CN1289065C - 含有皂苷和固醇的疫苗 - Google Patents

含有皂苷和固醇的疫苗 Download PDF

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CN1289065C
CN1289065C CNB021529787A CN02152978A CN1289065C CN 1289065 C CN1289065 C CN 1289065C CN B021529787 A CNB021529787 A CN B021529787A CN 02152978 A CN02152978 A CN 02152978A CN 1289065 C CN1289065 C CN 1289065C
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纳撒利·M·－J·C·加肯
马丁·弗里德
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Abstract

本发明涉及一种含有抗原，免疫活性的皂苷组分以及固醇的疫苗组合物。

Description

含有皂苷和固醇的疫苗
本申请是于1997年10月23日向中国专利局提交的中国申请号为96193443.3的国际申请(国际申请号为PCT/EP96/01464，国际公开号为WO96/33739)的分案申请。
技术领域
本发明涉及新的疫苗配方及其制备方法和在医学中的应用。本发明特别涉及那些含有一种抗原，一种来源于Quillaja Saponaria Molina树皮的免疫活性组分如QS21，以及一种固醇的疫苗。
背景技术
来源于南美洲的Quillaja Saponaria Molina树皮的免疫活性的皂苷组分具有佐剂的活性是本领域内众所周知的。比如QS21(也称为QA21)，一种HPLC纯化的来源于Quillaja Saponaria Molina树的组分及其制备方法公开于(作为QA21)美国专利5,057,540中。皂树皮皂苷作为佐剂也已由Scott等人披露(Int.Archs.Allergy Appl.Immun.，1985，77，409)。然而，QS21用作佐剂却伴随着某些缺憾。例如，将QS21作为游离分子注射入哺乳动物时，可以发现坏死，也就是说在注射部位发生了局部组织坏死。
现已意外地发现，在注射部位的坏死可以通过使用含有QS21和固醇相组合的制剂而得以避免。优选的固醇包括β-谷固醇，豆固醇，麦角固醇，麦角钙化(固)醇和胆固醇。这些固醇是本领域内众所周知的，比如胆固醇作为一种天然的发现于动物脂肪的固醇见于默克索引(Merck Index)，第11版，341页。
发明内容
因此，本发明的第一个方面是提供一种含有抗原，免疫活性的皂苷组分和固醇的疫苗组合物。本发明的组合物优选地含有大体上纯的免疫活性皂苷组分。本发明的组合物优选地含有大体上纯的QS21，也就是说该QS21是至少90％纯的，优选地是95％纯的而最优选地是98％纯的。其它在本发明的组合物中有用的免疫活性皂苷组分包括QA17/QS17。含有QS21和胆固醇的本发明组合物相比于无胆固醇的组合物表现出了降低的反应原性，而其佐剂的效果却不变。此外，已知该QS21在pH约为7或更高的碱性环境中降解。本发明还有一个优越性是QS21在含有胆固醇的配方中对碱介导的水解的稳定性增强。
本发明优选的组合物是形成了脂质体结构的那些。那些其中的固醇/免疫活性皂苷组分形成了ISCOM结构的组合物也构成了本发明的一个方面。
QS21∶固醇的比率通常为1∶100到1∶1的重量比(W/W)。优选固醇过量存在，而QS21∶固醇的比率至少为1∶2W/W。用于对人类给药的疫苗中，QS21和固醇通常是以每剂量大约1微克到100微克的范围，优选地为大约10微克到50微克的范围存在。
该脂质体优选地含有中性脂，如磷脂酰胆碱，其优选地在室温下是非晶态的，如蛋黄磷脂酰胆碱，二油酰磷脂酰胆碱或二月桂酰磷脂酰胆碱。该脂质体也可以含有带电的脂质，其能提高脂质体-QS21结构(其中的脂质体是由饱和脂所构成的)的稳定性。在这些情况下，该带电的脂质的量优选地为1-20％W/W，最优选地为5-10％。固醇对磷脂的比率为1-50％(mol/mol)，最优选地为20-25％。
本发明的组合物优选地含有MPL(3-脱-氧-酰单磷酰类脂A，也称作3D-MPL)。而作为3种脱-氧-酰化的单磷酰类脂A和4，5或6酰化的链的混合物的3D-MPL见于GB 2220211(Ribi)中并由蒙大拿的Ribi免疫化学公司制备。国际专利申请92/116556公开了一个优选的存在形式。
本发明的合适的组合物是那些其中的脂质体最初是在无MPL下制备，然后，再加入，优选地为100nm的颗粒的MPL。因此，该MPL没有包含在囊泡膜内(称为MPL外)。而那些其中的MPL包含在囊泡膜内的组合物(称为MPL内)也构成了本发明的一个方面。该抗原可以包含于囊泡膜内或外。优选地，可溶性抗原是包含于膜外的而疏水性的或者脂化的抗原则既可以包括于膜外又可以包括于膜内。
本发明的疫苗通常无需任何特殊的载体而可以在水或者其它的药物可接受的缓冲液中配制。在某些情况下可能有益的是本发明的疫苗还可以含有明矾或者存在于水包油的乳剂中，或者其它合适的赋形剂内，如脂质体，微球体或者微囊化的抗原颗粒。
该疫苗配方优选地含有一种能够诱发可以抵抗人类或者动物病原体的免疫反应的抗原或者抗原组合物。在本领域已知的抗原或者抗原组合物可以用于本发明的组合物中，其包括多糖类抗原，源于HIV-1的(如gP120或gP160)，任何猫科动物免疫缺陷病毒，人或动物疮疹病毒，如gD或其衍生物或源于HSVI1或HSV2的直接早期蛋白如ICP27，巨细胞病毒(特别是人)(如gB或其衍生物)，水痘带状疱疹病毒(如gPI，II或III)的抗原或者抗原组合物，或者源于诸如乙肝病毒的肝炎病毒的抗原如乙肝表面抗原或其衍生的甲肝病毒，丙肝病毒和戊肝病毒的抗原或者抗原组合物，或者来源于其它病毒性致病原的抗原，如呼吸道合胞病素(如美国专利5,149,650中公开的HSRV F和G蛋白或其免疫片段或者美国专利5,194,595中公开的含有来源于HSRV蛋白F和G的免疫片段的嵌合多肽，如FG糖蛋白)，来源于脑膜炎菌株如甲，乙和丙型脑膜炎，肺炎链球菌，人乳头瘤病毒，流感病毒，B型流感嗜血杆菌(Hib)，EB病毒(EBV)的抗原，或者来源于细菌性病原如沙门氏菌，疏螺旋体属(例如OspA或OspB或其衍生物)，或者衣原体属，或者博代杆菌属如P.69，PT和FHA的抗原，或者来源于寄生虫如疟原虫属或弓形虫属的抗原。
HSV糖白D(gD)或衍生物是优选的疫苗抗原。其位于病毒膜上，并且也见于感染的细胞的胞质中(Eisenberg R.J.等人；病毒学杂志1980 35 428-435)。其含有包括一个信号肽的393个氨基酸且分子量约为60KD。它可能是所有HSV被膜糖蛋白中特性最优者(Cohen等人，病毒学杂志60 157-166)。已知其在体内对病毒吸附于细胞膜起着重要的作用。此外，糖蛋白D在体内已表现出能诱发中和抗体并防止动物受致命的攻击。平头型的gD分子没有C末端锚形区且能够以可溶蛋白形式在哺乳动物细胞内产生，然后再分泌到该细胞培养的上清液中。该可溶型的gD是优选的。平头型的gD分子的生产见于EP 0139417中。该gD优选地来源于HSV-2。本发明的一个实施例是308个氨基酸平头型HSV-2糖蛋白D，其含有天然糖蛋白中的氨基酸1-306，并在无膜锚形区的平头型蛋白的C末端加入天冬酰胺和谷氨酰胺。此类蛋白包括信号肽，而信号肽裂解后便于该成熟的含有283氨基酸的可溶蛋白从宿主细胞中分泌出来。
在本发明的另一方面，乙肝表面抗原是优选的疫苗抗原。
这里用的“乙肝表面抗原”或者‘HBsAg’一词包括任何HBsAg抗原或其表现出HBV表面抗原的抗原性的片段。可以理解的是，除了该HBsAg抗原的226个氨基酸(见于Tiollais等人，自然，317，489(1985)及其中的参考文献)外，若需要，这里所述的HBsAg可以包括全部的或者部分的上述参考文献及EP-A-0278940中所述的一种前-S序列。特别地，该HBsAg可以包括含有一种氨基酸序列的多肽，该氨基酸序列先后分别包括对应于一种近血清型的乙肝病毒的开放阅读框的HBsAg的L-蛋白的12-52残基、133-145残基、175-400残基(此多肽是指L*；见于EP 0414374)。在本发明的范围内的HBsAg还可以含有EP 0198474(Endotronics)中所述的前-S1-前S2-S多肽或者其严格的如EP 0304578(Mc Cormick和Jones)中所述的类似物。这里所述的HBsAg还能指突变体，比如WO 91/14703或欧洲专利申请0511855 A1中所述‘逃避突变体’，尤其指在其中的145位氨基酸处由精氨酸取代了甘氨酸的HBsAg。
该HBsAg一般是微粒型的。该微粒可以单独含有诸如S蛋白或者是组合微粒，如(L*，S)，其中的L*如上文定义而S则指HBsAg的S-蛋白。该微粒最好是以在酵母中表达的形式。
乙肝表面抗原S-蛋白的制备是有充分的文献报道的。例如见于Harford等人(1983)，发育生物学规范(Develop.Biol.Standard)54，125页，Gregz等人(1987)，生物技术，5，479页，EP 0226846，EP 0299108及其中的参考文献。
在本发明的范围内的配方还可以含有抗-肿瘤抗原并用于肿瘤的免疫治疗。
通常，疫苗的制备见于Voller等人编辑的疫苗新趋势和进展(Park大学出版社，巴尔的摩，马里兰州，美国，1978)。在脂质体中成囊见于诸如Fullerton，美国专利4,235,877中。和蛋白质结合成大分子则公开于诸如Lkhite，美国专利4,372,945和Armor等人的美国专利4,474,757。
将每个疫苗剂量中的蛋白量定为能在常规疫苗中诱发免疫保护反应却不引起明显的副作用的量。此量的变化依赖于使用的具体免疫原以及其存在形式。一般地，所期望的是每个剂量中包含有1-1000微克蛋白，优选地为2-100微克，最优选地为4-40微克。微粒疫苗的最佳量可以通过包括检测实验对象的合适的免疫反应在内的常规研究而确定。初次接种后，受试对象还可以在充分的时间间隔后再接受一次或者几次加强接种。
本发明的配方既可用于预防，又可用于治疗目的。
相应地，本发明还有一个方面就是提供了本发明的疫苗的治疗病人的应用。本发明提供了一个包括对病人给于有效剂量的本发明的疫苗的治疗方法。本发明尤其是提供了一个包括对病人给于有效剂量的本发明的疫苗从而治疗病毒性的，细菌性的，寄生虫性的感染或者肿瘤的方法。
下列实施例和数据阐明了本发明。
附图说明
图1：用含有或者不含有胆固醇的脂质体抑制QS21的比较
图2：将20μg QS21在含胆固醇的SUV存在且pH9，37℃下培育16小时
图3(a)：balb/c小鼠用有QS21存在的gD120足垫注射进行免疫后，测定了脾细胞中胞毒T淋巴细胞的活性。
图3(b)：balb/c小鼠用有QS21+含有胆固醇的SUV存在的gD120足垫注射进行免疫后，测定了脾细胞中胞毒T淋巴细胞的活性。
具体实施方式
1.1制备脂质体的方法
将置于有机溶剂中的脂质(如来源于蛋黄的或者合成的磷脂酰胆碱)和胆固醇的混合物在真空(或者惰性气流)下干燥。然后，加入一种水溶液(如磷酸盐缓冲液)，振荡该容器直止脂质全部进入悬浊液中。然后，将该悬浊液微流化直至该脂质体大小降至100nm，再通过0.2μm的滤器进行无菌过滤。挤压和声处理可以代替该步骤。通常，胆固醇∶磷脂酰胆碱的比率是1∶4(W/W)，加入水溶液使胆固醇的终浓度为5-50mg/ml。如果将包含MPL的有机溶液加入溶于有机溶液的脂质内，那么最终的脂质体在膜内含有MPL(称为MPL内)。
将该脂质体的大小规定为100nm并且是指SUV(小单室囊泡)。如果反复冻融该溶液，那么囊泡融合成大小为500nm至15μm的大的多室结构。该脂质体本身是可以长期稳定的且没有致融能力。
1.2配制步骤
将QS21水溶液加入该脂质体中。然后，将该混合物加入到抗原溶液中，并且若需要，还可以含有呈100nm微粒状的MPL。
1.3含有胆固醇的脂质体抑制QS21的溶解活性
当QS21加入到红细胞中时可以溶解红细胞使其释放血红蛋白。该溶解活性也可以使用含有存在于膜内的胆固醇以及捕获的荧光染料，羧荧光素的脂质体进行检测-当该脂质体被溶解时便释放染料，而该染料又可用荧光分光镜进行检测。若在荧光脂质体的膜内不含胆固醇，那么不会观察到溶解作用。
若在加入到红细胞中之前，将该QS21和含有胆固醇的脂质体共同培育，那么该红细胞的溶解依赖于胆固醇对QS21的比率而降低。若使用的比率为1∶1，则没有检测到溶解活性。如果该脂质体不含胆固醇，则抑制溶解需要比QS21过量1000倍的磷脂。
用荧光脂质体检测溶解活性有同样的结果。在图1中，通过荧光检测了用无胆固醇(每mg/ml蛋黄磷脂酰胆碱)或含有胆固醇(每mg/ml磷脂酰胆碱，500μg胆固醇)的脂质体处理的4μgQS21的溶解活性。
数据显示QS21在膜内以特定的方式和胆固醇结合，从而引起溶解(细胞的或者荧光脂质体的)。如果QS21首先和脂质体中的胆固醇结合，那么不再溶解细胞或其它脂质体。这要求胆固醇：QS21(W/W)的最低比率为0.5∶1。
胆固醇在水溶液中不溶且也不能形成稳定的悬浊液。当有磷脂存在时，该胆固醇存在于磷脂双分子层中并能形成称为脂质体的稳定的囊泡悬浊液。为了避免需要加入磷脂而试验了一个可溶的衍生物。聚氧乙烷胆固醇癸二酸盐在水中的溶解能力达到60mg/ml，然而，既使使用超过QS21 2000倍的量，也没有检测到QS21溶解活性的降低。
1.4含有胆固醇的脂质体增加了QS21的稳定性
QS21在pH约为7的环境中极易水解。该水解作用可以在反相HPLC上通过检测对应于QS21的峰的降低而测定。例如，图2表明在pH9的37℃下，16小时内有90％的QS21被水解。如果在该QS21中以2∶1的比率(胆固醇：QS21W/W)加入含有胆固醇的脂质体，则在同样的条件下没有检测到水解作用。若比率为1∶1，则有10％的QS21被降解。
可以得出结论的是，当QS21和含有胆固醇的脂质体结合时，其变得极不易受碱介导的水解作用。据报道，该水解产物经注射给药，无佐剂活性，因而，含有QS21的疫苗必需在酸性pH中配制并保藏在4℃以维持佐剂组合物。使用脂质体可以避免该项要求。
1.5反应原性研究：
在小鼠胫骨肌注射5μgQS21(或者洋地黄皂苷)和逐步增加量的脂质体(以胆固醇的μg表示)。溶解活性表示为相当于QS21量(μg)，其含义是要达到样品中同样的溶血作用所需的QS21的量。
处死动物后，目测评分注射位点的肌肉的充血，坏死和毒性状况。
  配方   水解活性μg   充血   坏死   毒性
  QS21+PBS   5   +++   ±   +++
  QS21+1μg胆固醇(SUV)   4   +++   +   ++++
  QS21+5μg胆固醇SUV)   0   -   -   ±
  QS21+25μg胆固醇SUV   0   ±   -   +
  单独SUV   0   -   -   -
  洋地黄皂苷   5   -   -   ±
  PBS   0   -   -   -
数据显示当溶解活性由于含有胆固醇的脂质体的加入而消除后，源于QS21的毒性也随之消除。
1.6免肌内反应原性
U.I./L值
  实验   配方   第0天 溶血作用   第1天 溶血作用   第3天 溶血作用
  兔n°1兔n°2兔n°3兔n°4兔n°5 QS21 50μg   107811166605923400   ±   86504648481956627528   152314356846841736
  均值SD   13691160   62611757   1212495
  实验  配方   第0天 溶血作用   第1天 溶血作用   第3天 溶血作用
  兔n°6兔n°7兔n°8兔n°9兔n°10 QS21 50μgSUV内的胆固醇50μg(1∶1)   5965406115211092 ±   16706021873507787   460594803616555
  均值SD   672238   1088636   606125
  实验   配方  第0天 溶血作用   第1天 溶血作用   第3天 溶血作用
  兔n°11兔n°12兔n°13兔n°14兔n°15 QS21 50μgSUV内的胆固醇150μg(1∶3)   3328314645281027   344662356720568   387694519614849
  均值SD   637285   530173   613175
  实验   配方   第0天 溶血作用   第1天 溶血作用   第3天 溶血作用
  兔n°16兔n°17兔n°18兔n°19兔n°20 QS21 50μgSUV内的胆固醇250μg(1∶5)   5404984428223182 ±   7694047178012410   745471(4535)925960
  均值SD   10971175   1020793   775224   (1527)(1692)
  实验   配方   第0天 溶血作用   第1天 溶血作用   第3天 溶血作用
  兔n°21兔n°22兔n°23兔n°24兔n°25 PBS   3216606501395429 ±   290535603(3545)323   378755473(5749)263
  均值SD   691419   438155   (1059)(1396)   467210   (1523)(2369)
数据显示在配方中加入含有胆固醇的脂质体可以显著地降低QS21所致的CPK(肌酸磷酸激酶)升高。由于CPK的升高是肌肉损伤的量度，所以其意味着肌肉损伤的降低且已经组织病毒学证实。
1.7脂质体-QS21的复合物和明矾相结合。
将QS21和含有过量的胆固醇以及放射性胆固醇的中性脂质体一起培育，然后，再和溶于PBS中的明矾(Al(OH)3)一起培育。单独的中性脂质体和QS21都不能和溶于PBS的明矾相结合，而带有负电荷的脂质体也不能。然而，当QS21和中性脂质体一起都可以和明矾相结合。该上清液既不含QS21(苔黑酚试验检测)也不含放射性胆固醇。
这表明QS21已结合于脂质体且允许该脂质体-QS21结合物结合于明矾。这可能产生于由QS21加于该脂质体的负电荷，或者脂质体上的疏水区的暴露。该结果也意味着QS21不能从膜中抽提胆固醇。
这表明本发明的组合物可用于基于明矾的疫苗中，
1.8脂质体样QS21/MPL和游离QS21+MPL的抗体及CMI诱发的比较
用挤压技术制备SUV(EYPC∶胆固醇∶MPL 20∶5∶1)。
对MPL外而言，脂质体在无MPL的条件下制备并再以100nm的微粒态加入MPL。
QS21先于抗原加入。胆固醇∶QS21＝5∶1(W/W)
在抗原加入前，通过3次冻融SUV制备MLV。
对捕获抗原而言，抗原在冻融前加入到SUV中并在冻融后加入QS21.抗原成囊＝5％内，95％外。在小鼠(gD用balb/c，RTSs用BIOBR)的足垫处注射两次。gD是来源于单疱疹病毒的糖蛋白。RTSs是指经过遗传改良而含有一个来源于原生团恶性子孢子的抗原表位的乙肝表面抗原(HBsAg)。
  ag ＝10μgRTSs   强化后15天的抗HBsAg滴度
  配方   IgG1   IgG2a   IgG2b
  SUV/QS+MPL(外)       +Ag   1175   10114   71753
  MLV/QS+MPL(外)       +Ag   2247   11170   41755
  MLV/QS/MPL(内)       +Ag   969   7073   18827
  MLV/QS/MPL(内)/Ag(内)+Ag   1812   2853   9393
  QS+MPL               +Ag   372   9294   44457
                        Ag   ＜100   ＜100   ＜100
  SUV/QS+MPL(外)   ＜100   ＜100   ＜100
  MLV/QS/MPL(内)   ＜100   ＜100   ＜100
  ag＝20μg gD   抗gD   CMI
  配方   IgG   IFN-γ96小时(pg/ml)   IL2 48小时pg/ml
  SUV/QS+MPL(外)      +Ag   2347   1572   960
  SUV/QS/MPL(内)      +Ag   2036   1113   15
  MLV/QS+MPL(外)      +Ag   1578   863   15
  MLV/QS/MPL(内)      +Ag   676   373   15
  MLV/QS/MPL(内)/Ag(内)+Ag   1064   715   15
  QS+MPL              +Ag   1177   764   15
                       Ag   ＜100   567   44
  SUV/QS+MPL(外)   ＜100   181   15
  MLV/QS/MPL(内)   ＜100   814   105
数据显示：SUV/QS+MPL(外)诱导出至少和QS21+MPL相当的高抗体滴度，以及诱导出作为细胞介导免疫标记的IL-2，而抑制QS21的反应原性。
另外，用HSV gD作抗原在balb/c小鼠中对比QS21和有胆固醇(SUV)存在的QS21第二个实验的结果如下：
  配方   抗原  II后第7天IgG(GMT)   I后第14天IgG(GMT)   II后第7天同模标本
  IgG1μg/ml ％   IgG2aμg/ml ％   IgG2bμg/ml ％
  SUV/QS21+MPL外SUV/QS21/MPL内QS21+MPLSUV/QS21+MPL外QS21SUV/QS21   gD(5μg)gD(5μg)gD(5μg)无gD(5μg)gD(5μg)   2029012566105040346811253   1634310731101680413211589   3314182000156484   26443406657   716412285067304   56444802836   22211110701465   171218068
1.9比较分别加上脂质体样的MPL/QS21和游离的MPL/QS21的gD120脂质体＝在膜内含MPL的SUV
胆固醇∶QS21＝6∶1
在一次免疫接种后两周检测反应
  配方   增殖   IFN-gmg/ml   IL2pg/ml   IL5pg/ml
  SUV/MPL/QS21+Ag   12606   16.6   59   476
  MPL+QS21+Ag   16726   15.8   60   404
第二次免疫接种后：
  配方   增殖   IFN-gng/ml  IL4pg/ml   IL5pg/ml
  SUV/MPL/QS21+Ag   12606   135  0   250
  MPL+QS21+Ag   16726   60  0   500
数据显示QS21和含有胆固醇的脂质体以及MPL相结合能诱发出相当于MPL+QS21的Th1/Th0反应。
在此胆固醇对QS21的比率下，QS21对兔子无毒性(用CPK作指标)
在第二个试验中，balb/c小鼠用有QS21或者QS21+含有胆固醇的SUV存在的gD120足垫注射进行免疫。测定了脾细胞中胞毒T淋巴细胞的活性，如图3(a)和图3(b)所示。
这表明单独的QS21诱发CTL活性，而在有含胆固醇的脂质体存在的情况下的QS21至少能诱发出和单独的QS21相当或者更好的CTL活性。
2.疫苗
2.1HBsAgL*，S颗粒的配制
HBsAgL*，S颗粒可如下配制：
将10μg HBsAg L*，S颗粒/剂在室温下搅拌培育一小时。用注射用水和PBS溶液调节该体积并最终用QS21(10μg/剂)的水溶液将体积定为70μl/剂。pH维持在7±0.5。
使用1和50μg HBsAg L*，S可制备类似的配方，并且还可以使用HBsAg S抗原。
这些配方可在旱獭替代治疗模型中用旱獭HBV抗原作模型进行检测。
旱獭模型
DQ QS21(即QS21/胆固醇或抑制的QS21)可在长期注射病毒的旱獭的治疗模型中进行检测。具体的旱獭乙肝病毒疫苗可以和如此的QS21或者DQ混和并且可以带有或者不带MPL，其每月均对动物给药，连续六个月。该疫苗的效应可通过病毒DNA的清除率来评估。
2.2豚鼠模型(HSV)
2.2.1预防模型
将12只为一组的雌Harttey豚鼠用下述配方在零天和第28天肌内注射：
第一次实验：
gD 5μg+QS21 50μg+含50μg胆固醇的SUV
gD 5μg+QS21 100μg+含100μg胆固醇的SUV
gD 5μg+QS21 50μg+含250μg胆固醇的SUV
gD 5μg+QS21 50μg
第二次实验：
gD 5μg+MPL12.5μg+QS21 12.5μg+含62.5μg胆固醇的SUV，或者不处理。
在第二次免疫接种的第14和28天对动物进行放血，测定血清中gD-特异的ELISA抗体滴度。
然后，用105空斑单位(pfu)的HSV-2MS株阴道注射攻击动物。在第4-12天每天对动物进行初期疱疹损伤评估。得分如下：
阴道损伤：
-流血＝0.5
-充血1或2天但没有流血＝0.5
-充血并流血1天＝1
-充血但没有流血且持续至少3天＝1
外部疱疹水疱：
-＜4个小水疱＝2
-＞＝4个小水疱或者一个大水疱4＞＝4个大瘤8融合瘤＝16
-在全部外生殖区的融合大瘤＝32
结果如下表所示：
预防模型
实验1(chol是指含有胆固醇的SUV)
  数量   配方   初期病变
  无损伤的动物百分数(％)   阴道损伤发病率(％)   外部损伤发病率(％)   初期感染系数**   相对于对照组的降低   损伤严重性*
中数 数目
  1211121212   gD/QS21 50μggD/QS21 50μg-chol 1/5gD/QS21 50μg-chol 1/1gD/QS21 50μg-chol 1/1未处理   50641005025   33180330   171801775   7367054996   93％93％100％95％-   1.502.50-0.7555.00   64-69
实验2
  数量   配方   Ab滴度(GMT)   初期病变
  ELISA   中和   无损伤动物％   阴道损伤发病率％   外部损伤发病率％   初次感染系数**   相对于对照组的降低   损伤严重性*
  第二次后14天   第二次后28天   第二次后28天
中数n 数量
  1212   gD/QS21/SUV/MPL未处理   47006＜400   31574＜400   449＜50   58.3316.67   33.338.33   8.3375.00   37.50587.50   94％-   1.0011.50   510
*感染后4-12天内损伤评分的和(无损伤的动物不考虑)
损伤评分：无损伤(0)，阴道损伤(0.5或1)，外部皮肤水疱(2，4，8或16)
**初期感染系数＝和数(最大得分i)×(发病率％)；而i＝0，0.5，1，2，4，8或16
该图表显示出在预防模型中，用gD/MPL/QS21/SUV免疫接种诱发了极高水平的对初期病变的预防保护效应。无论是外部损伤发病率还是损伤的严重性在用gD/MPL/QS21/SUV免疫接种的动物组中均有极大程度的降低。
2.2.2治疗模型
在该治疗模型中，首先用105pfu HSV-2MS株攻击雌性的Hartloy豚鼠。将带有疱疹损伤的动物再进行随机分组，每组16只。
在第21天和42天，用下列配方之一免疫动物：
-gD+MPL50μg+QS21 50μg+含250μg胆固醇的SUV
-gD+Al(OH)3+MPL50μg+QS21 50μg+含有250μg胆固醇的SUV或者不处理。
从第22-75天每天监测动物以评估疾病的复发状况。评分如预防模型中所述。结果如下列图表所示：
治疗模型
  数量   配方   严重性*   持续时间**   发作病例数***
  中数   相对于对照组所降低的百分数(％)   中数   相以于对照组所降低的百分数(％)   中数   相对于对照组所降低的百分数(％)
  161516  gD+MPL+QS21+SUVgD+Al(OH)3+MPL+QS21+SUV未处理   9.008.5015.75   43％46％-   7.007.008.50   18％18％-   3.003.003.50   14％14％-
*感染后第22-75天的损伤得分的和
**感染后第22-75天，实验动物复发损伤的总天数
***感染后第22-75天的复发发作数例数.发作在先且在随后的一天无损伤，其特征是至少有两天的红斑(得分＝0.5)或者一天的外部水疱(得分＞＝2)
免疫治疗在第21天和第42天进行。
该结果表明在HSV-2感染的治疗模型中也能诱导出良好的保护水平。用含或不含明矾的gD/MPL/QS21/SUV免疫对复发疾病的严重性的中位数产生了显著的影响。它也略微降低了发作病例数和持续时间(见表)。

Claims (6)

1.使QS21在碱介导的水解中稳定的方法，包括使QS21与含有固醇的脂质体混合，其中QS2 1与固醇的重量比为1∶1-1∶100。
2.权利要求1的方法，其中QS21与固醇的重量比是至少1∶2。
3.权利要求1的方法，其中QS21与固醇的重量比是在1∶1到1∶5的范围内。
4.权利要求1-3之一的方法，其中OS21是至少90％纯。
5.权利要求4的方法，其中QS21是至少98％纯。
6.权利要求1-5之一的方法，其中固醇是胆固醇。
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AU6987398A (en) 1998-07-23
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KR19990008003A (ko) 1999-01-25
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