CN1296416A - 佐剂组合物 - Google Patents
佐剂组合物 Download PDFInfo
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- CN1296416A CN1296416A CN99804894A CN99804894A CN1296416A CN 1296416 A CN1296416 A CN 1296416A CN 99804894 A CN99804894 A CN 99804894A CN 99804894 A CN99804894 A CN 99804894A CN 1296416 A CN1296416 A CN 1296416A
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- polyoxyethylene
- antigen
- ether
- vaccine combination
- virus
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Abstract
本发明涉及包含聚氧乙烯醚或聚氧乙烯酯和可药用赋形剂的佐剂组合物,和包含所述佐剂组合物与抗原的疫苗。此外,本发明还涉及聚氧乙烯醚或聚氧乙烯酯在制备佐剂制剂和疫苗制剂中的应用,及其作为药物的应用。
Description
本发明涉及包含聚氧乙烯醚或聚氧乙烯酯和可药用赋形剂的佐剂组合物,和包含所述佐剂组合物与抗原的疫苗。此外,本发明还涉及聚氧乙烯醚或聚氧乙烯酯在制备佐剂制剂和疫苗制剂中的应用,及其作为药物的应用。
粘膜接种,例如鼻内和口内接种可代表着容易且比通过系统注射的常规接种更方便的接种途径。采用注射来给予一定剂量疫苗具有很多缺点,即注射后引起注射位点疼痛和刺激。这些因素可导致“针头恐惧”,已知这种“针头恐惧”会导致患者不愿意接种疫苗。此外,常规系统注射可能是导致皮肤穿刺区域感染的根源。
除了绕开注射需求之外,粘膜接种之所以具有吸引力还是因为,据在动物中显示,通过粘膜给予抗原在诱导的粘膜表面的保护反应方面具有更大效力,粘膜表面是多种病原体进入的途径。此外,已经有人提出,粘膜接种例如鼻内接种不仅在鼻粘膜中诱导粘膜免疫,还在远处粘膜位点例如生殖粘膜中诱导粘膜免疫(Mestecky,1987,《临床免疫杂志》(Journal of Clinical Immunology),7,265-276;McGhee和Kiyono,传染媒介和疾病(Infectious Agents andDisease),1993,2,55-73)。
为了使粘膜免疫接种替代通过注射的免疫接种或成为其可供选择的代替途径,该接种途径必须能诱导效力至少与注射诱导的系统免疫反应一样大的系统免疫反应。虽然据报道,当通过该途径接种时有一些抗原能诱导系统反应(Cahill等人,1993,FEMS Microbiology Letters,107,211-216),但是大多数通过鼻内接种的可溶性抗原其自身仅能诱导很小免疫反应或不能诱导任何免疫反应。
有很多作者已经研究了有潜力的粘膜佐剂来克服这个问题,所述粘膜佐剂是通过包括下述机制在内的各种机制来发挥其佐剂活性的:将抗原包封(例如脂质体和微颗粒);或通过与靶细胞直接作用,然后从靶细胞释放免疫刺激性细胞因子(例如霍乱毒素和大肠杆菌热不稳定毒素);或通过增强穿过上皮的抗原摄取(例如霍乱毒素)。
本申请人惊讶地发现,聚氧乙烯醚和聚氧乙烯酯能起疫苗佐剂的作用。本发明佐剂安全、易于灭菌、并便于给予。有利的是,当粘膜给予时,本发明组合物能足以诱导系统免疫反应,其所诱导的系统免疫反应至少与常规注射疫苗后所观察到的系统免疫反应一样高。
Merk索引(12thed:entry 7717)中描述了聚氧乙烯醚例如聚氧乙烯十二烷基醚,其中所指出的治疗应用包括:局部麻醉;抗痒;和硬化剂活性。从类别上看,这些聚氧乙烯醚或聚氧乙烯酯是非离子表面活性剂。
据描述,鼻内给予聚氧乙烯醚和酯可用于增强胰岛素在鼻腔内的吸收(Hirai等人,1981,《国际药剂学杂志》(International Journal ofPharmaceutics),9,165-172;Hirai等人,1981,《国际药剂学杂志》(International Journal of Pharmaceutics),9,173-184)。
其它非离子表面活性剂已用于疫苗制剂。据报道,包含聚氧乙烯蓖麻油或辛酸/癸酸甘油酯与聚氧乙烯脱水山梨醇单酯的混合物以及抗原的疫苗制剂局部施予粘膜后能诱导系统免疫反应(WO 9417827)。该专利申请公开,TWEEN20TM(聚氧乙烯脱水山梨醇单酯)和Imwitor742TM(辛酸/癸酸甘油酯)的组合,或TWEEN20TM与聚氧乙烯蓖麻油的组合能增强鼻内免疫接种后的系统免疫反应。文献中也已经详细描述了该制剂增强对鼻内给予抗原的免疫反应的作用(Gizurarson等人,1996.Vaccine Research,5,69-75;Aggerbeck等人,1997.Vaccine,15,307-316)。
Novasomes(US 5147725)是包封抗原的包含聚氧乙烯醚和胆固醇的paucilamenar囊状结构,并且在系统给予后能增强对抗原的免疫反应。
已经将表面活性剂以这样的方式配制以使之形成非离子表面活性剂囊(通常称为新成体,WO 95/09651)。在胆固醇存在下,这种囊形成能把抗原吸引入内水相或其自身双层的脂双层囊内。
本申请人惊奇地发现,相当低浓度的聚氧乙烯醚或酯能显著地增强对一起给予的抗原的系统免疫反应。此外,当用于粘膜疫苗制剂中时,这些佐剂的增强作用将系统免疫反应提高到与通过常规系统注射抗原所获得的系统免疫反应相等或比其要高的水平。这些分子代表一类适用于人常规系统接种疫苗或替代系统接种的粘膜接种的佐剂。
因为许多可用疫苗佐剂是由于包封抗原而起作用,所以本发明佐剂以非囊性溶液或悬浮液形式所起到的强效疫苗佐剂的作用令人惊奇。因此,本发明的一个实施方案提供了包含式(Ⅰ)表面活性剂的佐剂制剂,其中所述佐剂制剂是以非囊性溶液或悬浮液形式存在的。本发明另一实施方案是不使用胆固醇进行配制的、包含式(Ⅰ)表面活性剂的疫苗佐剂。
本发明疫苗和佐剂制剂包含通式(Ⅰ)分子:
HO(CH2CH2O)n-A-R其中n为1-50,A是一个键或-C(O)-,R是C1-50烷基或苯基C1-50烷基。
本发明一个实施方案是疫苗制剂,所述制剂包含通式(Ⅰ)聚氧乙烯醚,其中n为1-50,优选为4-24,最优选为9;R是C1-50烷基,优选为C4-C20烷基,最优选为C12烷基,且A是一个键。该聚氧乙烯醚的浓度为0.1%-20%,优选为0.1%-10%,最优选为0.1%-1%。优选的聚氧乙烯醚选自:聚氧乙烯-9-十二烷基醚、聚氧乙烯-9-十八烷基醚、聚氧乙烯-8-十八烷基醚、聚氧乙烯-4-十二烷基醚、聚氧乙烯-35-十二烷基醚和聚氧乙烯-23-十二烷基醚。
本发明另一实施方案是疫苗组合物,所述组合物包含通式(Ⅰ)聚氧乙烯酯,其中n为1-50,优选为4-24,最优选为9;R是C1-50烷基,优选为C4-C20烷基,最优选为C12烷基,且A是-C(O)-。该聚氧乙烯酯的浓度为0.1%-20%,优选为0.1%-10%,最优选为0.1%-1%。优选的聚氧乙烯酯选自:聚氧乙烯-9-十二烷基酯、聚氧乙烯-9-十八烷基酯、聚氧乙烯-8-十八烷基酯、聚氧乙烯-4-十二烷基酯、聚氧乙烯-35-十二烷基酯和聚氧乙烯-23-十二烷基酯。
本发明实施方案还有疫苗组合物,所述组合物包含通式(Ⅰ)聚氧乙烯苯基醚,其中n为1-50,优选为4-24,最优选为9;R是C1-50苯基烷基,优选为C4-C20苯基烷基,最优选为C12苯基烷基,且A是一个键。该聚氧乙烯醚的浓度优选为0.1%-10%,最优选为0.25%-1%。
通过粘膜途径,例如口/颊/肠/阴道/直肠或鼻内途径给予后,本发明疫苗制剂可用于保护或治疗易患疾病或患有疾病的哺乳动物。本发明疫苗制剂可以以小滴、喷雾、或干粉形式给予。喷雾或气雾疫苗制剂也构成本发明一部分。肠溶制剂例如耐胃作用的口服胶囊或颗粒、直肠或阴道给予的栓剂也构成本发明一部分。本发明还可用于增强施用在皮肤上(透皮或经皮给予途径)的抗原的免疫原性。此外,本发明佐剂可非胃肠道递送,例如肌内或皮下给予,其特征在于所述佐剂不呈囊形式。
在本发明优选的实施方案中,本发明提供了用于粘膜疫苗制剂的佐剂。所述佐剂在人体内能很好地耐受,并且能强有力地诱导系统免疫反应。本发明佐剂可呈溶液、或非囊性溶液或悬浮液剂型,其本身没有任何与生产、稳定性、均匀性、以及颗粒状佐剂系统的质量控制有关的问题。这些制剂是强效佐剂,并且还表现出低的反应原性,以及能被患者很好地耐受。
本发明聚氧乙烯醚优选具有溶血活性。可按照下述分析方法体外测定聚氧乙烯醚的溶血活性,其活性以不能引起红细胞溶解的去污剂最高浓度表示:
1.在台式离心机中将取自豚鼠的新鲜血液用磷酸盐缓冲盐水(PBS)洗涤3次。重悬至初体积后,用PBS将血液稀释10倍。
2.将50μl该血液悬浮液加到含有2倍稀释的去污剂的800μl PBS中。
3.8小时后,凭视力评定溶血,或者通过测定上清液的光密度评定溶血。在570nm有吸收光的红色上清液的存在表明发生了溶血。
4.结果以不再发生溶血的最初去污剂稀释液的浓度表示。
在这种生物分析的固有实验变异内,本发明聚氧乙烯醚或通式(Ⅰ)表面活性剂优选具有约0.5%-0.0001%、更优选0.05%-0.0001%、甚至更优选0.005%-0.0001%、最优选0.003%-0.0004%的溶血活性。理想的情况是,所述聚氧乙烯醚或酯应当具有与聚氧乙烯-9-十二烷基醚或聚氧乙烯-8-十八烷基醚的溶血活性相类似(即差别在10倍范围内)的溶血活性。
在表面活性剂中,聚氧乙烯片段长度与烷基链长度的比例(即n:烷基链长的比例)影响这类去污剂在水介质中的溶解度。因此,本发明佐剂可以呈溶液形式,或者可以形成颗粒结构例如微团。由于其非囊特性,本发明佐剂是澄清的,不是混浊或不透明的,是稳定的,并且易于通过220nm膜过滤来灭菌,以及能以容易且可控方式生产。
本发明疫苗可呈非囊性溶液或悬浮液形式,其中包含在可药用赋形剂例如PBS和水中的通式(Ⅰ)聚氧乙烯醚或酯和抗原或抗原制备物。在初次或强化接种中,可将本发明疫苗制剂施用在哺乳动物粘膜表面上;或者可系统给予本发明疫苗制剂,例如通过透皮、皮下或肌内途径给予。
已知能增强粘膜和系统免疫反应的其它佐剂包括源自霍乱和大肠杆茵的细菌肠毒素(即分别是霍乱毒素(CT)、和热不稳定肠毒素(LT))。CT和LT是由支撑毒性A亚单位的β-亚单位五聚环构成的异二聚物。其结构和生物活性公开在Clements和Finklestein,1979,《感染和免疫》(Infecion and Immunity),24:760-769;Clements等人,1980,《感染和免疫》(Infecion and Immunity),24:91-97中。最近已经开发出了LT的非毒性衍生物,其缺少一旦从细胞中释放出来即使LT非毒性形式“接通”变成其毒性形式所需的蛋白水解位点。这种形式的LT(称为mLT(R192G))通过192位氨基酸精氨酸被甘氨酸取代而被不易于发生蛋白水解裂解,并且据显示其毒性有很大降低,同时还保留着其强有力的佐剂活性。因此,mLT(R192G)被称为蛋白水解位点突变体。专利申请WO 96/06627中公开了制备mLT(R192G)的方法。其它LT突变体包括活性位点突变体例如mLT(A69G),其在LTA序列的69位包含取代了丙氨酸的甘氨酸。专利申请WO 96/06627中描述了mLT(R192G)作为粘膜疫苗的应用。这种佐剂可有利地与本发明非离子表面活性剂联合使用。
因此,在本发明另一实施方案中,将聚氧乙烯醚或酯与其它佐剂或免疫刺激剂联合使用,所述其它佐剂或免疫刺激剂包括霍乱毒素及其B亚单位,单磷酰脂A及其非毒性衍生物3-去-O-乙酰化单磷酰脂A(如在第GB 2220211号UK专利中所述的),皂甙例如Quil A(源自南美洲树Quillaja Saponaria Molina),和它们的分离部分,包括QS21和QS17(US 5057540;Kensil,C.R.,Crit Rev Ther Drug Carrier Syst,1996,12(1-2):1-55;EP 0362279B1;Kensil等人,1991.J.Immunologyvol 146,431-437;WO 99/10008),和含有未甲基化CpG二核苷酸的寡聚核苷酸佐剂系统(如WO 96/02555所述)。特别优选与POE联合使用的免疫刺激剂是CpG免疫刺激性寡聚核苷酸,其制剂能在较大动物中强有力地诱导和增强免疫反应。优选的寡聚核苷酸具有下述序列:这些序列优选含有全二硫代磷酸酯修饰的核苷酸间连接。
OLIGO 1:TCC ATG ACG TT6 CTG ACG TT
OLIGO 2:TCT CCC AGC GTG CGC CAT
OLIGO 3:ACC GAT GAC GTC GCC GGT GAC GGC ACC ACG
在本发明中使用的CpG寡聚核苷酸可通过本领域已知方法(例如EP468520)合成。可使用自动合成仪方便地合成这种寡聚核苷酸。
或者,可将聚氧乙烯醚或酯与由脱乙酰壳多糖或其它多阳离子聚合物组成的疫苗载体,聚交酯、聚交酯-共-乙交酯颗粒,由多糖或化学修饰多糖组成的颗粒,不含胆固醇的脂质体和以脂质为基质的颗粒,水包油乳液(WO 95/17210),由一甘油酯组成的颗粒等联合使用。还可将聚氧乙烯醚或酯与粉状赋形剂例如可作为干粉给予的含有抗原的乳糖混合在一起。
本发明佐剂包含表面活性剂:聚氧乙烯醚或酯,其中所述聚氧乙烯醚或酯不以囊形式存在。因此,本发明包括通式(Ⅰ)聚氧乙烯醚和酯在制备佐剂组合物和疫苗中的应用,其中通式(Ⅰ)表面活性剂不以囊形式存在。
本发明疫苗制剂优选含有能引起抗人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源自HⅣ-1(例如tat、nef、gp120或gp160),人疱疹病毒,例如gD或其衍生物、或源自HSV1或HSV2的立即早期蛋白例如ICP27,巨细胞病毒(尤其是人巨细胞病毒)(例如gB或其衍生物),轮状病毒(包括减毒活病毒),EB病毒(例如gp350或其衍生物),水痘-带状疱疹病毒(例如gpⅠ、gpⅡ和IE63),或源自肝炎病毒,例如乙型肝炎病毒(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,或源自其它病毒病原体,例如副粘病毒:呼吸道合胞体病毒(例如F和G蛋白或其衍生物),副流感病毒、麻疹病毒、流行性腮腺炎病毒、人乳头状瘤病毒(如HPV6、11、16、18,…)黄病毒(例如黄热病病毒、登革热病毒、蜱传脑炎病毒、日本脑炎病毒)或流感病毒(全活或灭活病毒、生长在鸡蛋或MDCK细胞中的分裂流感病毒、Vero细胞或全流感病毒体(如R Gluck,Vaccine,1992,10,915-920所述)或其纯化或重组蛋白,例如HA、NP、NA、或M蛋白、或它们的组合体),或者源自细菌病原体例如奈瑟氏球菌属(Neisseria spp.)细菌,包括淋病奈瑟氏球菌(N.gonorrhea)和脑膜炎奈瑟氏球菌(N.meningitidis)(例如荚膜多糖及其结合物、转铁蛋白结合蛋白、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、脂磷壁酸)、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(Moraxella spp.)细菌,包括粘膜炎莫拉氏菌(M.cartarrhalis),其也称为粘膜炎布兰汉氏菌(Branhamellacatarrhalis)(例如高分子量和低分子量粘附素和侵染素);博德氏菌属(Bordetella spp.)细菌,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、丝状血球凝集素、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(Mycobacterium spp.)细菌,包括结核分枝杆菌(M.tuberculosis)(例如ESAT6、抗原85A、抗原85B或抗原85C)、牛分枝杆菌(M.bovis)、麻风分枝杆菌(M.leprae)、鸟分枝杆茵(M.avium)、副结核分枝杆菌(M.paratuberculosis)、耻垢分枝杆菌(M.smegmatis);军团菌属(Legionella spp.)细菌,包括嗜肺军团菌(L.pneumophila);埃希氏茵属(Escherichia spp.)细茵,包括肠毒性大肠杆菌(enterotoxicE.coli)(例如定居因子、热不稳定毒素或其衍生物、热稳定性毒素或其衍生物)、肠出血性大肠杆菌(enterohemorragic E.coli)、肠致病性大肠杆菌(enteropathogenic E.coli)(例如志贺样毒素或其衍生物);弧菌属(Vibrio spp.)细菌,包括霍乱弧菌(V.cholera)(例如霍乱毒素或其衍生物);志贺氏菌属(Shigella spp.)细菌,包括索氏志贺氏菌(S.sonnei)、痢疾志贺氏菌(S.dysenteriae)、弗氏志贺氏菌(S.flexnerii);耶尔森氏菌属(Yersinia spp.)细菌,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(Campylobacter spp.)细菌,包括空肠弯曲杆菌(C.jejuni)(例如毒素、粘附素和侵染素)和大肠弯曲杆菌(C.coli);沙门氏菌属(Salmonella ssp.)细菌,包括伤寒沙门氏菌(S.trphi)、副伤寒沙门氏菌(S.paratyphi)、猪霍乱沙门氏菌(S.choleraesuis)、肠炎沙门氏菌(S.enteritidis);利斯特氏菌属(Listeria spp.)细菌,包括单核细胞增生利斯特氏菌(L.monocytogenes);螺杆菌属(Helicobacter spp.)细菌,包括幽门螺杆菌(H.pylori)(例如脲酶、过氧化氢酶、空泡毒素);假单胞菌属(Pseudomonas spp.)细菌,包括铜绿假单胞菌(P.aeruginosa);葡萄球菌属(Staphylococcusspp.)细菌,包括金黄色葡萄球菌(S.aureus)、表皮葡萄球菌(S.epidermidis);肠球菌属(Enterococcus spp.)细菌,包括粪肠球菌(E.faecalis)、屎肠球菌(E.faecium);梭菌属(Clostridium spp.)细菌,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)(例如梭状芽胞杆菌毒素A或B及其衍生物);芽孢杆菌属(Bacillus spp.)细菌,包括炭疽芽孢杆菌(B.anthracis)(例如梭状芽胞杆菌毒素及其衍生物);棒杆菌属(Corynebacterium spp.)细菌,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(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(Ehrlichia spp.),包括马埃里希氏体(E.equi)和Human Granulocytic Ehrlichiosis的介质;立克次氏体属(Rickettsia spp.),包括立氏立克次氏体(R.rickettsii);衣原体属(Chlamydia spp.),包括砂眼衣原体(C.trachomatis)(例如MOMP、肝素结合蛋白)、肺炎衣原体(C.Dneumoniae)(例如MOMP、肝素结合蛋白)、鹦鹉衣原体(C.psittaci);钩端螺旋体属(Leptospira spp.),包括问号钩端螺旋体(L.interrogans);密螺旋体属(Treponema spp.),包括苍白密螺旋体(T.pallidum)(例如罕见膜外蛋白)、齿垢密螺旋体(T.denticola)、猪痢疾密螺旋体(T.hyodysenteriae);或源自寄生虫,例如疟原虫属(Plasmodium spp.),包括恶性疟原虫(P.falciparum);弓形体属(Toxoplasma spp.),包括鼠弓形体(T.gondii)(例如SAG2、SAG3、Tg34);内阿米巴属(Entamoeba spp.),包括溶组织内阿米巴(E.histolytica);巴贝虫属(Babesia spp.),包括B.microti;锥虫属(Trypanosoma spp.),包括克氏锥虫(T.cruzi);贾第虫属(Giardiaspp.),包括兰伯氏贾第虫(G.lamblia);leshmania spp.,包括L.major;肺囊虫属(Pneumocystis spp.),包括卡氏肺囊虫(P.carinii);毛滴虫属(Trichomonas spp.),包括阴道毛滴虫(T.vaginalis);Schisostoma spp.,包括S.mansoni,或者源自酵母菌,例如念珠菌属(Candida spp.),包括白色念珠菌(C.albicans);隐球菌属(Cryptococcus spp.),包括新型隐球菌(C.neoformans)。
优选的细菌疫苗含有源自链球菌属、包括肺炎链球菌的抗原(例如荚膜多糖及其结合物、PsaA、PspA、链球菌溶血素、胆碱结合蛋白),和蛋白抗原肺炎球菌自溶酶(Biochem Biophys Acta,1987,67,1007;Rubins等人,Microbial Pathogenesis,25,337-342),以及它们的突变解毒衍生物(WO 90/06951;WO99/03884)。其它优选的细菌疫苗包含源自嗜血属(Haemophilus spp.)的抗原,包括B型流感嗜血菌(H.influenzae type B)(例如PRP及其结合物)、不可分型的流感嗜血菌(non typeable H.influenzae),例如OMP26、高分子量粘附素、P5、P6、蛋白D和脂蛋白D、和丝束蛋白以及丝束蛋白衍生肽(US 5843464)或它们的多拷贝变种或融合蛋白。其它优选的细菌疫苗包含源自粘膜炎莫拉氏菌(Moraxella Catarrhalis)的抗原(包括其膜外小泡、和OMP106(WO97/41731))和源自脑膜炎奈瑟氏球菌B(Neisseria mengitidis B)的抗原(包括其膜外小泡、和NspA(WO 96/29412))。
乙型肝炎表面抗原衍生物是本领域众所周知的,并尤其包括在欧洲专利申请EP-A-414374、EP-A-0304578和EP 198-474中描述的PreSl、PreS2 S抗原。在一个优选的方面,本发明疫苗制剂包含HⅣ-1抗原,gpl20,尤其是在CHO细胞中表达的gp120。在另一实施方案中,本发明疫苗制剂包含如上所述的gD2t。
在优选的实施方案中,含有本发明佐剂的本发明疫苗包含源自导致生殖器瘤的人乳头瘤病毒(HPV)的抗原(HPV 6或HPV 11等),和源自导致子宫颈癌的HPV病毒的抗原(HPV 16或HPV 18等)。
特别优选的生殖器瘤预防或治疗疫苗包含L1颗粒或壳粒、和含有一种或多种选自HPV 6和HPV 11蛋白E6、E7、L1和L2的抗原的融合蛋白。
最优选的融合蛋白是:如WO 96/26277所公开的L2E7和在GB9717953.5(PCT/EP98/05285)中公开的蛋白D(1/3)-E7。
优选的HPV子宫颈感染或癌预防或治疗疫苗组合物可含有HPV 18或HPV18抗原。例如L1或L2抗原单体、或作为病毒样颗粒(VLP)一起存在的L1或L2抗原、或单独在VLP或壳粒结构中存在的L1蛋白。这些抗原、病毒样颗粒和壳粒本身是已知的。参见例如WO 94/00152、WO94/20137、WO 94/05792和WO 93/021 84。
可包括单独或作为融合蛋白形式的其它早期蛋白,例如E7、E2或E5;在本发明特别优选的实施方案中,包括含有L1E7融合蛋白的VLP(WO96/11272)。
特别优选的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HPV 16的蛋白D-E6或D-E7融合蛋白,或其组合体;或E6或E7与L2的组合体(WO 96/26277)。
或者HPV 16或18早期蛋白E6和E7可存在于单一分子中,优选存在于蛋白D-E6/E7融合蛋白中。这种疫苗可任选含有HPV18的E6或E7蛋白或者E6和E7蛋白,优选呈蛋白D-E6或蛋白D-E7融合蛋白或者蛋白D-E6/E7融合蛋白形式。
本发明疫苗还可包含源自其它HPV株的抗原,优选来自HPV 6、11、31、33、或45株的抗原。
本发明疫苗还可包含源自引起疟疾的寄生虫的抗原。例如,源自恶性疟原虫的优选抗原包括RTS,S和TRAP。RTS是杂合蛋白,其基本上包含恶性疟原虫环子孢子(CS)蛋白的所有C-末端部分,所述CS蛋白的C-末端部分是通过乙型肝炎表面抗原preS2的4个氨基酸连接到乙型肝炎病毒表面(S)抗原上。公开号为WO 93/10152、并且要求第9124390.7号UK专利申请的优先权的国际专利申请PCT/EP92/02591公开了其全部结构。当在酵母中表达时,RTS是作为脂蛋白颗粒生成的,当与源自HBV的S抗原一起表达时,其会生成称为RTS,S的混合颗粒。公开号为WO 90/01496的国际专利申请PCT/GB89/00895中描述了TRAP抗原。本发明优选的实施方案是疟疾疫苗,其中所述抗原制剂包含RTS,S和TRAP的组合物。可作为多阶段疟疾疫苗组分的其它疟原虫抗原是恶性疟原虫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及它们的疟原虫属类似物。
本发明疫苗制剂还可含有抗肿瘤抗原,并可用于免疫治疗癌症。例如,佐剂制剂可以与肿瘤排斥抗原一起使用来增强其作用,例如排斥前列腺癌、乳腺癌、结直肠癌、肺癌、胰腺癌、肾癌或黑素瘤癌的抗原。这种抗原的实例包括用于治疗黑素瘤的MAGE1和MAGE3或其它MAGE抗原,PARME、BAGE或GAGE(Robbins和Kawakami,1996,Current Opinionsin Immunology 8,pps 628-636;Van den Eynde等人,InternationalJournal of Clinical & Laboratory Research(submitted 1997);Correale等人(1997),Journal of the National Cancer Institute 89,p293)。实际上,这些抗原是在很多种肿瘤例如黑素瘤、肺肿瘤、肉瘤和膀胱肿瘤中表达的。其它肿瘤特异性抗原也适于和本发明佐剂一起使用,其包括但不限于前列腺特异性抗原(PSA)或Her-2/neu、KSA(GA733)、MUC-1和癌胚抗原(CEA)。因此,在本发明一个方面,本发明提供了包含本发明佐剂组合物和肿瘤排斥抗原的疫苗。
此外,所述抗原可以是自身肽激素,例如全长度的促性腺素释放激素(GnRH,WO 95/20600),其是长度为10个氨基酸的短肽,可用于治疗多种癌症或用于免疫修正。
可以预计,本发明组合物可用于配制含有源自疏螺旋体属的抗原的疫苗。例如,抗原可包括核酸、病原体衍生抗原或抗原制备物、重组制得的蛋白或肽、和化学融合蛋白。抗原尤其是OspA。OspA可以是由于宿主细胞(大肠杆菌)所致的脂化形式的全成熟蛋白(称为Lipo-OspA)或非脂化衍生物。这种非脂化衍生物包括非脂化NS1-OspA融合蛋白,其具有流感病毒非结构蛋白(NS1)的前81个N-末端氨基酸、和全OspA蛋白,另一MDP-OspA是携带3个另外N-末端氨基酸的非脂化形式的OspA。
本发明疫苗可用于预防或治疗变态反应。这种疫苗包含变应原特异性抗原(例如Derpl)和变应原非特异性抗原(例如衍生自人IgE的肽,包括但不限于stanworth十肽(EP 0477231 B1))。
每剂疫苗中蛋白的量应当选取为,对于一般的疫苗能诱导免疫保护反应、同时没有显著的不利副作用。蛋白的量将随所用的具体免疫原及其存在形式的不同而不同。每剂疫苗中通常含有1-1000μg、优选1-500μg、更优选1-100μg、最优选1-50μg蛋白。可通过包括观察接种个体中适当免疫反应在内的标准实验来确定最佳量。初次接种后,接种个体可接受适当间隔的一次或多次强化免疫接种。
可以预计,本发明组合物可用于配制含有具有不同来源的抗原的疫苗。例如,抗原可包括人、细菌、或病毒核酸、病原体衍生抗原或抗原制备物、肿瘤衍生抗原或抗原制备物、宿主衍生抗原包括GnRH和IgE肽、重组制得的蛋白或肽、和化学融合蛋白。
本发明疫苗可通过口服途径给予。在这种情况下,可药用赋形剂可还包括碱性缓冲剂、或肠溶胶囊或微胶囊。本发明疫苗还可通过阴道途径给予。在这种情况下,可药用赋形剂可还包括乳化剂、聚合物例如CARBOPOL、以及阴道用霜剂和栓剂的其它已知稳定剂。本发明疫苗还可通过直肠途径给予。在这种情况下,可药用赋形剂可还包括本领域内用于形成直肠用栓剂的已知蜡和聚合物。
本发明制剂既可用于预防目的,也可用于治疗目的。因此,本发明提供了治疗易患有或患有传染性疾病或癌症或变态反应或自身免疫性疾病的哺乳动物的方法。另一方面,本发明提供了如本说明书所述用于医药的疫苗。《疫苗新趋势和开发》(New Trends and Developments inVaccines),Voller等人编辑,University Park Press,Baltimore,Maryland,U.S.A.1978中对疫苗制剂作了一般性描述。
本发明涉及通式(Ⅰ)聚氧乙烯醚或酯在制备含有通式(Ⅰ)表面活性剂和可药用赋形剂的佐剂制剂中的应用。本发明涉及通式(Ⅰ)聚氧乙烯醚或酯在制备含有通式(Ⅰ)表面活性剂和可药用赋形剂以及抗原的疫苗制剂中的应用。本发明还涉及通式(Ⅰ)聚氧乙烯醚或酯在制备不含有胆固醇的上述佐剂制剂或疫苗制剂中的应用。本发明还提供了通式(Ⅰ)聚氧乙烯醚或酯在制备上述佐剂制剂或疫苗制剂中的应用,其中所述制剂是非囊性溶液或悬浮液。
适当可药用赋形剂的实例包括水、磷酸盐缓冲盐水、等渗缓冲溶液。
CAS登记名册中公开了聚氧乙烯十二烷基醚的可替代术语或名称。聚氧乙烯十二烷基醚的CAS登记号为CAS REGISTRY NUMBER:9002-92-0。
下述实施例举例说明本发明,但不是对本发明的限制。
实施例1:用于测定抗原特异性抗体(Ab)反应的技术
用于测定OspA-特异性血清IgG的ELISA:
在4℃,用1μg/ml在PBS中稀释的抗原OspA以50μl/孔的量(平板的B-H排)或5μg/ml在PBS中稀释的纯化山羊抗鼠Ig(Boerhinger)以50μl/孔的量(平板的A排)将Maxisorp Nunc免疫平板过夜包被。用饱和缓冲液将该平板上的空余位点阻断(1小时、37℃),所述缓冲液为含有1%BSA、0.1%聚氧乙烯脱水山梨醇一月桂酸酯(TWEEN 20)、和4%正常牛血清(NBS)的PBS。然后,将加入的用于制作标准曲线的、在饱和缓冲液(50μl/孔)中稀释的、IgG同种型混合物的连续2倍稀释物(在饱和缓冲液中,50μl/孔)(得自Sigma的鼠单克隆抗体IgG1、IgG2a和IgG2b的混合物,初始浓度为200ng/ml,置于A排中)和血清样本(初始为1/100稀释,置于B-H排)在37℃培养1.5小时。然后将平板用洗涤缓冲液(PBS,0.1%聚氧乙烯脱水山梨醇一月桂酸酯(TWEEN 20))洗涤(×3)。之后把在饱和缓冲液中稀释1/5000的生物素化的山羊抗鼠IgG(Amersham)在37℃培养(50μl/孔)1.5小时。洗涤3次后,加入氯霉抗生物素蛋白-辣根过氧化物酶结合物(Amersham),将平板洗涤5次,与50μl/孔显示缓冲液(含有0.4mg/mlOPDA(Sigma)和0.03%H2O2的50mM pH4.5柠檬酸缓冲液)一起在室温培养20分钟。通过加入50μl/孔的2N硫酸来中止显示。用Biorad3550免疫读取器在492和630nm读取光密度。使用SoftMaxPro软件通过4参数数学方法计算抗体效价。
采用类似技术,通过用TT、FHA或全流感抗原替换OspA包被抗原来测定抗-TT、抗-FHA和抗流感的IgE效价。TT是商购获得的(Behring)。FHA是按照在EP 0427462中描述的方法制备和纯化的。用β-丙醇酸内酯(BPL)灭活的全流感病毒是由SSD GmBH(DresdenGermany)提供的。
用于测定小鼠肺炎链球菌多糖(PS14和PS19)-特异性血清IgG的ELISA:
在37℃,用在PBS中稀释的5μg/ml(PS14)或20μg/ml(PS19)抗原以100μl/孔的量将Maxisorp Nunc免疫平板包被2小时。然后将平板用洗涤缓冲液(含有0.1%聚氧乙烯脱水山梨醇一月桂酸酯(TWEEN20)的PBS)洗涤(×3)。之后,将加入的用于制作标准曲线的PS14或PS19-特异性单克隆Ab(mAb)IgG1的连续2倍稀释物(在PBS TWEEN20中稀释,100μl/孔)(对于PS14初始浓度为785ng/ml,对于PS19初始浓度为2040ng/ml,置于A排中)和血清样本(初始为1/20稀释,置于B-H排)在20℃培养30分钟。在加入并在平板上稀释之前,用普通多糖(CPS)将mAb标准物和血清样本在37℃预培养1小时,以消除非特异性反应。然后将平板用洗涤缓冲液(PBS TWEEN 20)洗涤(×3)。之后把在PBS TWEEN 20中稀释1/5000的结合有过氧化物酶的山羊抗鼠IgG(Jackson)在搅拌下于20℃培养(100μl/孔)30分钟。洗涤3次后,将平板与100μl/孔显示缓冲液(含有0.4mg/ml OPDA(Sigma)和0.03%H2O2的50mM pH4.5柠檬酸缓冲液)一起在室温培养15分钟。通过加入50μl/孔的1N盐酸来中止显示。用Biorad 3550免疫读取器在492和630nm读取光密度。使用SoftMaxPro软件通过4参数数学方法计算抗体效价。
用于测定猴OspA-特异性血清Ig Abs的ELISA:
在4℃,用1μg/ml在PBS中稀释的OspA以50μl/孔的量将MaxisorpNunc免疫平板过夜包被。用饱和缓冲液将该平板上的空余位点阻断(1小时、37℃),所述缓冲液为含有1%BSA、0.1%聚氧乙烯脱水山梨醇一月桂酸酯(TWEEN 20)的PBS。然后将加入的用于制作标准曲线的参照血清的连续2倍稀释物(用饱和缓冲液稀释,50μl/孔)(中间效价为60000 ELISA单位/ml的血清,初始浓度为12 EU/ml,置于A排中)和血清样本(初始为1/100稀释,置于B-H排)在37℃培养1.5小时。然后将平板用洗涤缓冲液(PBS,0.1%聚氧乙烯脱水山梨醇一月桂酸酯(TWEEN 20))洗涤(×3)。之后将在饱和缓冲液中稀释1/3000的生物素化的山羊抗鼠IgG(Amersham)在37℃培养(50μl/孔)1.5小时。洗涤3次后,加入氯霉抗生物素蛋白-辣根过氧化物酶结合物(Amersham),将平板洗涤5次,与50μl/孔显示缓冲液(含有0.4mg/mlOPDA(Sigma)和0.03%H2O2的50mM pH4.5柠檬酸缓冲液)一起在室温培养20分钟。通过加入50μl/孔的2N硫酸来中止显示。用Biorad3550免疫读取器在492和630nm读取光密度。使用SoftMaxPro软件通过4参数数学方法计算抗体效价。
采用类似技术,通过用由SSD GmBH(Dresden Germany)提供的、用β-丙醇酸内酯(BPL)灭活的全流感抗原替换OspA包被抗原来测定抗流感免疫球蛋白效价。
用于测定猴OspA-特异性鼻IgA Abs的ELISA:
在4℃,用1μg/ml在PBS中稀释的OspA以50 μl/孔的量(置于平板的B-H排)或者5μg/ml在PBS中稀释的纯化山羊抗-人IgA(Sigma)以50μl/孔的量(置于平板的A排)将Maxisorp Nunc免疫平板过夜包被。用饱和缓冲液将该平板上的空余位点阻断(1小时、37℃),所述缓冲液为含有1%BSA、0.1%聚氧乙烯脱水山梨醇一月桂酸酯(TWEEN 20)和4%正常牛血清(NBS)的PBS。然后将加入的用于制作标准曲线的参照分泌物的连续2倍稀释物(用饱和缓冲液稀释,50μl/孔)(中间效价为3000 ELISA单位/ml的分泌物,初始浓度为30 EU/ml,置于A排中)和鼻拭子(初始为1/5稀释,置于B-H排)在22℃培养2小时。然后将平板用洗涤缓冲液(PBS,0.1%聚氧乙烯脱水山梨醇一月桂酸酯(TWEEN 20))洗涤(×3)。之后将在饱和缓冲液中的0.2μg/ml生物素化的山羊抗-人IgA(ICN)在37℃培养(50μl/孔)1.5小时。洗涤3次后,加入氯霉抗生物素蛋白-辣根过氧化物酶结合物(Amersham),将平板洗涤5次,与50μl/孔显示缓冲液(TBM,Biorad)一起在室温培养10分钟。通过加入50μl/孔的0.4N硫酸来中止显示。用Biorad 3550免疫读取器在450和630nm读取光密度。使用SoftMaxPro软件通过4参数数学方法计算抗体效价。当样本IgA效价超过该分析的截距(0.3 EU/ml)时,则认为其为阳性。
用于测定血清LA2-样抗体对lipo-OspA的效价的抑制分析
测定疫苗在其LA2-样特异性方面的抗体效价。LA2是能识别细菌表面的OspA表位的鼠单克隆抗体,据表明其能在体外杀死Bburgdorferi,以及保护小鼠抗实验室生长的螺旋体的攻击(Schaible等人。1990.Proc Natl Acad Sci USA 87:3768-3772)。此外,据表明LA-2 mab与细菌抗体有关,并且对人血清的实验表明,在总的抗-OspA IgG效价和LA-2效价(通过ELISA测定的)之间有很好相关性。
在4℃用50μl/孔在PBS中稀释的0.5μg/ml lipo-OspA将Maxisorp Nunc免疫平板过夜包被。在37℃用饱和缓冲液(100μl/孔饱和缓冲液:PBS/BSA 1%/Tween 20 0.1%/NBS 4%)将空余位点阻断1小时。将初始浓度为4μg/ml的LA2单克隆Ab(mAb)的连续2倍稀释物在饱和缓冲液(50μl/孔)中稀释以制作标准曲线。还加入疫苗的血清样本稀释物(初始为1/10稀释),将平板在37℃培养2小时。培养后将平板用PBS/TWEEN 20(0.1%)洗涤3次。向每一孔中加入(50μl/孔)在饱和缓冲液中稀释的LA2mAb-过氧化物酶结合物(1/10000),并在37℃培养1小时。洗涤5次后,将平板与50μl/孔显示缓冲液(含有0.4mg/ml OPDA和0.03%H2O2的50mM pH4.5柠檬酸缓冲液)一起在室温培养20分钟。用2N硫酸来中止反应和颜色形成。用Biorad 3550免疫读取器在492和630nm读取光密度。使用SoftMaxPro软件通过4参数数学方法计算LA2-样Ab效价。通过与标准曲线比较来确定LA2-样抗体效价。
实施例2:用OspA抗原鼻内接种加强小鼠的免疫
通过肌内注射吸附在50μg/明矾上的1μg抗原lipo-OspA来给8周大小的雌性Balb/c小鼠(每组8只)免疫接种。3个月后,用含有下述组分的10μl溶液通过鼻内给予(每个鼻孔5μl,通过吸移管滴加)来强化小鼠(麻醉状态下)的免疫:A:5μg lipo-OspA;B:在36%Tween20、10%Imwitor 742中的5μg lipo-OspA;C:在36%Tween 20中的5μg lipo-OspA;D:在18%聚氧乙烯-9十二烷基醚中的5μg lipo-OspA。
强化接种14天后,通过IgG和LA2抗-OspA ELISA(参见实施例1)来分析血清以测定抗lipo-OspA的Abs。附图1所示结果表明,鼻内给予lipo-OspA能提高系统lipo-OspA特异性IgG效价。存在的Tween20加Imwitor742或者单独的Tween20很小程度地提高了该免疫增强作用。与之相反,聚氧乙烯-9十二烷基醚引起了非常显著的提高作用。对于LA2反应也观察到了类似模式(参见附图2)。
实施例3:用OspA抗原鼻内接种加强小鼠的免疫
各组小鼠的原始状况如实施例2所述。然后仅用5μg lipo-OspA(组A和C)或在下述组分存在下用lipo-OspA来加强小鼠的免疫(使用实施例2所述方法):B:1%牛磺胆酸钠;D:l%十二烷基麦芽糖苷;E:36%Tween20;或F:18%聚氧乙烯-9十二烷基醚。因为组A和B的实验与组C、D、E和F的实验是在不同时刻进行的,所以在附图(参见附图3)中将其分开。结果清楚地显示,与仅使用抗原所获得的结果相比,1%牛磺胆酸钠没有显著提高免疫加强作用。1%十二烷基麦芽糖苷或36%Tween20提供了轻微的促进效果,但是只有聚氧乙烯-9十二烷基醚非常显著地增强了IgG反应。对于LA2反应也观察到了类似作用(参见附图4)。
实施例4:鼻内接种加强小鼠免疫-剂量范围研究
为了确定提供在上一实施例中观察到的辅助作用所需的聚氧乙烯-9十二烷基醚浓度,我们进行剂量范围分析,为了证明使用其它聚氧乙烯醚也可获得该辅助作用,我们还使用聚氧乙烯-23十二烷基醚进行实验。对原始状况如实施例1所述的小鼠鼻内接种在下述材料中含5μglipo-OspA的10μl制剂来加强其免疫:A:PBS;B:1%聚氧乙烯-9十二烷基醚;C:2%聚氧乙烯-9十二烷基醚;D:5%聚氧乙烯-9十二烷基醚;E:1%聚氧乙烯-23十二烷基醚;F:10%聚氧乙烯-23十二烷基醚。接种14天后,如实施例2所述分析血清。
附图5和6表明,低至1%的聚氧乙烯-9十二烷基醚浓度使免疫反应有非常显著的增强。
聚氧乙烯-23十二烷基醚也显著地增强了鼻内接种的免疫反应。
实施例5:组合疫苗-鼻内强化接种
为了评价使用聚氧乙烯醚来强化鼻内接种后系统免疫反应的作用,通过肌内注射市售DTPa疫苗(Diptheria,Teanus,accelularPertussis疫苗:INFANRIXTM SmithKline Beecham,Belgium)来给雌性balb/c小鼠初始接种。用相当于20%人用剂量的2×50μl注射液通过肌内注射给小鼠进行一次初始接种。3个月后,通过下述途径给小鼠接种以强化免疫:A:鼻内给予(如实施例2所述)在PBS中的破伤风类毒素(TT:5μg)或丝状血凝集素(FHA:5μg);B:鼻内给予(如实施例2所述)在1%聚氧乙烯-9十二烷基醚中的破伤风类毒素(TT:5μg)或丝状血凝集素(FHA:5μg);C:肌内注射DTPa疫苗(2×50μl)。强化接种14天后,分析血清以测定其TT和FHA特异性IgG。效价如附图7和8所示。结果清楚地表明,对于TT,该蛋白自身不引起显著的提高免疫反应的作用,但是聚氧乙烯-9十二烷基醚能显著地提高其免疫反应。令人惊奇的是,在该佐剂存在下通过鼻内接种所获得的反应比通过肌内注射接种后所获得的反应要大。给予FHA自身诱导了免疫反应,该免疫反应通过加入作为佐剂的聚氧乙烯-9十二烷基醚而被显著地增强。
实施例6:鼻内强化接种AGMs
据表明许多佐剂在小的啮齿动物中起作用,但是当在较大哺乳动物中测试时则不起任何作用。为了评价聚氧乙烯醚在较大物种中是否能增强鼻内接种的免疫反应,通过肌内注射吸附在明矾(500μg)上的lipo-OspA(10μg)来给非洲绿猴(AGMs:每组4只)进行初次接种。10个月后,在麻醉状态下用产自Pfeiffer GmBH Germany的双剂量喷雾装置把200μl(每个鼻孔100μl)在A:PBS;或B:1%聚氧乙烯-9-十二烷基醚中含有60μg lipo-OspA的制剂给动物鼻内强化接种。接种14天后,测试血清中的抗-OspA免疫球蛋白和LA2效价。附图9和10表明了每一组的几何平均效价。对于由10只AGMs组成、并且初次接种和强化接种都是通过肌内注射吸附在明矾上的lipo-OspA来进行的组C,分析其抗-OspA免疫球蛋白反应(附图10仅表明了对于LA2的几何平均效价)。
当鼻内给予绿猴时,单独的lipo-OspA不能增强系统反应,但是加入1%聚氧乙烯-9十二烷基醚非常显著地提高了该免疫加强作用。令人惊奇的是,在聚氧乙烯-9十二烷基醚存在下鼻内强化接种后所获得的效价也比肌内注射(组C)后所获得的效价大。
实施例7:通过鼻内途径给AGMs实施初次接种和强化接种
在前述实施例中我们证实了聚氧乙烯醚能促进鼻内强化接种的系统反应。在本实施例中,我们测定能否通过鼻内途径给幼小动物进行初次接种和强化接种来诱导系统免疫反应。此外,为了研究这些佐剂对于较大动物的适用性,用非洲绿猴(AGMs)进行该实验。
用在200μl(每个鼻孔100μl,用产自Pfeiffer GmBH Germany的双剂量喷雾装置给予)A:PBS;或B:l%聚氧乙烯-9-十二烷基醚中的60μg lipo-OspA通过鼻内途径进行初次接种和强化接种。强化接种14天后,测试血清中的OspA特异性免疫球蛋白。附图11表明,当不用佐剂辅助lipo-OspA时,鼻内初次接种和强化接种后检测不到任何系统免疫反应。当使用聚氧乙烯-9十二烷基醚作为佐剂时,该接种方案诱导了显著的抗-OspA效价。
实施例8:CpG对于在灵长目动物中诱导对lipo-OspA的系统和鼻体液免疫反应的鼻内辅助作用
该模型是设计用来测定在灵长目动物初次接种和强化接种模型中,在和不在其它免疫刺激剂存在下,聚氧乙烯-9十二烷基醚(POE-9LE)的初次接种和强化接种的作用。测定血清和鼻免疫球蛋白反应。在该实验中使用的免疫刺激剂是如实施例9所述的CpG 1001。
实验方法
在第0(pⅠ)天和第14(pⅡ)天通过鼻内途径给非洲绿猴初次接种和强化接种。疫苗是用产自Pfeiffer公司的双剂量喷雾给药装置给予的(每个鼻孔100μl,在麻醉状态下)。测试制剂如下:
组 | 抗原 | 佐剂 | n= | 途径 |
1 | LipoOspA(60μg) | 无 | 2 | i.n. |
2 | lipoOspA(60μg) | CpG(100μg) | 3 | i.n. |
3 | lipoOspA(60μg) | CpG(100μg),POE-9LE(0.25%) | 3 | i.n. |
4 | lipoOspA(60μg) | POE(0.25%) | 4 | i.n. |
5 | lipoOspA(60μg) | POE(0.5%) | 4 | i.n. |
测定在pⅡ后第14天所采集的血清中的对lipo-OspA的Ig Ab效价。用非常灵敏的ELISA测定在同一时间采集的鼻拭子中的抗原特异性鼻IgA,当其IgA效价超过了明显在本底水平之上的预定水平时,则认为该动物显阳性。
结果:
血清OspA特异性免疫球蛋白
附图12表明了在pⅡ后第14天观测到的血清抗-lipo-OspA免疫球蛋白反应。单独作为初次接种和强化接种制剂的lipo-OspA没有诱导此后可检测到的血清免疫球蛋白。在CpG存在下不能改善该反应。与仅用CpG进行接种后所观测到的免疫反应相比,0.25%和0.5%POE-9LE诱导的免疫反应更大。然而,当与CpG联合使用时,0.25%POE-9LE诱导的Ab反应与用0.5%POE-9LE所获得的Ab反应相类似,这表明CpG和POE组分有协同作用。
鼻OspA-特异性IgA
如同所观测的血清Ig反应一样,仅含有lipo-OspA或与CpG合用的lipo-OspA不能引起可检测到的鼻IgA Abs(参见总结所有鼻反应的附图13)。在给予与0.25%聚氧乙烯十二烷基醚合用的lipo-OspA的动物中,仅有25%呈“鼻IgA”阳性(在0.5%POE-9LE中是50%)。当把CpG加到该0.25%POE制剂中时,100%动物表现出IgA反应。因此,对于诱导粘膜抗体,CpG和聚氧乙烯十二烷基醚也具有协同作用。
在诱导抗原特异性血清免疫球蛋白和鼻IgA方面,在猴子中获得了CpG和聚氧乙烯十二烷基醚之间的协同作用。
实施例9:CpG对于增强对lipo-OspA抗原的系统体液免疫反应的鼻内辅助作用
本实施例是设计用来测定在鼠强化免疫性接种模型中向聚氧乙烯醚(POE-9LE)佐剂系统内加入其它免疫刺激剂的作用。CpG是在PCT WO96/02555中描述过的免疫调节寡聚核苷酸。由这些疫苗制剂所增强的免疫反应至少与通过常规肌内注射强化接种所诱导的免疫反应一样高。将这些疫苗制剂与众所周知的鼻内佐剂-得自大肠杆菌的热不稳定肠毒素(mLT)作进一步比较。
在本实验中使用的CpG的序列是CpG 1001(TCC ATG AGC TTC CTG ACGTT)、CpG 1002(TCT CCC AGC CTG CGC CAT),阴性对照是非免疫刺激序列CpG 1005(TCC ATG AGC TTC CTG AGC TT)
实验方法
在第0天,通过肌内给予含有吸附在50μg氢氧化铝上的1μg lipo-OspA的100μl疫苗来对Balb/c小鼠进行初次接种。在第107天,在麻醉状态下用微量吸移管通过滴鼻方式给予10μl(每个鼻孔5μl)疫苗来进行强化接种。通过鼻内(i.n.)或肌内(i.m.)给予下述疫苗制剂来给由6只小鼠组成的各组进行强化接种:
组 | 抗原 | 佐剂 | 途径 |
1 | LipoOspA(5μg) | AlOH3(50μg) | i.m. |
2 | LipoOspA(5μg) | CpG1005(20μg),POE-9 LE(1%) | i.n. |
3 | LipoOspA(5μg) | CpG1002(20μg),POE-9 LE(1%) | i.n. |
4 | LipoOspA(5μg) | CpG1001(20μg),POE-9 LE(1%) | i.n. |
5 | LipoOspA(5μg) | CpG1005(20μg) | i.n. |
6 | LipoOspA(5μg) | CpG1002(20μg) | i.n. |
7 | LipoOspA(5μg) | CpG1001(20μg) | i.n. |
8 | LipoOspA(5μg) | POE-9LE(1%) | i.n. |
9 | LipoOspA(5μg) | mLT(5μg) | i.n. |
10 | LipoOspA(5μg) | 无 | i.n. |
11 | 未强化接种 |
在强化接种当天和强化接种(pⅡ)后14天采集血样。通过ELISA测定各血清中对OspA和LA2的特异性血清IgG效价。
结果
如附图14(表明通过抗原特异性ELISA测定的OspA特异性血清IgG)和附图15(表明血清中杀菌LA2效价)所示,单独的CpG不能使血清OspA-特异性Ab反应得到任何改善。OspA与聚氧乙烯十二烷基醚的制剂提高了IgG和LA2效价。当把聚氧乙烯十二烷基醚与CpG一起配制时,观测到了最佳反应。
实施例10:剂量研究
如实施例4所述,低至1%的聚氧乙烯-9十二烷基醚浓度使免疫反应有非常显著的提高。为了确定提供在前述实施例中观测到的鼻内免疫增强效果所需的聚氧乙烯-9十二烷基醚的浓度,使用较低剂量进行剂量-范围分析。
通过下述方式对按照实施例2所述方法进行过初次接种的Balb/c小鼠实施强化接种:鼻内给予在下述材料中含有5μg lipo-OspA的10μl制剂:A:PBS;B:1%聚氧乙烯-9十二烷基醚;C:0.5%聚氧乙烯-9十二烷基醚;D:0.25%聚氧乙烯-9十二烷基醚;或者E:通过肌内注射吸附在50μg明矾上的lμg lipo-OspA来进行强化接种。该强化接种后14天,如实施例1所述分析血清。
结果
附图16和17表明,低至0.25%的聚氧乙烯-9十二烷基醚浓度使免疫反应有非常显著的提高。即使采用这么低剂量的佐剂,所达到的Ab反应也与通过非胃肠道途径给予疫苗所达到的Ab反应相似。
实施例11:在小鼠中接种抗流感疫苗
为了确定聚氧乙烯醚在增强鼻内强化接种后系统抗流感免疫反应方面的适用性,用常规单价分裂流感疫苗通过肌内注射对雌性Balb/c小鼠实施初次接种。通过在第0和7天肌内注射2次含有1.5μgA/Singapore/6/86分裂单体的等效血凝集素A(HA)的100μl注射剂来给小鼠实施初次接种。3个月后,通过下述方式给小鼠实施强化接种:鼻内给予(如实施例2所述)在A:PBS;B:1%聚氧乙烯-9十二烷基醚中的1.5μg灭活的全A/Singapore/6/86病毒的等效HA;或者:C:肌内注射分裂A/Singapore/6/86疫苗(1.5μg等效HA)。强化接种后14天,分析血清的A/Singapore/6/86病毒-特异性IgG。
结果
效价如附图18所示。结果清楚地表明,该抗原自身没有引起显著的免疫加强,但是聚氧乙烯-9十二烷基醚能显著地提高免疫反应。在该佐剂存在下所达到的Ab效价不显著地低于通过非胃肠道途径接种疫苗所达到的Ab效价。
实施例12:在猴子中接种抗流感疫苗
在实施例11中,我们证实了聚氧乙烯-9十二烷基醚能显著增强流感抗原在小鼠中的免疫原性。为了确定该表面活性剂在较大物种中能否起类似辅助作用,给非洲绿猴(AGMs:2只/组,每次采集2只的血样)实施初次接种,并用在200μl A:PBS;B:0.5%聚氧乙烯-9十二烷基醚中的50μg灭活的全A/Beijing/262/95病毒的等效HA进行鼻内强化接种(如实施例6所示)。强化接种后第2、7和14天,分析血清中的A/Beijing/262/95病毒-特异性Ig Abs。附图19清楚地表明,当使用聚氧乙烯-9十二烷基醚作为佐剂时,改善了对流感抗原的免疫反应。
实施例13:用多糖抗原进行的接种实验
前述实施例证实了聚氧乙烯-9十二烷基醚能增强由蛋白型抗原引起的免疫反应。在本实施例中,我们在通过非胃肠道途径初次接种的小鼠中测定该佐剂能否增强鼻内给予多糖抗原的免疫加强作用。用含有与蛋白D载体结合的肺炎链球菌多糖PS14和PS19(每种是1μg)的100μl注射剂通过皮下注射给小鼠实施一次初次接种。2个月后,用在A:NaCl 150 mM pH 6.1;B:1%聚氧乙烯-9十二烷基醚中含有1μg PS14和1μg PS19结合物的40μl溶液(使用吸移管,在0分钟时每个鼻孔滴加10μl,30分钟后,每个鼻孔再滴加10μl)通过鼻内途径给小鼠(在麻醉状态下)实施强化接种。14天后,分析血清的PS14和PS19-特异性IgG Abs。
结果
如附图20和21所示,仅给予PS14或PS19本身即引起了免疫加强反应,加入作为佐剂的聚氧乙烯-9十二烷基醚使得该反应进一步增强了。
实施例14:聚氧乙烯-8十八烷基醚
为了证明使用其它聚氧乙烯醚也能获得聚氧乙烯-9十二烷基醚的免疫增强作用,我们用聚氧乙烯-8十八烷基醚进行了实验。
通过下述方式对按照实施例2所述方法进行过初次接种的Balb/c小鼠实施强化接种:鼻内给予在下述材料中含有5μg lipo-OspA的10μl制剂:A:PBS;B:1%聚氧乙烯-9十二烷基醚;C:1%聚氧乙烯-8十八烷基醚;或者D:通过肌内注射吸附在50μg明矾上的1μg lipo-OspA来进行强化接种。该强化接种后14天,如实施例1所述分析血清。
结果
附图22和23表明,在增强对抗原的反应方面,聚氧乙烯-8十八烷基醚与聚氧乙烯-9十二烷基醚一样有效。采用这两种聚氧乙烯醚所达到的Ab效价与通过非胃肠道途径给予疫苗所达到的Ab效价相似。
Claims (27)
1.包含聚氧乙烯醚或聚氧乙烯酯与可药用赋形剂以及抗原或抗原组合物的疫苗组合物,其中所述聚氧乙烯醚或酯不呈囊形式。
2.包含式(Ⅰ)表面活性剂:
HO(CH2CH2O)n-A-R其中n为1-50,A是一个键或-C(O)-,R是C1-50烷基或苯基C1-50烷基,
可药用赋形剂和抗原或抗原组合物的疫苗组合物,其中所述表面活性剂不呈囊形式。
3.权利要求2的包含式(Ⅰ)表面活性剂的疫苗组合物,其中n为4-24。
4.权利要求2的包含式(Ⅰ)表面活性剂的疫苗组合物,其中n为9。
5.权利要求2-4任一项的包含式(Ⅰ)表面活性剂的疫苗组合物,其中R是C8-20烷基或苯基C8-20烷基。
6.权利要求2-4任一项的包含式(Ⅰ)表面活性剂的疫苗组合物,其中R是C12烷基或苯基C12烷基。
7.权利要求2-6任一项的包含式(Ⅰ)表面活性剂的疫苗组合物,其中A是一个键,以由此形成醚。
8.权利要求2-6任一项的包含式(Ⅰ)表面活性剂的疫苗组合物,其中A是-C(O)-,以由此形成酯。
9.权利要求1的疫苗组合物,其中包含选自聚氧乙烯-9-十二烷基醚、聚氧乙烯-9-十二烷基酯、聚氧乙烯-9-十八烷基醚、聚氧乙烯-8-十八烷基醚、聚氧乙烯-4-十二烷基醚、聚氧乙烯-35-十二烷基醚、和聚氧乙烯-23-十二烷基醚的聚氧乙烯醚或酯。
10.权利要求2的疫苗组合物,其中包含选自聚氧乙烯-9-十二烷基醚、聚氧乙烯-9-十二烷基酯、聚氧乙烯-9-十八烷基醚、聚氧乙烯-8-十八烷基醚、聚氧乙烯-4-十二烷基醚、聚氧乙烯-35-十二烷基醚、和聚氧乙烯-23-十二烷基醚的表面活性剂。
11.权利要求1-10任一项的疫苗组合物,其中表面活性剂的浓度为0.1%-10%。
12.权利要求1-10任一项的疫苗组合物,其中表面活性剂的浓度为0.25%-1%。
13.权利要求1-12任一项的疫苗组合物,其中所述抗原或抗原组合物源自:人免疫缺陷病毒、水痘带状疱疹病毒、1型单纯性疱疹病毒、2型单纯性疱疹病毒、人巨细胞病毒、登革热病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、戊型肝炎病毒、呼吸道合胞体病毒、人乳头状瘤病毒、流感病毒、Hib、柔脑脊膜炎病毒、沙门氏菌属、奈瑟氏菌属、疏螺旋体属、衣原体属、博德特氏菌属、链球菌属、支原体属、分枝杆菌属、嗜血菌属、疟原虫属或弓形体属、stanworth十肽;或肿瘤相关抗原(TMA)、RAGE、BAGE、GAGE、MUC-1、Her-2 neu、LnRH、CEA、PSA、KSA、或PRAME。
14.权利要求1-13任一项的疫苗组合物,其中还包含其它佐剂。
15.权利要求1-13任一项的疫苗组合物,其中还包含选自LT、CT、MPL、CpG、QS21的其它佐剂。
16.权利要求15的疫苗组合物,其中所述CpG佐剂是TCC ATG ACG TTCCTG ACG TT。
17.权利要求1-16任一项的疫苗组合物,其中还包含载体,所述载体包含任一下述物质:脱乙酰壳多糖或其它多阳离子聚合物、聚交酯和聚交酯-共-乙交酯颗粒、由多糖或化学修饰多糖组成的颗粒、或由一甘油酯组成的颗粒。
18.聚氧乙烯醚或酯在制备佐剂组合物中的应用,其中所述聚氧乙烯醚或酯在佐剂组合物中以非囊形式存在。
19.通式(Ⅰ)表面活性剂在制备佐剂组合物中的应用,其中所述通式(Ⅰ)表面活性剂在佐剂组合物中以非囊形式存在。
20.权利要求1-17任一项的疫苗组合物在制备用于治疗病毒感染、细菌感染、寄生虫感染、变态反应或癌症的疫苗中的应用。
21.治疗患有或易患有病原体感染、或癌症、或变态反应的哺乳动物的方法,包括给予安全且有效量的权利要求1-17任一项的组合物。
22.治疗患有或易患有病原体感染、或癌症、或变态反应的哺乳动物的方法,包括粘膜给予安全且有效量的权利要求1-17任一项的组合物。
23.治疗患有或易患有病原体感染、或癌症、或变态反应的哺乳动物的方法,包括鼻内给予安全且有效量的权利要求1-17任一项的组合物。
24.制备权利要求1的疫苗组合物的方法,包括将聚氧乙烯醚或酯、可药用赋形剂、和抗原或抗原组合物混合在一起。
25.制备权利要求2-17任一项的疫苗组合物的方法,包括将通式(Ⅰ)表面活性剂、可药用赋形剂、和抗原或抗原组合物混合在一起。
26.包含聚氧乙烯醚或酯和可药用赋形剂的佐剂组合物,其特征在于,所述佐剂组合物不呈囊形式。
27.用作药物的前述权利要求所述的任一疫苗或佐剂。
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1999
- 1999-03-29 PL PL99354714A patent/PL354714A1/xx unknown
- 1999-03-29 EP EP99915735A patent/EP1069910A1/en not_active Withdrawn
- 1999-03-29 KR KR1020007011240A patent/KR20010042573A/ko not_active Application Discontinuation
- 1999-03-29 HU HU0101619A patent/HUP0101619A3/hu unknown
- 1999-03-29 CN CN99804894A patent/CN1296416A/zh active Pending
- 1999-03-29 IL IL13800099A patent/IL138000A0/xx unknown
- 1999-03-29 AU AU34197/99A patent/AU746163B2/en not_active Ceased
- 1999-03-29 TR TR2000/02930T patent/TR200002930T2/xx unknown
- 1999-03-29 BR BR9909915-2A patent/BR9909915A/pt not_active IP Right Cessation
- 1999-03-29 WO PCT/EP1999/002278 patent/WO1999052549A1/en not_active Application Discontinuation
- 1999-03-29 JP JP2000543159A patent/JP2002511423A/ja active Pending
- 1999-03-29 CA CA002325939A patent/CA2325939A1/en not_active Abandoned
- 1999-03-29 NZ NZ506603A patent/NZ506603A/xx unknown
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Cited By (2)
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CN101237881B (zh) * | 2005-08-03 | 2015-04-22 | 伊缪诺金公司 | 免疫偶联物剂型 |
CN106822883A (zh) * | 2010-12-14 | 2017-06-13 | 葛兰素史密丝克莱恩生物有限公司 | 分枝杆菌抗原组合物 |
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TR200002930T2 (tr) | 2000-12-21 |
WO1999052549A1 (en) | 1999-10-21 |
HUP0101619A2 (hu) | 2001-08-28 |
EP1069910A1 (en) | 2001-01-24 |
AR019026A1 (es) | 2001-12-26 |
KR20010042573A (ko) | 2001-05-25 |
CA2325939A1 (en) | 1999-10-21 |
NZ506603A (en) | 2002-10-25 |
IL138000A0 (en) | 2001-10-31 |
HUP0101619A3 (en) | 2003-11-28 |
NO20005051D0 (no) | 2000-10-06 |
AU3419799A (en) | 1999-11-01 |
JP2002511423A (ja) | 2002-04-16 |
NO20005051L (no) | 2000-11-21 |
BR9909915A (pt) | 2000-12-26 |
PL354714A1 (en) | 2004-02-09 |
AU746163B2 (en) | 2002-04-18 |
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