CN1086142A - 疫苗 - Google Patents

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CN1086142A
CN1086142A CN93107990A CN93107990A CN1086142A CN 1086142 A CN1086142 A CN 1086142A CN 93107990 A CN93107990 A CN 93107990A CN 93107990 A CN93107990 A CN 93107990A CN 1086142 A CN1086142 A CN 1086142A
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J·P·普里伊斯
N·M·-J·C·加康-约翰逊
M·施劳伊
P·帕拉
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GlaxoSmithKline Biologicals SA
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SmithKline Beecham Biologicals SA
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Abstract

本发明提供了包含3De-O-酰化的单磷酰类脂 A和QS21的疫苗组合物。该疫苗组合物是CTL和 γIFN应答的有效诱导物。

Description

本发明涉及新的疫苗制剂，其制备方法和其在医药上的应用。具体而言，本发明涉及包含QS21和3-De-O-酰化的单磷酰类脂A（3D-MPL）的疫苗，其中QS21为从Quillaja        Saponaria        Molina的茎皮得到的经高压液相色谱（Hplc）纯化的无毒成分。
3De-O-酰化的单磷酰类脂A可参见GB2，220，211（Ribi）。从化学上说，它是一种具有4、5或6酰化链的3-脱酰的单磷酰类酯A的混合物，是由Ribi    Immunochem        Montana制备的。
QS21是一种由南美树种        Ouillaja        Saponaria        molina的茎皮得到的皂苷经高压液相色谱（HpLe）纯化的无毒成分。其制备方法（以QA21）公开在US5，057，540中。
本发明是以下述惊人发现为基础的，即包含QS21和3D-MPL的组合体的制剂对于某种给定的抗原能协同增强免疫应答。
例如，疟疾抗原RTS，S佐以3D-MPL和QS21的疫苗制剂能有效地协同诱导脾脏中CS蛋白特异的细胞毒素的T淋巴细胞（CTL）的应答。
RTS是一种杂种蛋白，它包含有几乎所有的P.falciparum的环子孢子（CS）蛋白的C-末端部分，经乙肝表面抗原的preS2部分的四个氨基酸连接至乙肝病毒的表面（S）抗原上。其整体结构公开于审查中的国际专利申请PCT/EP92/02591中，以WO93/10152公开，优先权为UK专利申请号9124390.7。当以酵母表达时，RTS以脂蛋白颗粒产生，当其与来自HBV的S抗原一起表达时，产生一种称之为RTS，S的混合颗粒。
能够诱导强烈的溶细胞的T淋巴细胞应答的观测结果意义重大，因为在某些典型动物中这些应答已表现出可诱导对疾病的预防。
本发明人表明，两种佐剂QS21和3D-MPL与重组体颗粒抗原RTS，S的组合体能强有力地诱导脾脏中的CS蛋白特异性CTL.QS21自身也能增强诱导CTL，而3D-MPL则无此作用。可以说这种组合是以一种协同性的方式而起作用，这是因为，其效果大于每种佐剂单独的效果之和。这两种佐剂对CTL诱导的协同作用是一个惊人的发现，它有使用重组体分子作为用于诱导CTL介导的免疫的疫苗的重要结论。
当靶抗原在胞内合成时（如在病毒、胞内细菌的感染中，或在肿瘤中），易于发现CTL的诱导，这是因为由抗原的蛋白水解性分解产生的肽能够进入适宜的处理途径，从而导致与细胞膜上Ⅰ类分子有关的表现。但是，预形成的可溶性抗原通常不会到达该处理和表现途径，也不会诱出Ⅰ类约束的CTL。因而，传统的非活体疫苗在诱出抗体和T辅助应答时通常不能诱导CTL介导的免疫作用。两种佐剂QS21和3D-MPL的组合能够克服基于重组体蛋白的疫苗的这种严重的局限，且能诱导宽范围的免疫应答。
对CS蛋白的CTL特异性已表示出在小鼠模型体系中预防疟疾的功能（Romero等，Nature    341∶323（1989））。对人体进行实验时，使用辐照过的P.falciparum的子孢子使志愿者免疫，表明其可防止随后的疟疾进攻，因而显示出对CS表位特异性的CTL的诱导作用（Malik等Proc.Natl.Acad.Sci.USA.88∶3300（1991））。
由于根据免疫应答的产生和性能，使用辐照的子孢子将是不切实际的，因而诱导对于以重组体分子给药的抗原特异的CTL的能力与疟疾疫苗的开发是有关的。
除了疟疾疫苗，诱导CTL应答的能力还将有益于疫苗抵抗单纯疱疹病毒、细胞肥大病毒、人体免疫缺乏病毒，以及一般地病原体处于胞内生命期的所有病例。
同样，对于已知的肿瘤抗原特异的CTL也能通过一种重组体肿瘤抗原和两种佐剂的组合体进行诱导。这将有益于开发抗癌疫苗。
在一些体系中，3D-MPL和QS21的组合能协同增强干扰素γ的生成。本发明人通过利用称之为gD2t的单纯疱疹抗原表明了3D-MPL和QS21的协同作用潜力。gD2t是一种得自HSV-2的可溶性截断的糖蛋白D，并且可以按Berman等，Science 222 524-527所述的方法在CHO细胞中产生。
IFN-γ分泌与抗胞内病原体的保护性应答有关，所述病原体包括寄生物，细菌和病毒。由INF-γ活化巨噬细胞增强了微生物的胞内杀伤并增加了Fc受体的表达。直接的细胞溶解作用也可能发生，特别是与淋巴毒素（另一种THl细胞的产物）协同作用下发生。IFN-γ不仅是一种诱导物而且是NK细胞的一种产物，NK细胞为主要的先天保护效应物。或者通过IFN-γ或者通过其它机理实现的THI型应答优先有助于IgG2a免疫球蛋白同种型。
糖蛋白D位于病毒被膜上，也能在感染的细胞的细胞质上发现（Eisenberg R.J.等J.Of Virol 1980 35 428-435）。它含有393种包括一种信号肽的氨基酸，其分子量大约为60KD。在所有的HSV被膜糖蛋白中，这可能是最好的特征（Cohen等 J.Virology 60 157-166）。在体内公知它在病毒向细胞膜的附着中起中心作用。进而，糖蛋白D还表明能诱出体内中和抗体（Eing等 J.Med Virology 127∶59-65）。然而，潜伏的HSV2病毒仍然能被再活化并诱导疾病复发，尽管在患者的血清中存在高的中和抗体值。因而很明显，单独诱导中和抗体的能力并不足以适宜地控制疾病。
为了防止疾病复发，任何一种疫苗均需要不仅激发中和抗体，而且要激发通过T细胞特别是细胞毒性T细胞介导的细胞免疫。
在这种情况下，gD2l是308种氨基酸的HSV2糖蛋白D，所述氨基酸包括1至306天然存在的糖蛋白以及在截断蛋白的C末端处的天冬酰胺和谷氨酰胺。这种形式的蛋白包括信号肽，该肽被分成一种成熟的283氨基酸蛋白，在中国大田鼠（Chinese Hamster）的卵巢细胞中这种蛋白的生成在Genentech的EP-B-139417中有述。
从哺乳动物细胞中分泌出的成熟的截断糖蛋白D（rgD2t）或等价的蛋白是在本发明的疫苗制剂中优选使用的。
本发明的制剂能非常有效地诱导天竹鼠的生殖器疱疹模型中的保护免疫。即使采用非常低的抗原剂量（如低至5μg rgD2t），该制剂也能防止天竺鼠的原发感染且能促进特异性中和抗体应答。本发明人采用本发明的制剂已经表明了小鼠中效应物细胞介导的THI型应答。
相应地，本发明提供一种包含有一种抗原及3脱酰单磷酰类酯A和QS21的疫苗或药物制剂。该种制剂可适用于宽范围的单价或多价疫苗。
疫苗制剂最好包含一种抗原或抗原组合物，这种抗原或抗原组合物能够激发对人体或动物病原体的免疫应答，所述抗原或抗原组合物得自于：HIV-1（如gp120或gp160）、任一种猫免疫缺乏病毒、人或动物疱疹病毒如gD或其衍生物或Immediate    Early蛋白如由HSV1或HSV2得到的IGP27，细胞肥大病毒（特别是人的）如（gB或其衍生物）、Varicella    Zoster    Virus（水痘带状疱疹病毒）（如gPⅠ、Ⅱ或Ⅲ），或者得自于：肝类病毒如乙肝病毒如乙型肝炎表面抗原或其衍生物，肝类A病毒、肝炎C病毒和肝炎E病毒，或者得自于其它病毒病原体，如呼吸合胞体病毒、人类乳头状瘤病毒或流感病毒，或者得自于细菌性病原体如Salmonella（沙门氏菌）、Neisseria（奈瑟菌属）、Borrelia（疏螺旋体属）（如OspA或OspB或其衍生物）或Chlamydia（衣原体属）或Bordetella（博氏杆菌属）如P.69，PT和FHA，或者得自于寄生物如疟原虫或Toxoplasma（弓浆虫属）。
制剂还可以包含一种抗肿瘤抗原并用于免疫疗法治疗癌症。
制剂也可以用于与疱疹性轻颗粒一起使用，这些颗粒在国际专利申请PCT/GB92/00824和PCT/GB92/00179中有述。
乙型肝炎表面抗原衍生物在本领域中是公知的，它们包括在EP-A-414374;EP-A-0304578和EP198474中所述的PreS1，PreS2S抗原。
本发明的另一方面是提供了一种如下所述用于药物的疫苗。
QS21与3D-MPL的比值通常在1∶10～10∶1的数量级，优选1∶5～5∶1，更经常的是1∶1。为了最适宜的协同作用优选的范围是2.5∶1～1∶1    3DMPL∶QS21。对于人体给药，典型地在疫苗中每一个剂量中含QS21和3DMPL1μg～100μg，优选10μg-50μg。通常疫苗无需任何特殊的载体，它们能在水或其它药物可接受的缓冲液中配制。在有些情况下，本发明的疫苗最好还包含有明矾，或者是存在于水包油乳液中或其它适宜的载体中，如脂质体、微球体或包囊的抗原颗粒。
疫苗制剂通常描述在下述文献中：New    Trends        and        Developments        in        Vaccines，由Voller等编辑，University    Park        Press，    Baltimore，        Maryland，U.S.A.1978。在脂质体内的包囊也有述，如Fullerton的US4，235，877。蛋白与大分子的结合也有述，如Likhite的US4，372，945和Armor等的US4，474，757。
在每一疫苗剂量中蛋白的量应使其能诱导免疫保护应答但不会在典型的疫苗中造成显著且有害的副作用。这样的用量根据具体所采用的免疫原和它是如何存在的而改变。一般说来，最好每一剂量包含1-1000μg的蛋白，优选2-100μg，最优选4-40μg。对于特定的疫苗来说，其最适宜的用量可通过标准研究方法进行确定，该方法包括对主体观察其适宜的免疫应答。在开始接种后，主体可以接受一次或几次适当间隔的加强免疫接种。
本发明的制剂可用于预防和治疗。
相应地，本发明的另一个方面是提供一种治疗方法，包括对患者施用有效量的本发明的疫苗。
实施例
1.0        对诱导干扰素γ分泌的3D    MPL和QS21之间的协同作用
为了测定3D MPL和QS21为佐剂的含rgD2t的制剂诱导效应物细胞介导的免疫应答的能力，对几组Balb/c小鼠进行接种，按下述过程对其排液淋巴结细胞的IFN-γ分泌作用进行测试。
1.1 rgD2t制剂
该实验对三种佐剂的制剂进行比较：
ⅰ）在3D-MPL中的rgD2t
ⅱ）在QS21中的rgD2t
ⅲ）在3D-MPL/QS21中rgD2t
这些制剂制备过程如下：由CHO细胞产生rgD2t且相应于成熟的HSV-2gD的1-283氨基酸，按照Berman（Supra）的方法和EP0139417产生。
＊rgD2t/3D-MPL
在搅拌，室温下将5μg rgD2l/剂量培养1小时，然后与3D-MPL悬浮液（25μg/剂量）混合。用氯化钠溶液（5M，PH6.5±0.5）和注射用水调节体积至70μl/剂量得到最后的浓度为0.15M NaCl。PH保持在6.5±0.5。
＊rgD2l/QS21
在搅拌，室温下将5μg rgD2l/剂量培养1小时。用氯化钠溶液（5M，PH6.5±0.5）和注射用水调节其体积至70μl。然后加入QS21（10μg/剂量）。保持PH值为6.5±0.5，氯化钠的最后浓度为0.15M。
＊rgD2l/3D-MPL/QS21
在搅拌和室温下使5μg rgD2t培养1小时。然后加入3D-MPL（25μg/剂量）的水悬浮液。通过添加QS21（10μg/剂量）的水溶液使最后的体积为70μl，并保持PH值为6.5±0.5，氯化钠浓度为0.15M。
1.2免疫接种
用35μl/爪垫的制剂注射于小鼠的后爪垫中。因此，这样每个小鼠接受了70μl。第零天和第14天进行免疫接种，在第21天将小鼠杀死。
1.3干扰素γ测定
在体外使用10、1、0.1、1、0μg/ml的rgD2l来刺激经免疫的小鼠的腘淋巴结细胞。在园底96孔微量滴定（microtiter）极中作用2×105应答细胞和2×105辐照（3000rad）过的同源的首次用来用实验的脾细胞备好一式三份的培养物（200μl体积）。培养介质是含10%胎儿腓血清的RPMI1640。采集并汇集每一种复试验用的100μl培养介质的等分试样以作IFN-γ测定。培养物在72小时时分析测定。对于所有测定，均包括使用5μg/ml的ConA（Boehringer Mannheim）对照组。各组均呈阳性。
使用Holland        Biotechnology（Gibco分部）生产的商用ELISA测定仪测定IFN-γ的分泌。对由一式三份的试样容器得到的100μl汇集的上层清液进行测试。
对所有三种制剂组（见表）观察其以50Pg/μl为实验基准IFN-γ的分泌作用。此外，测得QS21和3D-MPL间的协同效应。虽然每种佐剂自身诱导细胞能分泌IFN-γ对rgD2t作出应答，但它们的组合诱导的应答则比单独每一个应答之和的两倍还多。
1.4结果
Figure 93107990X_IMG1
IFN-γ以pg/ml表示。
该表清楚地表明了组合的疫苗以协同方式诱导IFN-γ的分泌。
2.0    3D-MPL和QS21对CTLs诱导的协同作用
为了测试在基于3D    MPL和QS21的佐剂制剂中的RTS，S颗粒诱导CTLs的能力，对几组B10、BR小鼠进行免疫接种，并在体外刺激它们的脾脏细胞，并对以CS蛋白表示的L细胞的细胞毒性实验进行测试。
2.1RTS，S颗粒的制剂
以三种不同的组成来配制RTS，S颗粒：
1.含QS21（10μg）和3D-MPL（25μg）的RTS，S颗粒（10μg）;
2.含QS21（10μg）的RTS，S颗粒（10μg）;
3.含3DK-MPL（25μg）的RTS，S颗粒（10μg）;
制剂按下述过程制备：
RTS，S/3D        MPL
在室温搅拌下培养10μg的RTS，S颗粒/剂量1小时，然后使其与3D    MPL水悬浮液（25μg/剂量）混合。用注射用水和氯化钠溶液（5N，PH6.5±0.5）调节体积至70μl/剂量，NaCl的最后浓度为0.15M（PH保持在6.5±0.5）。
RTS，S/QS21
在室温搅拌下培养10μg的RTS，S颗粒/剂量1小时。用注射用水和氯化钠溶液（5N，PH6.5±0.5）调节体积，并用QS21的水溶液（10μg/剂量）使最后的体积为70μl/剂量。PH保持在6.5±0.5，氯化钠的最后浓度为0.15M。
RTS，S/3D        MPL/QS21
在室温搅拌下培养10μg的RTS，S颗粒/剂量1小时，然后使其与3D    MPL（水悬浮液（25μg/剂量）混合。然后用注射用水和氯化钠溶液（5N    PH6.5±0.5）调节其体积。最好的体积通过添加QS21的水溶液（10μg/剂量）来完成。PH值保持6.5±0.5，氯化钠的最后浓度为0.15M。
2.2用RTS，S颗粒对小鼠进行免疫接种
从IFFA CREDO（法国）购买4-6周的B10.BR（H-2K）种雌性小鼠。3个为一组对其进行免疫接种，即在每个后肢内爪垫内注射35μl的抗原制剂。两周后，用第二份相同剂量的抗原注射使小鼠加强接种。
2.3对于抗CS    CTL进行体外刺激
被加强后两周，采集脾脏细胞，并用经P.falciparum环子孢子蛋白基因（7G8克隆）转染的同源的成纤维细胞进行体外刺激。这些CS转染子细胞在Kumar，S.等（1988）的文章中有述，Nature    334∶258-260。
在本领域普通技术人员公知的条件下，以补充有10%的热失活的胎儿腓血清的常用的添加剂的RPMI1640介质中确立培养物。
在105CS转染子/ml存在下，以106细胞/ml的浓度对应答细胞进行培养。为了防止CS转染子细胞的再育，用2×104rad的剂量对其进行辐照。在第3天和第6天通过替换1/2的培养介质培育培养物，在第七天测试其细胞溶解活性。
2.4对于抗CS    CTL的细胞毒性实验
对应答细胞培养物进行采集、洗涤，并在200μl介质中在V型底96孔板中使其与常数为2000的靶细胞以100∶1～0.3∶1的比例进行混合。
靶细胞是同源的成纤维细胞，它已用51Cr进行标记。
使用两种不同类型的靶细胞：
1.L细胞
2.CS转染的L细胞
它们在下述文献中有述：Kumar，S等（1988），Nature    334∶258-260。
被化验物在37℃下进行培养6小时。测定经靶细胞的溶胞而释放进入上层清液的放射性量。
以%特异性溶胞来表示细胞溶解活性：结果：
Figure 93107990X_IMG2
用QS21和3D-MPL作佐剂的RTS，S（制剂＃1）对B10.BR小鼠的免疫接种在脾中诱导了对于RTS，S的环子孢子组分特异的高含量的CTL。用QS21作佐剂的RTS，S颗粒（制剂＃2）的免疫接种也能诱导脾中的CTL，但仅仅是制剂＃1所给出的含量的约1/30。用3D-MPL作佐剂的RTS，S（制剂＃3）则不能诱导CTL。
由于用于本实验的靶细胞并不表示MHCⅡ级分子，效应物细胞可被假定为CD8+，Ⅰ级限制的CTL。
3.其它制剂
乙型肝炎表面抗原，明矾3D-MPL和QS21。
乙型肝炎表面抗原（HBsAg）的制备已有许多论述，如可参见Harford等，Develop    Biol    Standard    54    P        125（1983），Gregg等，Biotechnology    5    p479（1987），EP-A-0226846和EP-A-299108，它们均被在此引用作为参考。
3D-MPL由Ribi    Immunochem得到，QS21由Cambridge    Biotech得到，氢氧化铝由Superfos（Alhydrogel）得到。
制备多种不同的制剂用以研究对小鼠的细胞介导的免疫性及对猕猴进行研究。
3.1在磷酸盐缓冲溶液（PH6.8）中制备制剂1，
每60μl剂量的制剂包含：
20μg        HBsAg
30μg Al（OH）3
30μg        3D-MPL
10μg        QS21
10mM PO4 3-
0.15M        NaCl
制剂按下述过程制备，在室温及温和的振荡下使20μg HBsAg剂量与Al（OH）3培养1小时。随后加入3D-MPL和水悬浮液，通过添加QS21、磷酸盐缓冲液和氯化钠完成制剂制备，并在室温下培养1小时。最后的制剂的PH值在6.5-7.0之间，并将其用于小鼠的爪垫研究。
3.2在磷酸盐缓冲溶液（PH6.8）中制备制剂2，每200μl剂量的制剂包含：
1μg        HBsAg
100μg Al（OH）3
50μg        3D-MPL
20μg        QS21
10mM PO4 3-
0.15M        NaCl
制剂按下述过程制备。在室温及温和的振荡下使用HBsAg与Al（OH）3一起培养1小时。通过添加Al（OH）3、3D-MPL的水悬浮液及QS21，用磷酸盐缓冲液和氯化钠溶液完成制剂的制备，并再培养30分钟。制剂的PH值保持在6.5-7.0之间，它用于小鼠的体液免疫性研究。
3.3用类似的方式在磷酸盐缓冲液（PH6.5-7.0）中制备制剂3，每1ml剂量中包含：
10μg            HBsAg
500μg Al（OH）3
50μg        3D-MPL
10μg        QS21
制剂被用于猴的研究。
4结论
两种佐剂QS21和3D-MPL与重组体颗粒性抗原RTS，S的组合能有效地诱导脾脏中CS蛋白特异的CTL。QS21自己增强了CTL的诱导，而3D-MPL则不能诱导。这种组合能以协同的方式起作用，由于其作用大于每种佐剂单独效用之和。两种佐剂对CTL诱导的协同性是一个令人惊奇的实验结果，该结果表明了QS21和3D-MPL对T细胞的诱导具有协同作用，所述T细胞能够分泌IFN-γ以应答对用可溶性重组体蛋白gD2t的刺激。该发现对于使用重组体分子用于诱导CTL介导的免疫的疫苗具有重要意义。这是因为两种佐剂QS21和3D-MPL的组合能够克服基于重组体蛋白的疫苗的严重的局限性，并较之现有的疫苗能在更宽范围内诱导免疫应答。
小鼠细胞介导的免疫原性数据表明，基于QS21的rgD2t制剂诱导了显著的协同性THI型T细胞应答（IFN-γ分泌）。
这种THI型T细胞已表明与诱导小鼠延迟型过敏性应答有关。我们自己的预防HSV疾病的数据表明，中和抗体值和抗原特异性DTH应答的伴随诱导对于抵抗单纯疱疹疾病提供最好的防护。
总之，这些数据向我们表明，rgD2t的QS21制剂可以有效地诱导一种保护性应答以抵抗HSV疾病。所提供的数据还表明了3D单磷酰类酯A（3D Monophosphoryl Lipid A）和QS21对于诱导IFN-γ分泌抗原特异性T细胞具有意外的协同作用。这种协同性可以表现为增强诱导保护性应答以抵抗HSV疾病的能力，而且这些制剂的确可有效地防护抵抗天竺鼠的疾病。

Claims (12)

1、一种疫苗组合物，它包含一种抗原和/或抗原组合物、QS21的3De-O-酰化的单磷酰类脂A(3D-MPL)。
2、一种按权利要求1的疫苗，其中QS21与3D-MPL的比值为1∶10-10∶1。
3、一种权利要求1或2所要求保护的疫苗组合物，能够在哺乳动物中对抗原或抗原组合物引起细胞溶解的T细胞应答。
4、一种按权利要求1-3任一项所要求保护的疫苗组合物，能够刺激干扰素γ生成。
5、一种按权利要求1-4任一项所要求保护的疫苗组合物，其中QS21与3D-MPL的比值为1∶1～1∶2.5。
6、一种按以上权利要求的疫苗组合物，包含一种抗原或抗原组合物，它们得自于下述中的任一种：人体免疫缺乏病毒、猫免疫缺乏病毒、单纯疱疹病毒1型、单纯疱疹病毒2型、人体细胞肥大病毒、肝炎A、B、C或E、呼吸全胞体病毒、人体乳头状瘤病毒、流感病毒、沙门氏菌、奈瑟菌属、疏螺旋体属、衣原体属、博代杆菌属、疟原虫属或弓浆虫属。
7、一种按权利要求1-5中任一项所要求保护的疫苗，其中抗原为一种肿瘤抗原。
8、权利要求1-5任一项所限定的组合物的用途，用于制造一种用于预防治疗病毒、细菌或寄生虫感染的疫苗。
9、权利要求1-5任一项所限定的组合物的用途，用于制造一种用于免疫疗法治疗病毒、细菌、寄生虫感染或癌症的疫苗。
10、一种治疗患有或可能被一种病原感染的哺乳动物的方法，该方法包括施用安全且有效量的权利要求1-5任一项的组合物。
11、一种治疗患有癌症的哺乳动物的方法，该方法包括施用安全且有效量的权利要求1-5任一项的组合物。
12、一种制备权利要求1-5的疫苗组合物的方法，该方法包括使QS21和3D-MPL与一种抗原或抗原组合物混合。
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