asn Lys Leu Arg Gly Val Leu Asn Ile
260 265 270
Ser Ala Val Lys Ala Pro Gly Phe Gly Asp Arg Arg Lys Ala Mat Leu
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Glu Asp Ile Ala Ile Leu Thr Gly Gly Glu Val Ile Ser Glu Glu Leu
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Gly Arg Thr Leu Glu Ser Ala Thr Ile Gln Asp Leu Gly Gln Ala Ser
305 310 315 320
Ser Val Ile Ile Asp Lys Asp Asn Thr Thr Ile Val Asn Gly Ala Gly
325 330 335
Glu Lys Ala Asn Ile Asp Ala Arg Val Asn Gln Ile Lys Ala Gln Ile
340 345 350
Ala Glu Thr Thr Ser Asp Tyr Asp Arg Glu Lys Leu Gln Glu Arg Leu
355 360 365
Ala Lys Leu Ser Gly Gly Val Ala Val Ile Lys Val Gly Ala Thr Thr
370 375 380
Glu Thr Glu Met Lys Glu Lys Lys Asp Arg Val Asp Asp Ala Leu Ser
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Ala Thr Lys Ala Ala Val Glu Glu Gly Ile Val Ile Gly Gly Gly Ala
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Ala Leu Ile Lys Ala Lys Ala Lys Ile Lys Leu Asp Leu Gln Gly Asp
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Glu Ala Ile Gly Ala Ala Ile Val Glu Arg Ala Leu Arg Ala Pro Leu
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Arg Gln Ile Ala Glu Asn Ala Gly Phe Asp Ala Gly Val Val Val Asn
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Ser Val Glu Asn Ala Lys Asp Glu Asn Thr Gly Phe Asp Ala Ala Lys
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Gly Glu Tyr Val Asn Met Leu Glu Ser Gly Ile Ile Asp Pro Val Lys
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Leu Thr Thr Glu Ala Thr Ile Ser Glu Ile Lys Glu Asp Lys Pro Thr
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Met Pro Asp Met Ser Gly Met Gly Gly Met Gly Gly Met Gly Gly Met
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Met
545
Claims (10)
1.预防家禽体内空肠弯曲菌(Campylobacter jejuni)定居的疫苗,其特征在于该疫苗包含针对无鞭毛空肠弯曲菌菌株产生的抗血清。
2.空肠弯曲菌之分子量为97KD(+/-5KD)的抗原性蛋白,其特征在于在空肠弯曲菌蛋白印迹中,将所述蛋白印迹膜与抗空肠弯曲菌无鞭毛突变体之抗体温育后可见该蛋白,而该蛋白印迹膜与抗野生型空肠弯曲菌之抗体温育后不可见。
3.权利要求2的抗原性蛋白在疫苗中的用途。
4.权利要求2的抗原性蛋白在生产抵抗空肠弯曲菌定居的药物组合物中的用途。
5.预防家禽体内空肠弯曲菌定居的疫苗,其特征在于该疫苗包含针对权利要求2所述抗原性蛋白的抗体。
6.预防家禽体内空肠弯曲菌定居的疫苗,其特征在于该疫苗包含权利要求2的抗原性蛋白。
7.抗无鞭毛空肠弯曲菌菌株、或抗权利要求2所述抗原性蛋白的抗体在制备可用于抗动物体内空肠弯曲菌定居之疫苗中的用途。
8.制备权利要求1或5的疫苗的方法,其特征在于包括在宿主动物体内产生抗无鞭毛空肠弯曲菌菌株之抗原物质的抗血清,并随后从该宿主动物体内分离抗血清。
9.制备权利要求1或5的疫苗的方法,其特征在于包括培养抗体生成细胞和收获抗体。
10.制备权利要求6的疫苗的方法,其特征在于包括将权利要求2的蛋白质与药学可接受的载体混合。
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US20070178110A1 (en) * | 2003-11-21 | 2007-08-02 | Ace Biosciences A/S | Surface-located campylobacter jejuni polypeptides |
WO2008146830A1 (ja) * | 2007-05-28 | 2008-12-04 | The Kitasato Institute | パラ百日咳菌全菌体ワクチン組成物 |
EP3556397A1 (en) * | 2010-06-09 | 2019-10-23 | The Board of Trustees of the University of Arkansas | Vaccine and methods to reduce campylobacter infection |
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US5200344A (en) * | 1990-11-13 | 1993-04-06 | Blaser Martin J | Diagnostic testing for campylobacter jejuni or campylobacter coli infections using novel antigens |
WO1995005850A1 (en) * | 1993-08-27 | 1995-03-02 | Enteric Research Laboratories, Inc. | Campylobacter jejuni antigens, and methods for their production and use |
US5681736A (en) * | 1994-10-05 | 1997-10-28 | Antex Biologics, Inc. | Methods for producing enhanced antigenic shigella bacteria and vaccines comprising same |
US5827654A (en) | 1995-05-08 | 1998-10-27 | University Of Toronto | Basal body rod protein genes of campylobacter |
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CA2227932A1 (en) * | 1997-04-08 | 1998-10-08 | Voon Loong Chan | Gene encoding invasion protein of campylobacter jejuni |
US6156546A (en) * | 1997-05-16 | 2000-12-05 | Washington State University Research Foundation | Identification and molecular cloning of a gene encoding a fibronectin binding protein (CadF) from Campylobacter coli and Campylobacter jejuni |
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- 2000-04-05 CA CA002303722A patent/CA2303722A1/en not_active Abandoned
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US6787137B1 (en) | 2004-09-07 |
AU2640600A (en) | 2000-10-12 |
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US20030072766A1 (en) | 2003-04-17 |
HUP0001423A3 (en) | 2005-05-30 |
CA2303722A1 (en) | 2000-10-09 |
MXPA00003427A (es) | 2004-10-28 |
PL339513A1 (en) | 2000-10-23 |
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US6790446B2 (en) | 2004-09-14 |
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