CN101557822B - 抵抗A组β溶血性链球菌的疫苗及其制备工艺 - Google Patents
抵抗A组β溶血性链球菌的疫苗及其制备工艺 Download PDFInfo
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Abstract
本发明提供一种抵抗A组β溶血性链球菌的疫苗及其制备工艺,其预测由克隆5δ基因产生重组蛋白质,其包括相应于52和/或87氨基酸残基的寡核苷酸序列,表位连续分子识别后与M蛋白质羧基末端区域分离,在01氨基酸残基不同,通过健康人类和风湿热携带者的抗体和T淋巴细胞识别,能够由基于T淋巴细胞的抗体产生保护反应,由所选表位的疾病的自身免疫发展的保护在体外评估,采用来自风湿热的损害的患者的心脏组织的T淋巴细胞。
Description
技术领域
本申请人已进行一专利申请P10501290-2,其申请日为2006年3月24日,名称为“抵抗A组β溶血性链球菌的疫苗及其制备工艺”。本发明涉及一种新疫苗,其目的相同,以及一获得此新疫苗的新工艺。
背景技术
在之前的专利申请P10501290-2中已经准确地描述抵抗β溶血性A组型链球菌的疫苗。在此再次描述工艺状态,既然本发明涉及相同的主题。如现有工艺所知,风湿热(RF)是一种疾病,其由A组β溶血性链球菌或酿脓链球菌所导致,此疾病呈现于3至18岁的儿童中,那些儿童存在基因易感性因素和未治疗儿童。疾病最初显现为多关节炎的临床形式(大关节中的疼痛),而后为包括两种主要表面的临床条件:西登哈姆氏舞蹈病和风湿性心肌炎。
舞蹈病呈现于约有20-30%的带有风湿热(RF)的患者中,受感染器官为中枢神经系统(CNS),症状转化为无意识地运动、精神紊乱,这些症状经过充分地治疗症状会消失。
风湿性心脏病呈现于约30-45%有风湿热(RF)的病人中,其特征在于最初在心肌的严重心脏炎症,在瓣膜组织中中产生严重的、累积的、固定的损害,主要影响冠状膜和大动脉膜,并触发风湿性心脏疾病(RHD)。在更发展的阶段的RHD治疗为外科手术上的。考虑到疾病的呈现年龄范围,7至12岁的儿童,他们不得不频繁地接受瓣膜损害纠正手术,或者以生物假体代替瓣膜(Snitcowski,1996)。在巴西,90%的儿童心脏手术是由风湿性瓣膜损害所引起的。
心脏手术在成人风湿个体中对应于此总数的30%(卫生部的数据,DATA-SUS)。传染病学:风湿热(RF)和慢性风湿心脏病(RHD)仍被认为是发展中国家和不发达国家中的公众健康问题。据估计,在世界上有超过5千万的风湿热的病例,根据世界卫生组织(WHO)的最近数据,世界上有1.4千万的慢性风湿心脏病(RHD)的病例的记录。在伊朗、泰国、中国、玻利维亚、巴基斯坦、印度、澳大利亚、阿根廷、埃及和摩洛哥等各个国家中,每1000个RF的儿童中,RHD患病率就高于多于10个儿童。
巴西每1000RF携带者中就有平均6.5个儿童RHD患者。更一步进地,在WHO(2004)的记录中,每年有多于1.8千万个链球菌病例,每年多于50万人死于链球菌。疾病的发病机理:风湿热(RF)被认为是自身免疫疾病,其来自于由抵抗A组β溶血性链球菌或酿脓链球菌而触发的防卫免疫反应,在一些个体中(易受疾病感染的人)中,产生抵抗穿过生物免疫机构的生物体自身蛋白的攻击性反应。
据当前所知,由T细胞淋巴球调节的抗体和免疫反应负责抵抗人类组织(心脏、关节、肾、大脑)蛋白质的交叉反应(revisedby Cunningham,2000;Guilherme etal,1995)。这此交叉反应的发生是由于氨基酸,特别是链球菌的M蛋白质,结构或残基的相似性。
19世纪80年代所分析和发表的M蛋白质序列(Manjula e Philipis,1984,andMiller et al,1998),通过多个研究小组所发表的多个科学工作,在能够触发疾病区域的知识方面取得了极大的进步。
M蛋白包括氨基酸残基的重复区域,并再细分为一氨基末端部和一羧基末端部。限定链球菌血清型的氨基酸的残基位于在氨基末端部。羧基末端部完全地保存在不同血清型中,且具有多次重复自己的氨基酸组。
描述氨基末端区域的多个片断,因为其涉及在疾病的触发(风湿热和/或慢性风湿心脏病),尤其是通过心脏组织蛋白的交叉反应(revised by Cunningham,2000 andGuilherme et al,2005)。
值得注意的是,直到80年代,人们相信链球菌和人类组织蛋白质的交叉反应仅来自于抗体调节免疫反应。从以CD4+T淋巴细胞(Raizada et al,1983,and Kemeny etal,1989)主导的心脏组织的炎症性渗入症状的描述,申请人证实心脏损害是由这些细胞(CD4+T淋巴细胞)所调节的。通过探测由人类心脏组织碎片所分离蛋白质间的交叉作用的免疫反应所限定的迹象,通过渗入由外科手术得到的携带RHD患者中心脏损害的T淋巴细胞,纠正瓣膜损害(Guilherme et al,1995)。而后,申请人描述大多数单核细胞的症状,其在遭受风湿性心脏疾病的患者的心脏组织(心肌、冠状和/或主动脉瓣膜)中产生显者的炎症细胞因子(γ干扰素、IFNg、α肿瘤坏死因子、TNFa)。此工作的相关发现为观察大量的细胞因子产生细胞的症状,其调节心肌的炎症(白细胞10和4、IL-10和IL-4),在瓣膜组织中稀有细胞产生IL-4调节细胞因子。此发现显示为何后链状球菌在约4个星期治愈,冠状和/或主动脉瓣膜的损害低、渐进的并固定的(Guilherme et al,2004)。
考虑到风湿热是自身免疫疾病,理解风湿热的发病机理是其预防的基础,因为考虑产生抵抗致病因子的疫苗,A组β溶血链球茵(酿脓链球菌),在不触发自身免疫疾病的意义上。已经具有多个抵抗A组β溶血链球茵的疫苗。
JamesB.Dale教授(田纳西州大学研究基金会)进行研究以产生基于赋予链球菌特殊性的M蛋白质残基的氨基末端的序列。
他具有多个已发表工作(Beachey et al,1987;Dale et al,1993;Dale et Chang,1995;Dale et al,1999,a,b and c),并且他已经分析在26种不同血清型动物模型中的反应能力。
具有多个以他名义申请的专利,其中包括在1998年9月10申请、2004年4月6日授权、专利号为6.716.433的美国专利(GROUP A STREPTOCOCCALVACCINES)。
最近,研究小组发表第一阶段工作,使用以包括06血清型的N基末端片断的重组体蛋白质形式的包括06不同血清型的疫苗构想。在人类组织切片上引导交叉反应控制,仅评估人类响应(抗体调节)(Kotloff,2004)。
产生多种疫苗以防止链球菌传染酿脓链球菌的26血清型,进行第二阶段的临床测试(McNeil et al,2005)。
Vincent Fischetti教授(洛克菲勒大学)研究基于M蛋白质的羧基末端残基的序列的疫苗的产生。通过克隆将M6蛋白编成法典的基因,研究小组发现,56不同链球菌血清型呈现羧基末端区域氨基酸序列的同族(Scott et al,1985 e 1986)。
通过鼻内接种M6蛋白的羧基末端区域的缩氨酸于白兔,Fischetti教授的研究小组展示改变A组链球菌的细菌定居的可能性(Bessen et Fischetti,1988,a and b)。用与合成缩氨酸共享序列共价相连且与亚单位的城巴霍乱毒素共轭的疫苗,其导致M蛋白质的IgA型抗体特性的形成,并保持在小鼠血清和唾液中的活性。
在后来的工作中,创始人利用牛痘病毒做为带菌者,包括M6蛋白质的C基端部的总体序列,以产生W-M6疫苗的重组体,这表明一个单一的鼻腔剂量能防止异源链球菌细菌定植。皮内免疫无效(Fischetti et al,1985)。在上述模型中共轭和鼻腔使用的牛痘病毒的高成本,限制这些模型作为一种安全、有效和可经济有效获得疫苗的使用。
以共生细菌作为载体的测试也被使用(Fischetti et al,1993;Medaglini et al,1995)。分析这种共生向量作为一种疫苗工具使用。
初步结果表明当在150个健康志愿者口服或鼻腔使用时,载体是安全的、耐受性好的(Kotloff et al,2005)。
具有多个以他名义申请的专利,其中包括在1995年1月6申请、2003年8月5日授权、专利号为6.602.507的美国专利(SYNTHETIC PEPTIDES FROMSTREPTOCOCCAL M PROTEIN AND VACCINES PREPARED THEREFROM)。C基末端部疫苗构想表现在如何融合链球菌表面的蛋白质,目前正在进行第一阶段的临床试验(WHO,2006)。
M.Good教授接近于使用C端部的缩氨酸作为在澳大利亚可用的疫苗模型,在澳大利亚的土著人口中链球菌感染的和风湿热的发病几率高。澳大利亚研究人员认定由C基端部的09氨基酸残基构成的缩氨酸,能够在免疫鼠中产生调节抗体。抗体还存在于正常个体和风湿疾病的患者的血清中(Pruksakom et al,1994,and Brandt et al,1997)。
最近,研究小组一直致力于来自澳大利亚人中占多数的血清型的氨基末端部片断和羧基末端部片断的结合,称为J14(Dunn et al,2002;Olive et al,2002)。
研究小组的最新成果显示,J14(29氨基酸残余)片断有利于保护抗体的发展,能够导致老鼠实验模型的,抵抗来自澳大利亚的地方区域的分离地点的酿脓链球菌的各种品种。这些动物的体内挑战巩固多个构想中J14缩氨酸的保护能力(Vohra etal,2005;Batzloff et al,2005;Olive et al,2005)。
发明内容
本发明的目的是提供一种抵抗A组β溶血性链球菌的新疫苗,以及获得此新疫苗的新工艺,此后提供两种模型,所提供的工艺为申请人在其前先专利申请Pl0501290-2所预计的获得工艺的改进。
附图说明
参考对以下附图的详细描述,有助于理解本发明的完整的价值和许多伴随优点。
图1所示为第一模型中所选残基序列(第一构想);以及
图2所示为第二模型中所选残基序列(第二构想)。
具体实施方式
本发明的目的为“抵抗A组β溶血性链球菌的新疫苗”,以及获得所述新疫苗的工艺,此后提供两种模型,所提供的工艺为申请人在其前先专利申请Pl 0501290-2所预计的获得工艺的改进。
简而言之,抗原B的序列的鉴定是通过分析在01氨基酸残基中不同79合成缩氨酸,每个血清620个体(健康人类和风湿热的携带者),抗原T次序地鉴定使用258个体的外周血的单核细胞(健康人类和风湿热的携带者),测试抵抗M蛋白质羧基末端部的38合成缩氨酸,选自由抗原B定义所测试79缩氨酸(Guilherme et al,2006;Patent Application Pl 0501290-2)。
基于此专利,涉及两个疫苗模型的构建,以合成缩氨酸形式和/或重组蛋白质形式,其包括:
1.由156pb(相应于氨基酸的52残基)合成的M蛋白质的羧基末端区域的T和B表位,其考虑氨基酸的以下序列:相应于T表位的22残基,其后为B表位的8中间残基和22残基,以及
2.由261pb(相应于氨基酸的87残基)构成的M蛋白质的氨基末端区域的T和B表位,其考虑氨基酸的以下序列:相应于T表位的22残基,其后为杂合T-B表位的8中间残基和B表位的22残基。
在第一模型中,疫苗作为合成缩氨酸和/或重组蛋白质包括M蛋白(T1表位的08中间残基和B表位)的羧基末端区域的52氨基酸残基的片断。
所附图1所示为此模型中所选残基序列。
在第二模型中,疫苗作为合成缩氨酸和/或重组蛋白质包括M蛋白质(T表位,08中间残基,杂合T-B,08中间残基和B表位)的羧基末端区域的87氨基酸残基的片断。
附图2所示为此模型中所选残基序列。
来自M蛋白质的羧基末端区域的氨基酸的这些残基能够由抗体和TCD4+淋巴细胞的调理产生响应,保护且不触发自身免疫疾病。这些序列不同于先前用于疫苗的制备序列,揭露如下:
James B.Dale使用各种血清型的氨基末端区域(美国第6.716.433号专利)。
Vincent A.Fischetti使用M6蛋白的羧基末端区域(美国第6.602.507号专利)。组成06组多肽。04组呈现与19氨基酸残基的一致性,构成片断包括申请人所选的T和B表位(Guilherme et al,2006)。
M.Good使用在澳大利亚土著中占优势品种的氨基末端相连的羧基末端区域。他展出与氨基酸的18残基一致性,构成片断包括申请人所选的T和B表位(Guilhermeet al,2006),其中14残基与V.A.Fischetti确认的M6蛋白的04组的构成一致。
以下描述获得新创疫苗的新工艺的步骤:
步骤1:克隆52和87氨基酸残余的区域,以产生δ因子的重组蛋白质;
步骤2:测试实验室动物,优选的为老鼠;
步骤3:安全测试:测试动物和连续性的体外测试以防止自身免疫(细胞激增测试和细胞因子测定)的连续性,通过使用T-细胞淋巴细胞系的疫苗表位,来自心肌组织风湿性疾病携带者的手术片断。
现在所创的疫苗不同与现有的疫苗,其带来与模型构造与关的优点,解释如下:保护表位的选择的进行基于改变M5蛋白质的公开序列(Robinson et al,1991),用于制备合成缩氨酸以评估病原性潜能(N基末端区域)(Guilherme et al 1995 and 2001)表位和来自C基末端区域表位,能够保护抵抗疾病,通过大量例子的体外测试评估(620个体血清和258个体的T细胞淋巴细胞)(Guilherme et al,2006)。
使用带有不同于01氨基酸残基的20氨基酸残基的79合成缩氨酸,进行扫描羧基末端区域(240至350残基)。此方法是带有保护能力的区域的独有的和允许的分子定义(Guilherme et al,2006,专利申请Pl 0501290-2)。
进行交叉作用测试,分析来自带有RHD患者的心脏组织的20渗入淋巴细胞的整体,其在进行纠正瓣膜损害的外科过程中获得的,并如前所述地在体外展开(Guilherme et al,1995)。
重组蛋白质的产生基于M5品种,由于合成缩氨酸所引导的研究是基于公开的蛋白质序列(Robinson et al,1991)。
参考文献:
美国专利文献:
US 6.602.507,1995年1月6日申请并2003年8月5日授权;
US 6.716.433,1998年9月10日申请并2004年4月6日授权;US 6.358.704,1999年1月28日申请并2002年3月19日授权。
其它参考文献:
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Claims (5)
1.一种抵抗A组β溶血性链球菌的疫苗,其特征在于,在第一模型中,片断来自M蛋白质的羧基末端区域的表位T、08中间残基和表位B的氨基酸的52残基,在第二模型中,片断来自M蛋白质的羧基末端区域的表位T、08中间残基、杂合T-B、08中间残基和表位B的氨基酸的87残基,所述来自M蛋白质的羧基末端区域的氨基酸的残基,能够产生由抗体和TCD4+淋巴细胞调节和保护的免疫反应,此免疫反应不触发自身免疫疾病。
2.如权利要求1所述的抵抗A组β溶血性链球菌的疫苗,其特征在于,预测M蛋白质的羧基末端区域的52和87残基的表位的连续分子识别,在01氨基酸残基差异,识别健康人类和风湿热携带者的抗体和T淋巴细胞,能够产生基于淋巴细胞的抗体的保护反应。
3.如权利要求1所述的抵抗A组β溶血性链球菌的疫苗,其特征在于,在第一模型中,M蛋白质的羧基末端区域的T和B表位的选定残基的序列为:
Lys-Gly-Leu-Arg-Arg-Asp-Leu-Asp-Ala-Ser-Glu-Arg-Ala-Lys-Lys-GIn-Leu-Glu-Ala-Glu-GIn-GIn-Lys-Leu-Glu-Glu-GIn-Asn-Lys-lle-Ser-Glu-Ala-Ser-Arg-Lys-Gly-Leu-Arg-Arg-Asp-Leu-Asp-Ala-Ser-Arg-Glu-Ala-Lys-Lys-GIn-Val.
4.如权利要求1所述的抵抗A组β溶血性链球菌的疫苗,其特征在于,在第二模型中,M蛋白质的羧基末端区域的T和B表位的选定残基的序列为:
Lys-Gly-Leu-Arg-Arg-Asp-Leu-Asp-Ala-Ser-Glu-Arg-Ala-Lys-Lys-GIn-Leu-Glu-Ala-Glu-His-GIn-Lys-Leu-Glu-Glu-GIn-Asn-Lys-lle-Ser-Glu-Ala-Ser-Arg-Lys-Gly-Leu-Arg-Arg-Asp-Leu-Asp-Ala-Ser-Glu-Arg-Ala-Lys-Lys-GIn-Leu-Glu-Ala-Glu-GIn-Gln-Lys-Leu-Glu-Glu-Gln-Asn-Lys-lle-Ser-Glu-Ala-Ser-Arg-Lys-Gly-Leu-Arg-Arg-Asp-Leu-Asp-Ala-Ser-Arg-Glu-Ala-Lys-Lys-GIn-Val.
5.一种抵抗A组β溶血性链球菌的疫苗的制备工艺,其特征在于,预测下述发展步骤:
步骤1:克隆包括表位T和B的156pb(52氨基酸残基)和261pb(87氨基酸残基),以生产重组蛋白质;
步骤2:测试实验室动物,优选的为老鼠;
步骤3:安全测试:测试动物和体外测试以防止自身免疫的细胞激增测试和细胞因子测定的连续性,通过使用T-细胞淋巴细胞系的疫苗表位,来自心肌组织风湿性疾病携带者的手术片断。
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