CN1372473A - 包含皂甙和免疫刺激寡核苷酸的佐剂组合物 - Google Patents
包含皂甙和免疫刺激寡核苷酸的佐剂组合物 Download PDFInfo
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- CN1372473A CN1372473A CN00808836A CN00808836A CN1372473A CN 1372473 A CN1372473 A CN 1372473A CN 00808836 A CN00808836 A CN 00808836A CN 00808836 A CN00808836 A CN 00808836A CN 1372473 A CN1372473 A CN 1372473A
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Abstract
本发明涉及适合用于疫苗的佐剂组合物。具体来说,本发明佐剂组合物包含皂甙和免疫刺激寡核苷酸以及任选包含载体。本发明还提供包含本发明佐剂和抗原的疫苗。还提供生产本发明佐剂和疫苗的方法及其用作药物的用途。还提供通过给予本发明疫苗治疗疾病易感个体或患病个体的方法。
Description
本发明涉及用于疫苗的新型佐剂组合物。具体来说,本发明佐剂组合物包含组合的皂甙和免疫刺激寡核苷酸,所述组合还任选包含载体。本发明还提供包含本发明佐剂组合物和至少一种抗原的疫苗。还提供生产本发明佐剂组合物和疫苗的方法及其用作药物的用途。此外,本发明提供通过胃肠外或粘膜给予本发明疫苗治疗疾病易感个体或患病个体的方法。
本领域已知含未甲基化的CpG二核苷酸(“CpG”)的免疫刺激寡核苷酸当通过***和粘膜途径给予时用作佐剂(WO 96/02555,EP468520,Davis等,J.Immunol,1998,160(2):870-876;McCluskie和Davis,J.Immunol.,1998,161(9):4463-6)。CpG是DNA中存在的胞嘧啶-鸟苷二核苷酸基元的缩写。从前观测到BCG的DNA部分能够发挥抗肿瘤作用。在进一步的研究中,证实得自BCG基因序列的合成寡核苷酸能够诱导免疫刺激作用(在体外和体内)。这些研究的作者的结论是:某些回文序列,包括中央的CG基元,具有这种免疫刺激活性。后来,Krieg在Nature 374,p546 1995中发表文章阐明了CG基元在免疫刺激中的主要作用。详细的分析证实,CG基元必须处于一定的序列环境中,而且这种序列是细菌DNA中的常见序列,但是在脊椎动物DNA中非常罕见。免疫刺激序列通常为:嘌呤、嘌呤、C、G、嘧啶、嘧啶;其中所述二核苷酸CG基元是未甲基化CG基元,但是已知其它未甲基化CpG序列是免疫刺激序列而且可用于本发明。
在所述6个核苷酸的某些组合中存在回文序列。在同一个寡核苷酸中可存在若干个这种基元,或者为重复的一个基元或组合的不同基元。含一个或多个这样的免疫刺激序列的寡核苷酸可激活不同免疫亚组细胞,包括天然杀伤细胞(它产生γ干扰素而且具有裂解细胞活性)和巨噬细胞(Wooldrige等,第89卷(第8期),1977)。尽管目前证实不具有该共有序列的含其它未甲基化CpG的序列是免疫调节序列。
当CpG配制成疫苗时,一般以自由溶液和自由抗原一起(WO96/02555;McCluskie和Davis,同上)或者与抗原共价结合(PCT公布号WO 98/16247)或者用载体如氢氧化铝配制后((肝炎表面抗原)Davis等,同上;Brazolot-Millan等,Proc.Natl.Acad.Sci.,USA,1998,95(26),15553-8)给予。
在Lacaille-Dubois,M和Wagner H(1996,关于皂甙的生物和药理活性的综述。Phytomedicine第2卷第363-386页)中介绍了皂甙。皂甙是广泛分布于植物和海洋动物的类固醇糖苷或三萜烯糖苷。皂甙因为形成胶体水溶液以及沉淀胆固醇而引起人们的注意,所述胶体水溶液振荡时形成泡沫。当皂甙接近细胞膜时,它们在膜上形成孔样结构,引起细胞膜破裂。红细胞溶血就是这种现象的一个实例,它是某些皂甙但是不是所有皂甙的一个特性。
已知皂甙用作***给予疫苗的佐剂。本领域深入研究了各种皂甙的佐剂活性和溶血活性(Lacaille-Dubois和Wagner,同上)。例如US5,057,540和“皂甙用作疫苗佐剂”,Kensil,C.R.,Crit Rev Ther DrugCarrier Syst,1996,12(1-2):1-55和EP 0 362 279 B1介绍了Quil A(从南美洲的树Quillaja Saponaria Molina树皮分离制得)及其部分。包含QuilA部分的颗粒结构称为免疫刺激复合物(ISCOMS),它具有溶血活性,而且已经将其用于生产疫苗(Morein,B.,EP 0 109 942 B1)。据报道这些结构具有佐剂活性(EP 0 109 942 B1;WO 96/11711)。
溶血性皂甙QS21和QS17(HPLC纯化的Quil A部分)被描述为有效***佐剂,美国专利号5,057,540和EP 0 362 279 B1公开了其生产方法。这两种参考文献还介绍了用作***疫苗有效佐剂的QS7(Quil-A的非溶血性部分)的作用。Kensil等(1991,J.Immunology第146卷,431-437)还介绍了QS21的作用。QS21和聚山梨酯或环糊精的组合是已知的(WO 99/10008)。WO 96/33739和WO 96/11711介绍了包含部分QuilA如QS21和QS7的颗粒性佐剂***。
用于***免疫接种研究的其它皂甙包括得自其它植物种如丝石竹属(Gypsophila)和肥皂草属(Saponaria)的皂甙(Bomford等,Vaccine,10(9):572-577,1992)。
此外,已知皂甙用于粘膜用疫苗研究,它在诱导免疫反应方面获得了不同程度的成功。以前证实,当鼻内给予抗原时,Quil-A皂甙对诱导免疫反应没有作用(Gizurarson等1994,Vaccine Research 3,23-29)。而部分其他作者应用这种佐剂获得了成功(Maharaj等,Can.JMicrobiol,1986,32(5):414-20;Chavali和Campbell,Immunobiology,174(3):347-59)。在胃肠道和鼻内疫苗制剂中使用了包含Quil A皂甙的ISCOM,显示它具有佐剂活性(McI Mowat等,1991,Immunology,72,317-322;McI Mowat和Donachie,Immunology Today,12,383-385)。
QS21为Quil A的无毒性部分,还介绍它用作口服或鼻内给药的佐剂(Sumino等,J.Virol.,1998,72(6):4931-9;WO 98/56415)。
已有关于其它皂甙在鼻内免疫接种研究中应用的介绍。例如昆诺藜(Chenopodium quinoa)皂甙既用于鼻内疫苗,又用于胃肠道疫苗(Estrada等,Comp.Immunol.Microbiol.Infect.Dis.,1998,21(3):225-36)。
本发明涉及令人惊奇的发现,即免疫刺激寡核苷酸(CpG)和皂甙组合是极其有效的佐剂。因此,本发明提供包含组合的皂甙和免疫刺激寡核苷酸的佐剂组合物。最好是本发明的佐剂还包含载体。在一个优选形式的本发明中,所述佐剂和疫苗组合物中的皂甙和寡核苷酸在诱导抗原特异性抗体中协同作用,而且强力诱导通常与Th1型免疫***有关的免疫反应。因此,所述佐剂组合不仅适用于免疫预防疾病,而且令人惊奇地免疫治疗疾病,例如持续病毒、细菌或寄生虫感染,此外还适用于慢性病症如癌症。
用于本发明佐剂或疫苗的优选寡核苷酸优选包含2个或2个以上二核苷酸CpG基元,这些基元被至少3个、更优选至少6个或更多核苷酸间隔开。本发明寡核苷酸通常为脱氧核苷酸。在一个优选实施方案中,所述寡核苷酸中的内部核苷酸为二硫代磷酸酯、或更优选为硫代磷酸酯键,尽管磷酸二酯和其它内部核苷酸键属于本发明范畴,包括具有混合内部核苷酸键的寡核苷酸。US5,666,153、US5,278,302和WO95/26204介绍了生产硫代磷酸寡核苷酸或二硫代磷酸酯的方法。
优选寡核苷酸实例具有以下序列。所述序列优选包含硫代磷酸酯修饰的内部核苷酸键。OLIGO 1(SEQ ID NO:1):TCC ATG ACG TTC CTG ACG TT(CpG1826)OLIGO 2(SEQ ID NO:2):TCT CCC AGC GTG CGC CAT(CpG 1758)OLIGO 3(SEQ ID NO:3):ACC GAT GAC GTC GCC GGT GAC GGCACCACGOLIGO 4(SEQ ID NO:4):TCG TCG TTT TGT CGT TTT GTCGTT(CpG 2006)OLIGO 5(SEQ ID NO:5):TCC ATG ACG TTC CTG ATG CT(CpG1668)
替代CpG寡核苷酸可包含以上优选序列,因为其中含有不重要的缺失或添加。可用本领域已知的任何方法(例如EP 468520)合成用于本发明的CpG寡核苷酸。通常可应用自动合成仪合成这样的寡核苷酸。
用于本发明的寡核苷酸通常为脱氧核苷酸。在一个优选实施方案中,所述寡核苷酸中的内部核苷酸键是二硫代磷酸键、或更优选硫代磷酸键,尽管磷酸二酯键属于本发明范畴。设计了包含不同内部核苷酸键的寡核苷酸,例如混合的硫代磷酸酯磷酸二酯。可使用稳定所述寡核苷酸的其它内部核苷酸键。
可用于本发明佐剂组合的皂甙包括得自皂树(Quillaja SaponariaMolina)树皮的称为Quil A的皂甙及其部分,它们介绍于US 5,057,540和“用作疫苗佐剂的皂甙”,Kensil,C.R.,Crit Rev Ther Drug CarrierSyst,1996,12(1-2):1-55和EP 0 362 279 B1中。特别优选的Quil A部分为QS21、QS7和QS17。
β-七叶素是另一种用于本发明佐剂组合物的优选溶血性皂甙。默克索引(Merck index)(第12版,条目3737)介绍的七叶素为欧洲七叶树(Aesculus hippocastanum)种子中天然存在的皂甙混合物。据介绍,其分离方法为层析法(Fiedler,Arzneimittel-Forsch,4,213(1953)),其纯化方法为离子交换树脂层析(Erbring等,US 3,238,190)。纯化获得了七叶素α和七叶素β部分,而且证实它们具有生物活性(Yoshikawa M,等(Chem Pharm Bull(Tokyo)1996年8月;44(8):1454-1464))。β-七叶素也称为七叶素。
用于本发明的另一种优选溶血性皂甙为洋地黄皂甙。默克索引(第12版,条目3204)将洋地黄皂甙描述为皂甙,洋地黄皂甙得自紫花洋地黄(Digitalis purpurea)的种子,而且按照Gisvold等,J.Am.Pharm.Assoc.,1934,23,664和Ruhenstroth-Bauer,Physiol.Chem.,1955,301,621介绍的方法纯化。据介绍,其用途为临床胆固醇测定试剂。
本发明的佐剂组合还可包含载体,使得皂甙或CpG或二者可与颗粒载体结合,增强所述组合的佐剂活性。例如特别优选的***疫苗包含载体分子。
用于本发明佐剂组合的CpG可为自由溶液或者可以复合在颗粒载体上,例如矿物盐(例如但不限于铝盐或钙盐)、脂质体、ISCOM、乳液(水包油、油包水、水包油包水)、聚合物(例如但不限于聚乳酸、聚乙醇酸、聚磷腈(polyphosphazine)、聚氨基酸、藻酸盐、壳聚糖)或微型颗粒。所述载体优选为阳离子载体。本发明疫苗还包含可与CpG-载体复合物结合的抗原、或者不能与CpG-载体复合物结合的抗原。在这种情况下,所述抗原可以为自由悬浮液或可与另外的载体结合的抗原。
构成本发明组成部分的皂甙可以为独立的微胶粒,或者当用胆固醇和脂质配制时它可以为大的有序结构,例如ISCOM(EP 0 109 942 B1)或脂质体(WO 96/33739),或者它为水包油乳液(WO 95/17210)。皂甙优选与金属盐结合,例如氢氧化铝或磷酸铝(WO 98/15287)。另一方面,皂甙可与颗粒载体如壳聚糖结合。皂甙也可以为固态如粉末。当最终制剂给予到疫苗接受者的粘膜表面时,最好是它为天然溶血性制剂。皂甙可以与抗原通过直接键合或共同作用于同一颗粒载体分子而物理性结合,或者皂甙可以不与抗原结合(GB 9822712.7;WO98/16247)。本发明佐剂或疫苗中的CpG和皂甙本身可以是独立的制品,或者它们结合在一起。例如CpG和皂甙可以为自由悬浮液,或者可以通过载体结合在一起,更优选通过颗粒载体如氢氧化铝或阳离子脂质体或ISCOM结合在一起
本发明的优选佐剂组合由在2个相邻CG基元之间含有至少3个、优选至少6个核苷酸的1个或多个CpG寡核苷酸和QS21以及颗粒载体组成,所述颗粒载体选自水包油乳液或DQ。最优选佐剂组合包含与QS21混合的CpG 2006(SEQ ID NO:4)或CpG 1758(SEQ ID NO:2)或CpG 1826(SEQ ID NO:1)以及选自水包油乳液或DQ的颗粒载体。因此,特别优选的疫苗例如包括这样的佐剂组合和抗原。本发明的优选疫苗用于通过***途径给予个体后产生***免疫反应。
本发明的佐剂组合既可以用作***佐剂,也可以用作粘膜佐剂。在本发明的一个具体形式中,提供通过***途径或胃肠外途径给予的***疫苗,所述途径例如肌肉、皮内、透皮、皮下、腹膜内或静脉内给予。给予疫苗的优选途径是通过透皮途径,例如皮肤贴片。
本发明的***疫苗制剂可用来通过肌肉、腹膜内、皮内、透皮、静脉内或皮下给予所述疫苗的方法而保护或治疗疾病易感哺乳动物或患病哺乳动物。***给予疫苗制剂的方法包括常规注射器和针头、或设计用于冲击性给予固体疫苗的装置(WO 99/27961)、或无针压力式液体喷射装置(US 4,596,556;US 5,993,412)、或透皮贴片(WO 97/48440;WO 98/28037)。本发明还可用来增强用于皮肤的抗原的免疫原性(透皮或经皮给药WO 98/20734;WO 98/28037)。因此,本发明提供预装有本发明疫苗或佐剂组合物的***给予传递装置。因此提供对个体诱导免疫反应的方法,该方法包括给予所述个体包含抗原和免疫刺激寡核苷酸、皂甙和载体的疫苗,其中所述疫苗通过胃肠外途径或***途径给予。诱导免疫反应的优选方法包括给予这样的疫苗:它包含SEQ IDNO:1、2、3、4或5中一种寡核苷酸和得自Quil A的皂甙如QS21以及载体,例如水包油乳液、含胆固醇的脂质体或明矾。
另一方面,本发明疫苗制剂可用来通过粘膜途径如口腔/消化道途径或鼻途径给予所述疫苗的方法保护或治疗疾病易感哺乳动物或患病哺乳动物。可选择的粘膜途径有***内或直肠内途径。优选的粘膜给药途径是通过鼻途径,称为鼻内免疫接种。鼻内免疫接种的方法是本领域周知的,包括将所述疫苗滴鼻剂、喷雾剂或干粉剂给予到需要免疫个体的鼻咽部。雾化疫苗制剂也构成本发明的一部分。肠制剂如口服给予的胃耐受胶囊剂和颗粒剂、直肠或***给予的栓剂也构成本发明的一部分。
本发明的佐剂组合为一类通过粘膜免疫接种代替***免疫接种的适用于人类的粘膜佐剂。在一个优选形式的本发明中,纯皂甙与免疫刺激寡核苷酸的组合用作粘膜给予抗原的佐剂,以实现***免疫反应,所述皂甙例如为Quil A或其衍生物,包括QS21、七叶素、洋地黄皂甙或满天星皂甙或昆诺藜(Chenopodium quinoa)皂甙。
本发明的佐剂组合可用于配制通过***途径或粘膜途径给予的疫苗。当疫苗用于粘膜给予时,所述佐剂组合优选包含溶血性皂甙。
对于粘膜给予而言,本发明组合物最好包含溶血性皂甙。参照以下测定方法测定本发明目的的溶血性皂甙或皂甙制剂:
1.用磷酸缓冲盐水(PBS)以台式离心机洗涤豚鼠新鲜血液3次。重悬浮至原体积后,再用PBS将血液稀释10倍。
2.在800μl含2倍稀释的表面活性剂或皂甙的PBS中加入50μl该血液悬浮液。
3. 8小时后肉眼或通过检测上清液光密度评价溶血。存在于570nm吸收光的红色上清液说明存在溶血。
4.结果以不再出现溶血的第一个皂甙稀释液的浓度表示。
对于本发明目的,如果皂甙佐剂制剂溶解红细胞的浓度为0.1%以下时,则认为它是溶血性的。按照此参考标准,根据该测定方法定义,大致纯Quil A、QS21、QS7、洋地黄皂甙和β-七叶素样品均为溶血性皂甙。在这种生物测定的固有实验变异内,本发明皂甙的溶血活性优选为约0.5-0.00001%、更优选0.05-0.00001%、甚至更优选0.005-0.00001%、最优选0.001-0.0004%。理想的是,所述皂甙的溶血活性与QS21的溶血活性相似(即在10倍差异范围内)。
本发明疫苗也可以通过口服途径给予。在这种情况下,药学上可接受的赋形剂也可以包括碱性缓冲剂或肠溶胶囊或微型颗粒。本发明疫苗也可以通过***途径给予。在这种情况下,药学上可接受的赋形剂也可以包括乳化剂、聚合物如CARBOPOL以及***乳膏和栓剂的其它已知稳定剂。本发明疫苗也可以通过直肠途径给予。在这种情况下,所述赋形剂也可以包括用于制备直肠栓剂的本领域已知的蜡和聚合物。
在本发明的佐剂组合中1种以上的皂甙的制剂也构成本发明的一部分。例如至少2种以下皂甙的组合,所述皂甙包括QS21、QS7、Quil A、β-七叶素或洋地黄皂甙。另外,本发明组合物可包含1种以上的免疫刺激寡核苷酸的组合。
在本发明的一个类似实施方案中,用于***给予和粘膜给予的CpG/皂甙组合还可以与其它佐剂组合,所述其它佐剂包括单磷酰脂质A及其无毒衍生物3-脱氧酰化单磷酰脂质A。另一方面,皂甙制剂可与以下物质组合:壳聚糖或其它聚阳离子聚合物组成的疫苗载体、聚交酯和聚交酯-共-乙交酯颗粒、聚-N-乙酰葡糖胺基聚合物基质、多糖或化学修饰多糖组成的颗粒、脂质体和脂质基颗粒、甘油一酯组成的颗粒等。也可以在存在胆固醇情况下配制皂甙成颗粒结构,例如脂质体或ISCOM。此外,皂甙可与聚氧乙烯醚或聚氧乙烯酯配制为非颗粒性溶液或悬浮液,或者配制为颗粒结构,例如薄层(paucilamelar)脂质体或ISCOM。皂甙也可以用诸如CarbopolR的赋形剂配制,以提高粘度,或者可以用粉型赋形剂如乳糖配制成干粉。
3脱氧酰化单磷酰脂质A是众所周知的佐剂,由RibiImmunochem(Montana)生产。可用GB 2122204B介绍的方法制备3脱氧酰化单磷酰脂质A。3脱氧酰化单磷酰脂质A的优选形式为直径小于0.2μm的小颗粒乳液(EP 0 689 454 B1)。特别优选的佐剂为3D-MPL和QS21的组合(EP 0 671 948B1)、包含3D-MPL和QS21的水包油乳液(WO 95/17210,WO 98/56414)或用其他载体配制的3D-MPL(EP 0689 454 B1)。
本发明的疫苗制剂最好包含能够引发对抗人类病原体的免疫反应的抗原或抗原组合物,所述抗原或抗原组合物得自HIV-1(如tat、nef、gp120或gp160)、人类疱疹病毒(如gD或其衍生物或立即早期蛋白如HSV1或HSV2的ICP27)、巨细胞病毒((特别是人类)(如gB或其衍生物))、轮状病毒(包括活减毒病毒)、埃-巴二氏病毒(如gp350或其衍生物)、水痘-带状疱疹病毒(如gp I、II和IE63),或者所述抗原或抗原组合物来自肝炎病毒如乙型肝炎病毒(例如乙型肝炎表面抗原或其衍生物)、甲型肝炎病毒、丙型肝炎病毒和戊型肝炎病毒,或者所述抗原或抗原组合物来自其它病毒性病原体,如副粘病毒:呼吸道合胞病毒(如F蛋白和G蛋白及其衍生物)、副流感病毒、麻疹病毒、腮腺炎病毒、人***瘤病毒(例如HPV6、11、16和18等)、黄病毒(如黄热病毒、登革热病毒、蜱传脑炎病毒、日本脑炎病毒)或流感病毒(以卵或MDCK细胞培养的完整活病毒或灭活病毒、***的流感病毒,或完整的流感病毒体(如R.Gluck,Vaccine,1992,10,915-920介绍)或其纯化或重组蛋白,例如HA、NP、NA或M蛋白或其各种组合),或者所述抗原或抗原组合物来自细菌病原体,如奈瑟氏菌属菌(Neisseriaspp),包括淋病奈瑟氏菌(N.gonorrhea)和脑膜炎奈瑟氏菌(N.meningitidis)(例如荚膜多糖及其偶联物、运铁蛋白结合蛋白、乳铁蛋白结合蛋白、PilC、粘附素);酿脓链球菌(S.pyogenes)(例如M蛋白或其片段、C5A蛋白酶、脂磷壁质)、无乳链球菌(S.agalactiae)、变异链球菌(S.mutans);杜氏嗜血菌(H.ducreyi);莫拉氏菌属菌(Moraxellaspp.),包括粘膜炎莫拉氏菌(M.catarrhalis),也称为卡他布兰汉民菌(Branhamella catarrhalis)(例如高分子量粘附素和低分子量粘附素及侵染素);博德特氏菌属菌(Bordetella spp.),包括百日咳博德特氏菌(B.pertussis)(例如pertactin、百日咳毒素或其衍生物、丝状血凝素、腺苷酸环化酶、菌毛)、副百日咳博德特氏菌(B.parapertussis)和支气管炎博德特氏菌(B.bronchiseptica);分枝杆菌属菌(Mycobacterium spp.),包括结核分枝杆菌(M.tuberculosis)(例如ESAT6、85A抗原、85-B抗原或85-C抗原)、牛分枝杆菌(M.bovis)、麻风分枝杆菌(M.leprae)、鸟分枝杆菌(M.avium)、副结核分枝杆菌(M.paratuberculosis)、耻垢分枝杆菌(M.smegmatis);军团菌属菌(Legionella spp.),包括嗜肺军团菌(L.pneumophila);埃希氏菌属菌(Escherichia spp.),包括肠毒性大肠杆菌(E.coli)(例如定居因子、热不稳定毒素或其衍生物、热稳定毒素或其衍生物)、肠出血性大肠杆菌、肠致病性大肠杆菌(例如志贺毒素样毒素或其衍生物);弧菌属菌(Vibrio spp.),包括霍乱弧菌(V.cholera)(例如霍乱毒素或其衍生物);志贺氏菌属菌(Shigella spp.),包括宋内氏志贺氏菌(S.sonnei)、痢疾志贺氏菌(S.dysenteriae)、弗氏志贺氏菌(S.flexnerii);耶尔森氏菌属菌(Yersinia spp.),包括小肠结膜炎耶尔森氏菌(Y.enterocolitica)(例如Yop蛋白)、鼠疫耶尔森氏菌(Y.pestis)、假结核耶尔森氏菌(Y.pseudotuberculosis);弯曲杆菌属菌(Campylobacterspp.),包括空肠弯曲杆菌(C.jejuni)(例如毒素、粘附素和侵袭素)和大肠弯曲杆菌(C.coli);沙门氏菌属菌(Salmonella spp.),包括伤寒沙门氏菌(S.typhi)、副伤寒沙门氏菌、猪霍乱沙门氏菌(S.choleraesuis)、肠炎沙门氏菌(S.enteritidis);李斯特氏菌属菌(Listeria spp.),包括单核细胞增生李斯特氏菌(L.monocytogenes);螺旋杆菌属菌(Helicobacterspp.),包括幽门螺旋杆菌(H.pylori)(例如脲酶、过氧化氢酶、空泡毒素(vacuolating toxin));假单胞菌属菌(Pseudomonas spp.),包括铜绿假单胞菌(P.aeruginosa);葡萄球菌属菌(Staphylococcus spp.),包括金黄色葡萄球菌(S.aureus)、表皮葡萄球菌(S.epidermidis);肠球菌属菌(Enterococcus spp.),包括粪肠球菌(E.faecalis)、屎肠球菌(E.faecium);梭菌属菌(Clostridium spp.),包括破伤风梭菌(C.tetani)(例如破伤风毒素及其衍生物)、肉毒梭菌(C.botulinum)(例如肉毒杆菌毒素及其衍生物)、艰难梭菌(C.difficile)(例如梭菌毒素A或梭菌毒素B及它们的衍生物);芽孢杆菌属菌(Bacillus spp.),包括炭疽芽孢杆菌(B.anthracis)(例如肉毒杆菌毒素及其衍生物);棒杆菌属菌(Corynebacterium spp.),包括白喉棒杆菌(C.diphtheriae)(例如白喉毒素及其衍生物);疏螺旋体属菌(Borrelia spp.),包括布氏疏螺旋体(B.burgdorferi)(例如OspA、OspC、DbpA、DbpB)、嘎氏疏螺旋体(B.garinii)(例如OspA、OspC、DbpA、DbpB)、阿氏疏螺旋体(B.afzelii)(例如OspA、OspC、DbpA、DbpB)、B.andersonii(例如OspA、OspC、DbpA、DbpB)、赫氏蜱疏螺旋体(B.hermsii);埃里希氏体属菌(Ehrlichia spp),包括马埃里希氏体(E.equi)和人粒细胞增多埃里希病的病原体;立克次氏体属菌(Rickettsia spp.),包括立氏立克次氏体(R.rickettsii);衣原体属菌(Chlamydia spp.),包括沙眼衣原体(C.trachomatis)(例如MOMP、肝素结合蛋白)、肺炎衣原体(C.pneumoniae)(例如MOMP、肝素结合蛋白)、鹦鹉热衣原体(C.psittaci);钩端螺旋体属菌(Leptospira spp.),包括问号钩端螺旋体(L.interrogans);密螺旋体属菌(Treponema spp.),包括苍白密螺旋体(T.pallidum)(例如稀有外膜蛋白)、齿垢密螺旋体(T.denticola)、猪痢疾密螺旋体(T.hyodysenteriae);或所述抗原或抗原组合物得自寄生虫,例如疟原虫属寄生虫(Plasmodium spp.),包括恶性疟原虫;弓浆虫属寄生虫(Toxoplasma spp.),包括鼠弓浆虫(T.gondii)(例如SAG2、SAG3、Tg34);内阿米巴属寄生虫(Entamoeba spp.),包括痢疾内变形虫(E.histolytica);巴贝虫属寄生虫(Babesia spp.),包括田鼠巴贝虫(B.microti);锥虫属寄生虫(Trypanosoma spp.),包括克鲁兹锥虫(T.cruzi);贾第鞭毛虫属寄生虫(Giardia spp.),包括吸吮贾第虫(G.lamblia);Leshmania属寄生虫,包括L.major;肺囊虫属寄生虫(Pneumocystis spp.),包括卡氏肺囊虫(P.carinii);毛滴虫属寄生虫(Trichomonas spp.),包括***毛滴虫(T.vaginalis);Schisostoma属寄生虫,包括S.mansoni,或所述抗原或抗原组合物得自酵母,例如念珠菌属酵母(Candida spp.),包括白色念珠菌(C.albicans);隐球酵母属酵母(Cryptococcus spp.),包括新型隐球菌酵母(C.neoformans)。
其它优选的结核分枝杆菌具体抗原有例如Tb Ra12、Tb H9、TbRa35、Tb38-1、Erd 14、DPV、MTI、MSL、mTTC2和hTCC1(WO 99/51748)。结核分枝杆菌的蛋白还包括其融合蛋白和变异体蛋白,其中至少2种、优选3种结核分枝杆菌多肽融合为更大的蛋白。优选融合蛋白包括Ra12-TbH9-Ra35、Erd14-DPV-MTI、DPV-MTI-MSL、Erd14-DPV-MTI-MSL-mTCC2、Erd14-DPV-MTI-MSL、DPV-MTI-MSL-mTCC2、TbH9-DPV-MTI(WO 99/51748)。
最优选的衣原体抗原包括例如高分子量蛋白(HWMP)(WO99/17741)、ORF3(EP 366 412)和推定的膜蛋白(Pmp)。所述疫苗制剂的其它衣原体抗原可选自WO 99/28475介绍的衣原体抗原。
优选细菌疫苗包含得自包括肺炎链球菌(例如荚膜多糖及其偶联物、PsaA、PspA、链球菌溶血素、胆碱结合蛋白)在内的链球菌属细菌的抗原和蛋白抗原肺炎链球菌溶血素(Biochem Biophys Acta,1989,67,1007;Rubins等,Microbial Pathogenesis,25,337-342)及其变异的去毒衍生物(WO 90/06951;WO 99/03884)。其它优选细菌疫苗包含得自嗜血菌属细菌(Haemophilus spp.)的抗原,包括B型流感嗜血菌(H.influenzae)(例如PRP及其偶联物)、未定型(non typeable)流感嗜血菌,例如OMP26、高分子量粘附素、P5、P6、蛋白D以及脂蛋白D和丝束蛋白以及丝束蛋白衍生的肽(US 5,843,464)或其多拷贝变异体或融合蛋白。
乙型肝炎表面抗原的衍生物是本领域众所周知的,特别包括欧洲专利申请EP-A-414 374、EP-A-0304 578和EP 198-474介绍的PreS1、PreS2 S抗原。在一个优选方面,本发明疫苗制剂包含HIV-1抗原、gp120,尤其是当用CHO细胞表达时。在另一个实施方案中,本发明疫苗制剂包含本文以上定义的gD2t。
在本发明的一个优选实施方案中,包含要求保护的佐剂的疫苗包含得自认为与生殖器疣有关的人***瘤病毒(HPV)(HPV 6或HPV 11以及其它HPV病毒)和与***有关的HPV病毒(HPV16、HPV18以及其它HPV病毒)的抗原。
特别优选形式的生殖器疣预防或治疗疫苗包含L1颗粒或病毒壳粒和融合蛋白,该融合蛋白包含一种或多种选自HPV 6和HPV 11蛋白E6、E7、L1和L2的抗原。
最优选形式的融合蛋白为:WO 96/26277公开的L2E7和GB9717953.5(PCT/EP98/05285)公开的蛋白D(1/3)-E7。
优选HPV宫颈感染或***的预防或治疗疫苗组合物可包含HPV 16或18抗原。例如L1或L2抗原单体、或以病毒样颗粒(VLP)一起存在的L1或L2抗原或者只以VLP或壳粒结构存在的L1单一蛋白。这类抗原、病毒样颗粒和壳粒本身是已知的。参见例如WO94/00152、WO94/20137、WO94/05792和WO93/02184。
VLP可包含单一或为融合蛋白的其它早期蛋白,例如E7、E2或优选E5;这样特别优选的实施方案包括含L1E7融合蛋白的VLP(WO96/11272)。
特别优选HPV 16抗原包含与蛋白D载体融合的早期蛋白E6或E7,以形成蛋白D-HPV 16的E6或E7融合,或其组合;或者E6或E7与L2的组合(WO 96/26277)。
另一方面,HPV 16或18早期蛋白E6和E7可以以一个分子、优选蛋白D-E6/E7融合蛋白存在。这种疫苗可任选包含HPV18的E6和E7之一或二者,该疫苗优选为蛋白D-E6或蛋白D-E7融合蛋白或蛋白D E6/E7融合蛋白形式。
本发明疫苗还可包含其它HPV病毒株、优选病毒株HPV 31或33的抗原。
本发明疫苗还包含从引起疟疾的寄生虫获得的抗原。例如恶性疟原虫(Plasmodia falciparum)的优选抗原包括RTS、S和TRAP。RTS是一种杂合蛋白,主要包含恶性疟原虫环子孢子蛋白(CS)的基本上所有C-末端部分,该部分通过乙型肝炎表面抗原preS2部分的4个氨基酸与乙型肝炎病毒表面抗原(S)连接。国际专利申请号PCT/EP92/02591公开了其完整结构,所述专利以公布号WO 93/10152公布,它要求英国专利申请第9124390.7号的优先权。当用酵母表达时,产生的RTS为脂蛋白颗粒,当它与HBV的S抗原共表达时,它产生称为RTS,S的混合颗粒。以WO 90/01496公布的国际专利申请号PCT/GB89/00895介绍了TRAP抗原。本发明的一个优选实施方案是疟疾疫苗,其中所述抗原制剂包含组合的RTS、S和TRAP抗原。其它可能候选为多阶段疟疾疫苗组分的疟原虫抗原有恶性疟原虫MSP1、AMA1、MSP3、EBA、GLURP、RAP1、RAP2、钳合蛋白、PfEMP1、Pf332、LSA1、LSA3、STARP、SALSA、PfEXP1、Pfs25、Pfs28、PFS27/25、Pfs16、Pfs48/45、Pfs230及其疟原虫属类似物。
所述制剂还可含有抗肿瘤抗原,并可用于免疫治疗癌症。例如所述佐剂制剂可用于肿瘤排斥抗原,例如***癌、乳腺癌、结肠直肠癌、肺癌、胰腺癌、肾脏癌症或黑素瘤抗原。典型抗原包括MAGE 1和MAGE3或其它MAGE抗原(用于治疗黑素瘤)、PRAME、BAGE或GAGE(Robbins和Kawakami,1996,Current Opinions in Immunology 8,第628-636页;Van den Eynde等,International Journal of Clinical &Laboratory Research(1997年递交);Correale等(1997),Journal of theNational Cancer Institute 89,第293页)。实际上,这些抗原在种类繁多的肿瘤类型表达,例如黑素瘤、肺癌、肉瘤和膀胱癌。其它肿瘤特异性抗原适用于本发明佐剂,包括但不限于肿瘤特异性神经节苷脂、***特异性抗原(PSA)或Her-2/neu、KSA(GA733)、PAP、mammaglobin、MUC-1、癌胚抗原(CEA)。因此,在本发明的一个方面,提供包含本发明的佐剂组合物和肿瘤排斥抗原的疫苗。
本发明一个特别优选的方面是所述疫苗包含肿瘤抗原;这种疫苗令人惊奇地有效治疗癌症,例如***癌、乳腺癌、结肠直肠癌、肺癌、胰腺癌、肾脏癌、卵巢癌或黑素瘤。因此,所述制剂可含有肿瘤相关抗原以及支持肿瘤形成(例如血管形成、肿瘤侵袭)的相关抗原。另外,治疗癌症疫苗特别相关的抗原还包括***特异性膜抗原(PSMA)、***干细胞抗原(PSCA)、酪氨酸酶、survivin、NY-ESO1、prostase、PS108(WO 98/50567)、RAGE、LAGE、HAGE。此外,所述抗原可以是自身肽激素,例如全长***释放激素(GnRH,WO 95/20600),该激素为10个氨基酸长的短肽,可用于治疗许多癌症或免疫***。
预期本发明组合物可用于配制含得自疏螺旋体属菌的抗原的疫苗。例如抗原可包括核酸、病原体衍生的抗原或抗原性制品、重组产生的蛋白或肽以及嵌合融合蛋白。所述抗原特别为OspA。OspA为借助于宿主细胞(大肠杆菌)的脂质化型完全成熟蛋白,称为Lipo-OspA,或者为非脂质化衍生物。该非脂质化衍生物包括非脂质化NS1-OspA融合蛋白,它含有流感病毒非结构蛋白(NS1)的前81个N-末端氨基酸和完整的OspA蛋白,非脂质化衍生物还包括另一种MDP-OspA,它为具有3个其它N-末端氨基酸的非脂质化OspA。
本发明疫苗可用于预防或治疗***反应。这种疫苗应该包含变应原特异性抗原(例如Der p1)和变应原非特异性抗原(例如人IgE产生的肽,包括但不限于stanworth十肽(decapeptide)(EP 0 477 231 B1))。
本发明疫苗还可用于预防或治疗***反应、癌症或感染性疾病以外的慢性病症。这类慢性病症为诸如动脉硬化和阿尔茨海默氏病的疾病。
预防和治疗这类阿尔茨海默氏神经变性性疾病易感者或患者的相关抗原具体有淀粉样前体蛋白的N末端39-43个氨基酸片段(Aβ)和小片段。该抗原公开于国际专利申请号WO 99/27944-(AthenaNeurosciences)。
根据在典型疫苗接受者诱导免疫保护性反应而没有显著副作用的剂量,选定每个疫苗剂量中的蛋白剂量。该剂量随使用的具体免疫原和如何提呈免疫原而不同。一般来说,预期每个疫苗剂量包含1-1000μg蛋白、优选1-500μg、优选1-100μg、最优选1-50μg。应用标准研究可确定具体疫苗的最佳剂量,所述标准研究包括观测接种疫苗者的合适免疫反应。初次免疫接种后,疫苗接受者可间隔适当时间后再接受1次或若干次加强免疫接种。在激发免疫接种或加强免疫接种方案中,该疫苗制剂可施用于哺乳动物粘膜表面;或者***给予,例如通过透皮、皮下或肌肉途径***给予。
本发明佐剂或疫苗中的CpG或免疫刺激寡核苷酸含量一般较小,但是根据疫苗制剂可以为1-1000μg/剂、优选1-500μg/剂而更优选1-100μg/剂。
用于本发明佐剂的皂甙量可以为1-1000μg/剂、优选1-500μg/剂、更优选1-250μg/剂而最优选1-100μg/剂。所以,CpG:皂甙(w/w)的比值为1∶1000至1000∶1,通常为1∶100至100∶1,优选1∶10至1∶1或1∶1至10∶1,最优选1∶1、4∶1或10∶1。
本发明制剂可用于预防和治疗目的。因此,本发明提供组合的皂甙和CpG分子用于生产预防和治疗病毒感染、细菌感染、寄生虫感染、***反应、癌症和其它非慢性病症的疫苗的用途。所以,本发明提供治疗感染性疾病或癌症或***反应或自身免疫性疾病易感或患病哺乳动物的方法。本发明的再一方面,提供包含皂甙和CpG的本文描述的疫苗组合或佐剂组合,以用作药物。New Trends and Developments inVaccines,Voller等编著,University Park Press,Baltimore,Maryland,U.S.A.1978全面介绍了疫苗制剂。
预期本发明组合物可用于配制含各种来源获得的抗原的疫苗。例如,抗原可包括人类、细菌或病毒的核酸、病原体衍生的抗原或抗原性制品、肿瘤衍生抗原或抗原性制品、宿主衍生抗原(包括IgE产生的肽,例如IgE的释放组织胺的十肽(称为Stanworth十肽))、重组产生的蛋白或肽以及嵌合融合蛋白。
本发明提供包含抗原、皂甙和免疫刺激寡核苷酸的疫苗组合物。因此,本发明提供治疗疾病易感或患病个体的方法,该方法为通过所述个体的***途径给予本文大致介绍的组合物。还提供防止个体罹患疾病的方法,该方法为通过所述个体的***途径给予本文大致介绍的组合物,所述疾病包括感染性细菌疾病和病毒疾病、寄生虫病、***癌、乳腺癌、结肠直肠癌、肺癌、胰腺癌、肾脏癌、卵巢癌或黑素瘤;非癌性慢性病症、***反应、阿尔茨海默氏病、动脉硬化。
另一方面,本发明提供包含抗原和溶血性皂甙的粘膜疫苗组合物。因此,本发明提供通过将本文大致介绍的组合物给予到所述个体的粘膜表面而治疗疾病易感个体或患病个体的方法。
此外,本发明介绍了诱导哺乳动物***性抗原特异性免疫反应的方法,包括将包含抗原和溶血性皂甙的组合物给予到所述哺乳动物的粘膜表面上。进而本发明还提供生产疫苗或佐剂的方法,包括制备皂甙、制备CpG分子以及将它们与抗原混合。
用于本发明组合的合适的药学上可接受的赋形剂实例包括水、磷酸缓冲盐水、等渗缓冲溶液。
附图说明
图1:鼻内加强免疫后14天的OspA特异性IgG滴度。
图2:鼻内加强免疫后14天的OspA特异性LA2滴度。
图3:鼻内加强免疫后14天的血清Flu病毒株特异性IgG滴度。
图4:鼻内加强免疫后14天的血清Flu病毒株特异性血清的血细胞凝集抑制(HAJ)滴度。
图5:小鼠的OspA特异性LA2滴度。
图6:免疫小鼠脾细胞的gp120特异性淋巴细胞增殖活性。全部4个实验组的抗原特异性活性以不同抗原浓度的SI表示。
图7:免疫小鼠脾细胞的HBsAg特异性CTL活性。通过检测P815细胞(空心圆)或s-转染P815细胞(实心圆)释放的51Cr评价效应细胞活性。
图8:免疫小鼠的HBsAg特异性抗体反应。采用ELISA实验测定特异性抗体滴度(以EU/ml表示)和同种型分布。合并血清的数字用表表示,而同种型分布仍用图说明。
图9:免疫小鼠脾细胞的HBSAg和gp120特异性淋巴细胞增殖活性。全部4个实验组的抗原特异性活性以不同抗原浓度的SI表示。
图10:免疫小鼠脾细胞的HBsAg和gp120特异性CTL活性。通过检测对照P815细胞(空心三角)或呈现HBsAg或gp120 CTL表位的P815细胞(实心三角)释放的51Cr评价效应细胞活性。
图11:免疫小鼠的gp120特异性和HbsAg特异性抗体反应。采用ELISA实验测定特异性抗体滴度(以μg/ml表示)(图11A)和同种型分布。合并血清的数字用表表示,而同种型分布仍用图说明。图11B显示gp120特异性抗体的同种型分布。
图12:每组10只动物在不同时间的平均肿瘤生长情况。
本发明通过下列实施例阐明,但不限于下列实施例。实施例1应用QS21和CpG鼻内加强***性抗Lipo-OspA抗体
我们用该实施例研究溶血性皂甙如QS21和免疫刺激剂如CpG是否能够以协同方式增强小鼠对鼻内加强免疫的***性免疫反应。用配制在明矾(50μg)上的lipo-OspA(1μg)肌肉注射免疫8周龄雌性Balb/c小鼠(每组5只小鼠)。3个月后,用10μl含5μg lipo-OspA的A:PBS;B:20μg CpG 1001(TCC ATG AGC TTC CTG ACG TT,Krieg 1826);C:5μg QS 21(得自Cambridge Biotech,USA);D:20μg CpG 1001+5μgQS21的溶液鼻内(麻醉下)加强免疫小鼠,或者E:肌肉注射1μg吸附在明矾(50μg)上的lipo-OspA加强免疫小鼠。图1和2显示鼻内加强免疫后14天的OspA特异性IgG滴度和LA2滴度。方法用于测定小鼠OspA特异性血清IgG的ELISA:
用50μl/孔的1μg/ml用PBS稀释的OspA(板的B至H行)或50μl的5μg/ml纯化山羊抗小鼠Ig(Boerhinger)的PBS(A行)使MaxisorpNunc免疫板于4℃包被过夜。用饱和缓冲液:含1%BSA的PBS、0.1%聚氧乙烯山梨糖醇酐单月桂酸酯(吐温20)和4%正常牛血清(NBS)封闭(1小时,37℃)各板的游离位点。然后使连续2倍稀释的IgG同种型混合物和血清样品(从100倍稀释度开始,加入B至H行)于37℃温育1.5小时,所述混合物用饱和缓冲液稀释(50μl/孔)并加入各板中以制备标准曲线(小鼠单克隆抗体IgG1、IgG2a和IgG2b(Sigma)的混合物,从200ng/ml开始,加入A行)。再后用洗涤缓冲液(PBS,0.1%聚氧乙烯山梨糖醇酐单月桂酸酯(吐温20))洗涤(×3)各板。然后使用饱和缓冲液稀释5000倍的生物素化山羊抗小鼠IgG(Amersham)于37℃温育(50μl/孔)1.5小时。洗涤3次后加入链霉抗生物素蛋白-辣根过氧化物酶缀合物(Amersham),洗涤板5次,以50μl/孔显色缓冲液(OPDA0.4mg/ml(Sigma)和0.03%H2O2的50mM pH4.5柠檬酸缓冲液)使板于室温下温育20分钟。加入50μl/孔2N硫酸终止显色。用Biorad 3550免疫读数器于492和630nm读出光密度。采用SoftMaxPro软件通过4参数数学方法计算抗体滴度。用于测定血清抗lipo-OspA的LA2类(LA2-like)抗体滴度的抑制测定法
就其LA2类特异性研究疫苗接受者的抗体滴度。LA2是识别细菌表面的OspA构象表位而且证实能够体外杀伤B.burgdorferi以及保护小鼠免受实验性培养的螺旋体攻击的小鼠单克隆抗体(Schaible UE等1990,Proc Natl Acad Sci USA 87:3768-3772)。而且证实LA-2 mab与杀细菌抗体有关,关于人血清的研究也表明,总的抗OspA IgG滴度和LA-2滴度具有良好的相关性(根据ELISA测定)。
用50μl/孔的0.5μg/ml用PBS稀释的lipo OspA使Maxisorp Nunc免疫板于4℃包被过夜。用饱和缓冲液于37℃封闭游离位点1小时(100μl/孔饱和缓冲液:PBS/BSA 1%/吐温20 0.1%/NBS 4%)。用饱和缓冲液(50μl/孔)从4μg/ml开始稀释连续2倍稀释的LA2单克隆抗体(mAb),以制备标准曲线。另外加入得自疫苗接受者的稀释血清样品(从10倍稀释度开始),于37℃温育板2小时。温育后用PBS/吐温20(0.1%)洗涤板3次。在每孔中(50μl/孔)加入用饱和缓冲液稀释(10,000倍)的LA2 mAb-过氧物酶缀合物,于37℃温育1小时。洗涤板5次后,以50μl/孔显色缓冲液(OPDA 0.4mg/ml和H2O2 0.03%的50mM pH4.5柠檬酸缓冲液)使板于室温下(避光)温育20分钟。用2N硫酸终止反应和颜色形成。用Biorad 3550免疫读数器于492和630nm读出光密度。采用SoftMaxPro软件通过4参数数学方法计算LA2类抗体滴度。通过与标准曲线比较确定LA2类抗体滴度。结果
CPG和QS21显著改善鼻内加强免疫的***性抗Lipo-OspA抗体。而且当这两种佐剂联用时,明确证实对这些反应的协同作用,对于LA2抗体尤其如此。在QS21和CpG存在下激发的体液免疫反应显著高于胃肠外加强免疫诱导的体液免疫反应。总之,这些结果明确证实联用溶血性皂甙和免疫刺激剂的鼻内制剂的潜力。实施例2用于增强鼻内加强免疫的***性抗流感病毒抗体的QS21和CpG的协同组合
我们用该实施例研究溶血性皂甙如QS21(见实例)和免疫刺激剂如CpG是否能够以协同方式增强小鼠鼻内加强免疫的***抗体,所述小鼠用灭活完整流感病毒鼻内激发免疫。
用β-丙酸内酯灭活的三价完整流感病毒(A/Beijing/262/95;A/Johannesburg/33/94;B/Panama/45/90;5μg HA/病毒株)鼻内激发免疫8周龄雌性Balb/c小鼠(每组10只小鼠),以模拟人类天然激发免疫。28天后,用20μl含1.5μg HA/病毒株的β-丙酸内酯灭活三价完整流感病毒(与激发免疫接种的病毒株相同)的A:PBS;B:50μg CpG(TCGTCG TTT TGT CGT TTT GTC GTT,Krieg 2006);C:4.5μg QS 21(得自Cambridge Biotech,USA);D:50μg CpG+4.5μg QS21的溶液(每个鼻孔10μl,用吸移管滴鼻给予)鼻内(麻醉下)加强免疫小鼠,或者E:肌肉注射1.5μg HA/病毒株的三价***流感病毒(与激发免疫接种的病毒株相同)加强免疫小鼠。Flu抗原由SSD GmBH生产商(Dresden,Germany)供应。
图3和4显示鼻内加强免疫后14天的血清Flu病毒株特异性IgG滴度和血细胞凝集抑制(HAI)滴度。方法用于测定小鼠抗流感病毒IgG滴度的ELISA:
用50μl/孔的1μg/ml用PBS稀释的完整流感病毒抗原(板的B至H行)或50μl的5μg/ml纯化山羊抗小鼠Ig(Boerhinger)的PBS(A行)使Maxisorp Nunc免疫板于4℃包被过夜。用饱和缓冲液:含1%BSA的PBS、0.1%聚氧乙烯山梨糖醇酐单月桂酸酯(吐温20)和4%正常牛血清(NBS)封闭(1小时,37℃)各板的游离位点。然后使连续2倍稀释的IgG同种型混合物和血清样品(从100倍稀释度开始,加入B至H行)于37℃温育1.5小时,所述混合物用饱和缓冲液稀释(50μl/孔)并加入各板中以制备标准曲线(小鼠单克隆抗体IgG1、IgG2a和IgG2b(Sigma)的混合物,从200ng/ml开始,加入A行)。再后用洗涤缓冲液(PBS,0.1%聚氧乙烯山梨糖醇酐单月桂酸酯(吐温20))洗涤(×3)各板。然后使用饱和缓冲液稀释5000倍的生物素化山羊抗小鼠IgG(Amersham)于37℃温育(50μl/孔)1.5小时。洗涤3次后加入链霉抗生物素蛋白-辣根过氧化物酶缀合物(Amersham),洗涤板5次,以50μl/孔显色缓冲液(OPDA 0.4mg/ml(Sigma)和H2O2 0.03%的50mM pH4.5柠檬酸缓冲液)使板于室温下温育20分钟。加入50μl/孔2N硫酸终止显色。用Biorad 3550免疫读数器于492和630nm读出光密度。采用SoftMaxPro软件通过4参数数学方法计算抗体滴度。用于包被、用β-丙酸内酯(BPL)灭活的完整流感病毒(病毒株A/Beijing/262/95)由SSDGmBH生产商(Dresden,Germany)供应。小鼠Flu特异性血清抗体的血细胞凝集抑制(HAI)活性
首先用100μl 0.5M硼酸盐缓冲液(pH9)和125μl购自DadeBehring的高岭土于室温下(RT)处理血清(25μl)20分钟。离心(30分钟,3000RPM或860g)后,取100μl上清液(相当于10倍稀释的血清),于4℃与0.5%鸡红细胞温育1小时。于3200RPM(970g)离心10分钟后收集上清液。进行2次操作以消除血清中含有的天然血细胞凝集因子。然后,在96孔Greiner板中用25μl PBS(从20倍稀释度开始连续2倍稀释)稀释25μl处理血清。以4个血细胞凝集单位浓度(即低于激发红细胞凝集的最后稀释度4倍的稀释度)加入(25μl/孔)BPL灭活的完整病毒,振荡下于RT处理30分钟。然后在RT下加入鸡红细胞(25μl/孔)处理1小时。最后板于4℃保持过夜后变红。HAI滴度相当于抑制病毒诱导的血细胞凝集的最后血清稀释度。结果
CPG和QS21没有提高鼻内加强免疫的抗Flu病毒株的IgG或HAI抗体。然而,当这两种佐剂联用时,明确证实对这些反应的协同作用。在QS21和CpG存在下激发的HAI反应非常类似胃肠外加强免疫诱导的反应。这些结果证实了联周溶血性皂甙和免疫刺激剂的鼻内制剂的潜力。它们还表明,数个CpG序列在这种条件下均是有效的(本实施例中的Krieg 2006以及实施例3和5中的Krieg 1826)。实施例3用于增强鼻内加强免疫的***性抗Lipo-OspA抗体的β-七叶素和CpG的协同组合
我们用该实施例评价用其它溶血性皂甙(见实例)如β-七叶素是否能够获得类似于QS21和CpG观测到的协同作用。还测试了非溶血性皂甙,即甘草酸。
用配制在明矾(50μg)上的lipo-OspA(1μg)肌肉注射激发免疫8周龄雌性Balb/c小鼠(每组6只小鼠)。3个月后,用10μl含5μg lipo-OspA的A:PBS;B:50μg CpG 1001(TCC ATG AGC TTC CTG ACG TT,Krieg 1826);C:5μg β-七叶素(购自Sigma);D:50μg CpG 1001+5μgβ-七叶素;E:5μg甘草酸(购自Sigma);F:50μg CpG 1001+5μg甘草酸的溶液(每个鼻孔5μl,用吸移管滴鼻给予)鼻内(麻醉下)加强免疫小鼠,或者G:肌肉注射1μg吸附在明矾(50μg)上的lipo-OspA加强免疫小鼠。图5显示鼻内加强免疫后14天的OspA特异性LA2滴度。方法
该方法与实施例1详细介绍的方法相同。结果
β-七叶素与CpG协同作用增强鼻内加强免疫的***性LA2抗体。这种组合比胃肠外加强免疫增强激发的抗体反应的作用更强。相反,联用CpG和甘草酸不能获得这种协同作用。
这些结果和本专利前面的结果一起证实,CpG和不同溶血性皂甙能够以协同方式辅助增强免疫反应。实施例4:利用以CpG和/或DQS21配制的恶性疟原虫RTS,S和HIV-1gp120研究免疫原性1.实验概述
进行2只小鼠的免疫原性研究,以评价CpG寡核苷酸(CpG)和QS21的潜在累加或协同作用。单独或联合用CpG和QS21配制的RTS,S和gp120免疫各组小鼠。还在载体氢氧化铝或水包油(o/w)乳液存在下测试了这些佐剂组合。
2次胃肠外免疫后测定所述制剂的免疫原性。分析血清中存在的抗原特异性抗体和抗体同种型分布。用脾细胞评价细胞介导的免疫反应。测试这些细胞中存在的细胞毒性T淋巴细胞(CTL)和淋巴细胞增殖的细胞。
表1:实验1的各组小鼠
组别 | 抗原 | 佐剂 |
1 | RTS,S/gp120 | CpG/DQS21 |
2 | RTS,S/gp120 | DQS21 |
3 | RTS,S/gp120 | CpG/DQS21/Al(OH)3 |
4 | RTS,S/gp120 | CpG/Al(OH)3 |
表2:实验2的各组小鼠
2.制剂2.1.实验1配制方法:
组别 | 抗原 | 佐剂 |
1 | RTS,S/gp120 | CpG |
2 | RTS,S/gp120 | CpG/DQS21 |
3 | RTS,S/gp120 | CpG/QS21/o/w乳液 |
每次注射前3天制备制剂。必要时,使RTS,S(10μg)和gp 120(10μg)吸附在100μg氢氧化铝上。必要时,加入MPL(5μg)并温育30分钟,然后加入10倍浓缩的PBS pH7.4和水的混合物的缓冲液,例外的是没有DQ的实验组,缓冲液为PO4,NaCl 10/150 pH6.8。30分钟后,需要的话,在所述制剂中加入以QS21/胆固醇1/5重量比与脂质体混合的QS21(称为DQ)(5μg)。30分钟后,如果用所述寡核苷酸配制,则在加入100μg CpG30分钟后,加入50μg/ml作为防腐剂的硫柳汞。
所有温育均在室温下振荡进行。2.2.实验2配制方法:
氢氧化铝+RTSS+gp120-1小时-MPL-30分钟-预混合-30分钟-DQ-30分钟-CpG-30分钟-Thio |
同时配制两种注射剂。每只小鼠的注射体积为100μl。加入50μg/ml用作防腐剂的硫柳汞。
第1组:用水和PBS pH6.8等渗性稀释RTS,S(10μg)和gp120(10μg)。5分钟后所述制剂吸附在CpG 1856(100μg)上。
第2组:用水和PBS pH7.4等渗性稀释RTS,S(10μg)和gp120(10μg)。30分钟后RTS,S和gp120吸附在DQ(5μg)上。吸附30分钟后,所述制剂吸附在CpG 1856(100μg)上。
第3组:用水和PBS pH6.8等渗性稀释RTS,S(10μg)和gp120(10μg)。5分钟后所述制剂吸附在o/w乳液上。吸附5分钟后,所述制剂吸附在QS21(5μg)上后,加入CpG(100μg)。3.免疫方法
每组9只(Balb/C×C57B1/6)F1小鼠,在小鼠的后足垫注射2×50μl疫苗,间隔2周注射2次。2周后取血清测定抗体反应,收获脾细胞测定细胞介导的免疫反应。
对于淋巴细胞增殖分析,将细胞以2×106/ml浓度一式四份接种在96孔圆底微量滴定板中。在不同浓度RTS,S或gp120抗原存在下,用添加抗生素、谷氨酰胺和1%(v/v)正常小鼠血清的RPMI-1640培养细胞72或96小时。对照细胞的培养不含抗原。然后以1μCi/孔[3H]-胸苷脉冲处理所述细胞过夜,收获细胞,用β计数器测定掺入的放射性。结果以平均计数/分钟(cpm)表示。
对于CTL分析,在10μg/ml相当于HBsAg CTL表位的合成肽pCMI003(IPQSLDSWWTSL)(Schirmbeck等,1995)或代表gp120 CTL表位的合成肽pCMI007(GIHIGPGRAFYAARK)(Casement等,1995)存在下,在6孔板中培养细胞7天。结束培养后,采用对照细胞和S-转染P815细胞以标准[51Cr]-释放测定法一式二份测定效应细胞的HBsAg特异性细胞溶解活性。用留置未处理的P815靶细胞或用肽pCMI007脉冲处理1小时的P815靶细胞测定gp120特异性细胞毒性。分别用没有效应细胞的靶细胞和加入3%(v/v)Triton X-100的靶细胞测定最小释放和最大释放。结果以[51Cr]释放百分率(实验培养物cpm-自然释放cpm/最大释放cpm-自然释放cpm)表示。
采用以HbsAg包被的板以标准酶联免疫吸附测定法(ELISA)方式对合并血清进行滴定和同种型分型。从400倍稀释度开始,用PBS/BSA稀释血清。用Ig或同种型IgG1、IgG2a和IgG2b特异性生物素化二抗,接着用辣根过氧化物酶-链霉抗生物素蛋白缀合物检测结合抗体。根据SoftmaxPro的参考值计算ELISA滴度,以ELISA单位(EU/ml)表示。用gp120蛋白包被的板以标准ELISA测定gp120特异性抗体滴度。从100倍稀释度开始,以PBS/吐温20/BSA稀释血清。用Ig或同种型IgG1、IgG2a和IgG2b特异性生物素化二抗,接着用辣根过氧化物酶-链霉抗生物素蛋白缀合物检测结合抗体。相对于标准小鼠Ig计算滴度,以μg/ml表示。4.结果实验1
淋巴细胞增殖反应分析显示,各组间对RTS,S的反应性没有任何显著性差异。相反,同时含有CpG和DQS21的第1组和第3组显示,gp120特异性淋巴细胞增殖反应比只含CpG或DQS21的各组更好(图6)。
在本实验中,只检测了HBsAg特异性CTL。接受CpG和DQS21组合的第1和3组与只接受两种佐剂组分之一免疫的第2和4组之间在诱导CTL作用方面没有显著性差异,而观测到在氢氧化铝存在下联合用CpG和DQS21的第1组CTL活性降低(图7)。但是存在这样的趋势:CpG和DQS21比单独的DQS21更好,在氢氧化铝存在下CpG和DQS21组合诱导CTL比单独的CpG诱导CTL的作用更强(图7)。
对小鼠的体液免疫反应只检测了HBsAg特异性抗体的存在。所有各组的滴度相似,例外的是,第3组显示滴度增加约3倍,证实在氢氧化铝存在下,DQS21和CpG组合比单独的CpG的免疫原性更好(图8)。含氢氧化铝的第3和4组的同种型分布相似,而缺乏氢氧化铝时,CpG和DQS21组合诱导的TH1-类同种型分布比单独的DQS21更强(图8)。实验2
在本实验中,RTS,S和gp120特异性淋巴细胞增殖反应非常相似。数据表明,加入DQS21(单独加入或用o/w乳液加入)增强两种抗原的淋巴细胞增殖反应(图9)。
同时用HBsAg和gp120 CTL表位肽检测了CTL反应。在两种情况下,单独用CpG免疫第1组后均能够检测到CTL(图10)。但是,加入DQS21使两种抗原的CTL显著增强(图10)。存在o/w乳液或者中和DQS21(gp120)的正性作用或者增强体外测定的本底(HBsAg)。
在CpG佐剂中加入DQS21增强抗HBsAg和gp120的抗体反应(图11A)。当所述制剂中包含o/w乳液时观测到其作用进一步增强(图11A)。在CpG中加入DQS21使gp120同种型分布向更显著的TH1偏移(图11B),而在本实验中对HBsAg同种型分布的影响较弱。5.结论
以组合的CpG和DQS21配制的RTS,S和gp120免疫增强抗原特异性免疫反应。与单一组分相比,佐剂组分CpG和DQS21组合:
-增强淋巴细胞增殖反应
-增强CTL活性
-提高抗体滴度和TH1同种型分布。实施例5.CpG和/或DQS21制剂在TC1肿瘤模型中的治疗潜力1.实验设计
4组C57bl/6小鼠(每组10只)在第0天于胁腹皮下注射接受10e6(200μl)TC1细胞(表达E7的肿瘤细胞)。
然后在肿瘤攻击后14天和21天,用5μg配制的PD1/3E7 HPV16通过足垫注射免疫小鼠2次。每周分别测定肿瘤生长两次。
小鼠分组:
1.无疫苗组
2.PD1/3E7+CPG(10μg ODN 2006)
3.PD1/3E7+DQS21(0.5μg)
4.PD1/3E7+CPG+DQS21
通过每周2次测量各肿瘤监测肿瘤生长情况。2.制剂
在注射当天进行配制。每只小鼠的注射体积为100μl。需要的话,用水和PBS pH7.4等渗性稀释PD1/3E7(5μg)。5分钟后,如果需要的话,在所述制剂中加入以QS21/胆固醇1/5重量比与脂质体混合的QS21(称为DQ)(0.5μg)。30分钟后,对于含有所述寡核苷酸的制剂,加入10μg CpG(ODN 2006),30分钟后加入1μg/ml用作防腐剂的硫柳汞。
3.结果
水+PBS pH7.4+PD1/3E7-5分钟+DQ-30分钟+CpG-30分钟-Thio |
各组小鼠(每组10只)在不同时间的平均肿瘤生长情况见图12。100%接受10e6 TCl细胞的肿瘤攻击小鼠的肿瘤生长呈进行性发展。
70%-80%没有免疫的小鼠或没有用E7蛋白的DQS21免疫小鼠在35天内死亡。
用DQS21配制的E7蛋白免疫2次对肿瘤生长几乎没有作用。相反,IFP(第14、21天)5μg ProtD 1/3 E7 HPV16的CPG佐剂免疫2次使这些预建立的肿瘤消退,保护小鼠免于死亡:70-80%小鼠在第35天仍然存活。证实2种免疫刺激剂CPG和DQS21组合的有益作用略微优于单独使用CpG。
说明书的核苷酸和氨基酸序列表
序列表<110>Friede,Martin
Garcon,Nathalie
Hermand Philippe<120>佐剂制剂<130>B45181<160>5<170>FastSEQ for Windows Version 3.0<210>1<211>20<212>DNA<213>人<400>1tccatgacgt tcctgacgtt 20<210>2<211>18<212>DNA<213>人<400>2tctcccagcg tgcgccat 18<210>3<211>30<212>DNA<213>人<400>3accgatgacg tcgccggtga cggcaccacg 30<210>4<211>24<212>DNA<213>人<400>4tcgtcgtttt gtcgttttgt cgtt 24<210>5<211>20<212>DNA<213>人<400>5tccatgacgt tcctgatgct 20
Claims (29)
1.一种佐剂组合物,该组合物包含皂甙和免疫刺激寡核苷酸。
2.权利要求1的佐剂组合物,它还包含载体。
3.权利要求1或2要求保护的佐剂组合物,其中所述皂甙选自Quil A或纯化皂甙如QS21、QS7、QS17;β-七叶素或洋地黄皂甙。
4.权利要求1-3任一项要求保护的佐剂组合物,其中所述免疫刺激寡核苷酸包含嘌呤、嘌呤、C、G、嘧啶、嘧啶序列。
5.权利要求1-4要求保护的佐剂组合物,其中所述免疫刺激寡核苷酸选自:TCC ATG ACG TTC CTG ACG TT(SEQ ID NO:1);TCTCCC AGC GTG CGC CAT(SEQ ID NO:2);ACC GAT GAC GTC GCCGGT GAC GGC ACC ACG(SEQ ID NO:3);TCG TCG TTT TGT CGTTTT GTC GTT(SEQ ID NO:4);TCC ATG ACG TTC CTG ATG CT(SEQ ID NO:5)。
6.权利要求1-4的佐剂组合物,其中所述免疫刺激寡核苷酸包含被至少3个核苷酸分隔开的至少2个未甲基化CG重复基元。
7.权利要求6的佐剂组合物,其中所述免疫刺激寡核苷酸包含被6个核苷酸分隔开的至少2个未甲基化CG重复基元。
8.权利要求2-7任一项要求保护的佐剂组合物,其中所述载体为颗粒性载体,该颗粒性载体选自矿物盐、乳液、聚合物、脂质体、ISCOM。
9.一种包含权利要求1-8任一项要求保护的佐剂组合物的疫苗组合物,它还包含抗原。
10.权利要求9要求保护的疫苗组合物,其中所述抗原从生物获得,所述生物选自人类免疫缺陷病毒、水痘带状疱疹病毒、1型单纯疱疹病毒、2型单纯疱疹病毒、人类巨细胞病毒、登革热病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒或戊型肝炎病毒、呼吸道合胞病毒、人***瘤病毒、流感病毒、Hib、脑膜炎病毒、沙门氏菌属(Salmonella)、奈瑟氏菌属(Neisseria)、疏螺旋体属(Borrelia)、衣原体(Chlamydia)、博德特氏菌属(Bordetella)、链球菌属(Streptococcus)、支原体属(Mycoplasma)、分枝杆菌属(Mycobacteria)、嗜血杆菌属(Haemophilus)、疟原虫属(Plasmodium)或弓浆虫属(Toxoplasma)、stanworth十肽;或肿瘤相关抗原(TAA)、MAGE、BAGE、GAGE、MUC-1、Her-2 neu、CEA、PSA、KSA或PRAME;或自身肽激素GnRH。
11.权利要求9要求保护的疫苗组合物,其中所述抗原得自(a)肿瘤相关抗原PSMA、PSCA、酪氨酸酶、survivin、NY-ESO1、prostase、PS108、RAGE、LAGE、HAGE;(b)或淀粉样前体蛋白的N末端39-43个氨基酸片段(Aβ);(c)或动脉硬化相关抗原。
12.权利要求9-11要求保护的疫苗组合物,其中所述疫苗通过***途径给予。
13.权利要求9-11要求保护的疫苗组合物,其中所述疫苗通过粘膜给予。
14.权利要求13要求保护的疫苗组合物,其中所述佐剂组合物中的皂甙是溶血性皂甙。
15.一种预填充权利要求9-11的疫苗的传递装置,该装置设计用于通过***途径给予所述疫苗。
16.一种诱导个体免疫反应的方法,该方法包括***给予安全有效量的权利要求9-11要求保护的疫苗组合物。
17.一种治疗疾病易感个体或患病个体的方法,该治疗方法给予个体有效量的权利要求9-14任一项要求保护的疫苗。
18.权利要求17要求保护的治疗方法,其中所述疫苗的给予是通过***途径给予。
19.一种治疗疾病患病个体的方法,该方法包括给予权利要求9-11任一项要求保护的疫苗,其中所述疾病选自***癌、乳腺癌、结肠直肠癌、肺癌、胰腺癌、肾癌、卵巢癌或黑素瘤;非癌性慢性疾病、***反应、阿尔茨海默氏病、动脉硬化。
20.一种防止个体罹患疾病的方法,该方法包括给予权利要求9-11任一项要求保护的疫苗,其中所述疾病选自***癌、乳腺癌、结肠直肠癌、肺癌、胰腺癌、肾癌、卵巢癌或黑素瘤;非癌性慢性疾病、***反应、阿尔茨海默氏病、动脉硬化。
21.权利要求19和20要求保护的治疗方法,其中所述疫苗通过***途径给予。
22.权利要求9或11要求保护的疫苗,它用作药物。
23.皂甙和CpG分子组合用于生产疫苗的用途,所述疫苗用于预防和治疗病毒感染、细菌感染、寄生虫感染、***反应、癌症或其它慢性病症。
24.皂甙、免疫刺激寡核苷酸和载体组合用于生产疫苗的用途,所述疫苗用于预防和治疗病毒感染、细菌感染、寄生虫感染、***反应、癌症或其它慢性病症。
25.一种诱导哺乳动物***性抗原特异性免疫反应的方法,该方法包括将包含抗原和溶血性皂甙以及CpG分子的组合物给予到所述哺乳动物的粘膜表面上。
26.一种制备佐剂组合物的方法,该方法包括混合皂甙与免疫刺激寡核苷酸。
27.一种制备佐剂组合物的方法,该方法包括混合皂甙、免疫刺激寡核苷酸和载体。
28.一种制备疫苗的方法,该方法包括混合下列组分:(a)皂甙,(b)免疫刺激寡核苷酸,以及(c)抗原。
29.一种制备疫苗的方法,该方法包括混合下列组分:(a)皂甙,(b)免疫刺激寡核苷酸,(c)载体以及(d)抗原。
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CN104857511A (zh) * | 2015-02-13 | 2015-08-26 | 浙江大学 | 含人参皂甙的疫苗稀释剂 |
CN104857511B (zh) * | 2015-02-13 | 2018-03-30 | 浙江大学 | 含人参皂甙的疫苗稀释剂 |
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