CN1694723A - 疫苗 - Google Patents
疫苗 Download PDFInfo
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- CN1694723A CN1694723A CNA018157467A CN01815746A CN1694723A CN 1694723 A CN1694723 A CN 1694723A CN A018157467 A CNA018157467 A CN A018157467A CN 01815746 A CN01815746 A CN 01815746A CN 1694723 A CN1694723 A CN 1694723A
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Abstract
本发明涉及两种或更多种肺炎链球菌蛋白的组合，它们的制备以及它们作为疫苗在医学中的用途。这样的组合尤其可保护婴幼儿和老年人抗御链球菌感染。
Description
发明领域
本发明涉及两种或两种以上肺炎链球菌(S.pneumoniae)蛋白的组合，其制备方法及其作为疫苗在医学中的应用。该组合物尤其对预防婴儿和老年人链球菌感染有效。
发明背景
肺炎链球菌是一种导致很高发病率和死亡率(特别是年幼者和老年人)的革兰氏阳性菌，它引起肺炎、菌血症、脑(脊)膜炎等侵袭性疾病和急性中耳炎等菌群定居(colonisation)相关性疾病。美国60岁以上人群肺炎球菌性肺炎的发病率为每100,000人中估计有3～8人，其中20％导致菌血症和其他症状，例如脑膜炎，即使用抗生素治疗，其死亡率也接近30％。
肺炎球菌被赋予血清型特异性的化学连接的多糖包裹。有90种公知的肺炎双球菌血清型，荚膜是肺炎双球菌毒力的主要决定因素，因为荚膜不但保护细菌内表面不受补体影响，其本身也具有弱免疫原性。多糖是T非依赖型抗原，不能被加工或呈递在MHC分子上，从而不能与T细胞相互作用，但它们能通过一种涉及B细胞表面受体交联的不同的机制刺激免疫系统。
若干试验表明：侵袭性肺炎双球菌疾病的预防与荚膜特异性抗体密切相关，且该保护作用具有血清特异性。
肺炎链球菌是婴儿和儿童侵袭性细菌疾病和中耳炎最常见的致病因素。同样，老年人对肺炎球菌疫苗反应较弱[Roghmann等，(1987)，J.Gerontol.42：265-270]，因此在这些人群中细菌性肺炎的发病率升高[Verghese和Berk，(1983)Medicine(Baltimore)62：271-285]。
23-价非偶联肺炎球菌疫苗的临床疗效变化幅度大，从0％～81％不等(Fedson等，(1994)Arch Intern Med.
154：2531-2535)。其疗效似乎与正被免疫的危险人群相关，例如老年组、何杰金氏病组、脾切除术组、镰刀细胞疾病组和无γ球蛋白血症组(Fine等，(1994)Arch Intern Med.154：2666-2677)，此外还与疾病症状相关。23-价疫苗对肺炎球菌性肺炎(某些高危组，例如老年组)和中耳炎不显示预防性。
为克服婴儿这种缺乏免疫原性所作的策略包括多糖与大分子免疫蛋白的连接，该大分子免疫蛋白提供旁路T细胞辅助，并且对与之结合的多糖抗原引起免疫记忆。
然而，还需要更好的肺炎球菌疫苗组合物，特别是能更有效地预防或改善老年人和儿童肺炎球菌疾病(尤其是肺炎)的肺炎球菌疫苗组合物。
本发明提供这种更好的疫苗。
发明概述
本发明一方面是一种免疫原性组合物，该组合物至少包含两种选自多组氨酸三联体家族(PhtX)、胆碱结合蛋白家族(CbpX)、CbpX截短物、LytX家族、LytX截短物、CbpX截短物-LytX截短物嵌合蛋白、肺炎球菌溶血素(Ply)、PspA、PsaA、Sp128、Sp101、Sp130、sp125和sp133的肺炎链球菌蛋白。一个优选实施方案中，一种蛋白质选自多组氨酸三联体家族(PhtX)。另一个优选实施方案中，一种蛋白质选自胆碱结合蛋白家族(CbpX)，或CbpX截短物，或CbpX片段-LytX截短物嵌合蛋白。
本方明一个相关方面提供一种用于治疗或改善婴儿中耳炎或老年人肺炎的疫苗。任选地，该疫苗可以另外包含一种佐剂，优选地，该佐剂为TH1应答的诱导物。
本发明另一相关方面是本发明疫苗的制备方法，该方法通过选择和分离两种不同的肺炎链球菌蛋白并将这两种蛋白与可药用载体混合。
发明描述
本方明通过依赖基于肺炎球菌蛋白的途径提供一种用于治疗或改善老年人(例如肺炎)和/或婴儿(例如中耳炎)肺炎球菌感染的改进的疫苗。一个优选实施方案中，该疫苗适用于预防和改善老年人肺炎球菌感染。大部分成人都接触过肺炎链球菌，通过服用至少两种本发明的肺炎球菌蛋白，该疫苗能激发成人和老年人的潜在免疫应答至保护水平。该肺炎球菌蛋白在没有肺炎链球菌多糖的条件下服用。
在本发明的内容中，55岁或55岁以上的人视为老年人，通常为60岁以上，更普遍的为65岁以上。因此，本发明的一个实施方案提供一种用于预防老年人肺炎的包含肺炎球菌蛋白的疫苗组合物。
另一实施方案中，本发明提供一种包含两种或两种以上本发明肺炎球菌蛋白的适用于婴儿(通常为0～2岁)的疫苗组合物。
本发明的肺炎球菌蛋白
本发明的肺炎链球菌蛋白为至少在肺炎球菌生命周期期间暴露的表面，或者是由肺炎球菌分泌或释放的蛋白。本发明的蛋白组合优选从以下蛋白中选取不同的两种，例如：具有LXXC(X为任何氨基酸，例如：多组氨酸三联体家族(PhtX))II型信号序列基序的蛋白，胆碱结合蛋白(CbpX)，具有I型信号序列基序的蛋白(例如Sp101)，具有LPXTG基序的蛋白(X为任意氨基酸，例如Sp128、Sp130)和毒素(例如Ply)等。上述种类(或基序)的优选例为下列蛋白或其免疫功能等效物。
本发明的免疫原性组合物包含至少两种选自多组氨酸三联体家族(PhtX)、胆碱结合蛋白家族(CbpX)、CbpX截短物、LytX家族、LytX截短物、CbpX截短物-LytX截短物嵌合蛋白(或融合体)、肺炎球菌溶血素(Ply)、PspA、PsaA、Sp128、Sp101、Sp130、Sp125和Sp133的蛋白。但是，如果CbpX为PspC，则第二种蛋白不为PspA或PsaA。优选地，该免疫原性组合物包含两种或两种以上选自多组氨酸三联体家族(PhtX)、胆碱结合蛋白家族(CbpX)、CbpX截短物、LytX家族、LytX截短物、CbpX截短物-LytX截短物嵌合蛋白(或融合体)、肺炎球菌溶血素(Ply)、PspA、PsaA和Sp128的蛋白。更优选地，该免疫原性组合物包含两种或两种以上选自多组氨酸三联体家族(PhtX)、胆碱结合蛋白家族(CbpX)、CbpX截短物、LytX家族、LytX截短物、CbpX截短物-LytX截短物嵌合蛋白(或融合体)、肺炎球菌溶血素(Ply)和Sp128的蛋白。
Pht家族(多组氨酸三联体)包含PhtA、PhtB、PhtD和PhtE蛋白。该家族的特点是脂质化序列，两个功能区被脯氨酸富集区和数个组氨酸三联体分隔，可能涉及金属或核苷的结合或酶活性，(3-5)卷曲的螺旋区域，一个保守的N-末端和一个异源的C-末端。它出现在所有受检肺炎双球菌菌株中。其它链球菌和奈瑟菌属中也发现有同源蛋白。优选该家族成员包含PhtA、PhtB和PhtD，更优选包含PhtA或PhtD。但是，应该理解：PhtA、B、D和E是指具有公开于下述引文序列的蛋白质以及具有与参考蛋白至少90％序列同源性的其天然(和人工)变体，优选与参考蛋白至少95％相同，最优选97％相同。
PhtX蛋白中，PhtA公开于WO98/18930，也被称为Sp36。如上所述，PhtA来自多组氨酸三联体家族，具有II型LXXC信号基序。
PhtD公开于WO00/37105，也被称为Sp036D。如上所述，PhtD也来自多组氨酸三联体家族，具有II型LXXC信号基序。
PhtB公开于WO00/37105，也被称为Sp036B。PhtB家族的另一成员是C3降解的多肽，公开于WO00/17370。该蛋白也来自多组氨酸三联体家族，具有II型LXXC信号基序。优选免疫功能等效物为WO98/18930中公开的Sp42。PhtB截短物(约为79kD)公开于WO99/15675，也被视为PhtX家族成员之一。
PhtE公开于WO00/30299中，也被称为BVH-3。
胆碱结合蛋白家族(CbpX)成员最初被视为能用胆碱亲和层析纯化的肺炎球菌蛋白。所有胆碱结合蛋白都非共价结合于细胞壁磷壁酸和膜结合脂磷壁酸的磷酸胆碱部分。虽然该蛋白质的确切性质(氨基酸序列、长度等)可以不同，但整个家族具有数个在结构上相同的区域。一般来说，胆碱结合蛋白包含N-末端区域(N)，保守重复区域(R1和/或R2)，脯氨酸富集区域(P)和保守的胆碱结合区域(C)，该胆碱结合区由多个重复单元组成，约占该蛋白的一半。本申请中所用的术语“胆碱结合蛋白家族(CbpX)”选自WO97/41151中所鉴定的胆碱结合蛋白、PbcA、SpsA、PspC、CbpA、CbpD和CbpG。CbpA公开于WO97/41151，CbpD和CbpG公开于WO00/29434，PspC公开于WO97/09994，PbcA公开于WO98/21337，SpsA是WO98/39450中公开的胆碱结合蛋白。该胆碱结合蛋白优选选自CbpA、PbcA、SpsA和PspC。
另一优选方案是CbpX截短物，其中“CbpX”如上述定义，“截短物”指缺省50％或更多胆碱结合区域(C)的CbpX蛋白。优选这样的蛋白质缺省整个胆碱结合区域。更优选这样的蛋白质截短物缺省(i)胆碱结合区域和(ii)该蛋白质的N-末端一半的一部分，但至少保留一个重复区域(R1或R2)。更优选地，该截短物具有两个重复区域(R1和R2)。该优选实施方案的例子是在WO99/51266或WO99/51188中举例说明的NR1xR2和R1xR2，但其它缺乏相似胆碱结合区域的胆碱结合蛋白也纳入本发明的考虑范围。
LytX家族是与细胞溶解有关的膜相关蛋白(membrane associatedproteins)。N-末端区域包含胆碱结合区域，但是，LytX家族并不具有在上述CbpA家族中发现的所有特征，因此，对于本发明来说，LytX家族不同于CbpX家族。与CbpX家族相比，LytX的C-末端区域包含LytX蛋白家族的催化区域。该家族包含LytA、B和C。LytX家族中，LytA公开于Ronda等，Eur J Biochem，164：621-624(1987)。LytB公开于WO98/18930，也被称为Sp46。LytC也公开于WO98/18930，也被称为Sp91。该家族的优选成员是LytC。
另一优选方案是LytX截短物，其中“LytX”如上述说明，“截短物”指缺省50％或50％以上胆碱结合区域的LytX蛋白。优选这样的蛋白质缺省整个胆碱结合区域。这样的截短物例子可在本发明的实施例部分找到。
本发明的另一优选实施方案是CbpX截短物-LytX截短物嵌合蛋白(或融合体)。优选该蛋白包含CbpX的NR1xR2(或R1xR2)和LytX的C-末端部分(Cterm，即缺省胆碱结合区域)(例如LytCCterm或Sp91Cterm)。更优选CbpX选自CbpA、PbcA、SpsA和PspC，其中更优选CbpX为CbpA。优选LytX为LytC(也被称为Sp91)。
本发明的另一优选实施方案是PspA或PsaA截短物，该截短物缺省胆碱结合区域(C)，并且表达为带LytX的融合蛋白，优选LytX为LytC。
肺炎球菌溶血素是一种具有明显溶细胞(溶血)作用和补体活化作用的多功能毒素(Rubins等，Am.Respi.Cit Care Med，153：1339-1346(1996))。该毒素不由肺炎双球菌分泌，但它在肺炎双球菌受自溶素的影响而裂解时被释放。它的作用包括例如：刺激人体单核细胞产生炎性细胞因子，抑制人体呼吸上皮纤毛颤动，降低嗜中性粒细胞的杀菌活性和迁移性。肺炎球菌溶血素最明显的作用是在裂解红细胞方面的作用，该作用涉及与胆固醇结合。由于肺炎球菌溶血素是一种毒素，因此在体内给药前必须脱毒(即用于预防的该药的剂量对人体是无毒的)。该领域中已知野生型或天然肺炎球菌溶血素的表达和克隆，参见例如：Walker等(Infect Immun，55：1184-1189(1987))，Mitchell等(Biochim Biophys Acta，1007：67-72(1989)和Mitchell等(NAR，18：4010(1990))。Ply的脱毒可以用化学方法，例如用福尔马林或戊二醛或二者的组合进行处理，这样的方法在许多毒素脱毒技术中公知。或者，ply可以用基因方法脱毒。因此，本发明包括肺炎球菌蛋白衍生物，该衍生物可能是例如突变蛋白。此处所用的术语“突变”是指用公知的定点诱变技术或其它常规方法使分子缺失、增加或取代一个或多个氨基酸。例如：如上所述，突变型ply蛋白可以被改变，以使其失去生物学活性但仍保持其致免疫表位，参见例如：WO90/06951，Berry等，(Infect Imun，67：981-985(1999))和WO99/03884。
此处所用的术语“Ply”是指适于医用(即无毒的)的突变或脱毒的肺炎球菌溶血素。
PsaA和PspA在本领域公知。例如：Berry & Paton，Infect Immun 1996Dec；64(12)：5255-62中描述了PsaA和其跨膜缺失变体(transmembranedeletion variants)。PspA和其跨膜缺失变体公开于例如US5804193，WO92/14488和WO99/53940。
Sp128和Sp130公开于WO00/76540。
Sp125是带有LPXTG(其中X为任何氨基酸)细胞壁锚定基序的肺炎球菌表面蛋白的例子。在本发明的发明内容中发现：具有此基序的这类肺炎球菌表面蛋白中的任何蛋白都有用，因此将其视为本发明的另一种蛋白。Sp125本身公开于WO98/18930，也称为ZmpB，即锌金属蛋白酶。
Sp101公开于WO98/06734(其中它参考#y85993)，其特征是I型信号序列。
Sp133公开于WO98/06734(其中它参考#y85992)，其特征是I型信号序列。
本发明的蛋白也可以进行有益的组合，优选组合物包括但不限于PhtD+NR1xR2、PhtD+NR1xR2-Sp91Cterm嵌合或融合蛋白、PhtD+Ply、PhtD+Sp128、PhtD+PsaA、PhtD+PspA、PhtA+NR1xR2、PhtA+NR1xR2-Sp91Cterm嵌合或融合蛋白、PhtA+Ply、PhtA+Sp128、PhtA+PsaA、PhtA+PspA、NR1xR2+LytC、NR1xR2+PspA、NR1xR2+PsaA、NR1xR2+Sp128、R1xR2+LytC、R1xR2+PspA、R1xR2+PsaA、R1xR2+Sp128、R1xR2+PhtD、R1xR2+PhtA。优选NR1xR2(或R1xR2)来自CbpA或PspC，更优选来自CbpA。
特别优选的肺炎球菌蛋白的组合包含Ply(或其截短物或免疫功能等效物)+PhtD(或其截短物或免疫功能等效物)+NR1xR2(或R1xR2)。优选NR1xR2(或R1xR2)来自CbpA或PspC，更优选来自CbpA。
本发明也包括本发明蛋白的“免疫功能等效物”。“免疫功能等效物”定义为包含至少一种来自本发明蛋白的保护性表位的肽或蛋白质。这些表位的特征是表面暴露，高度保守，能引起宿主的杀菌抗体应答或预防毒性作用。优选地，该功能等效物至少含有15个，优选30个或30个以上来自本发明蛋白质的连续的氨基酸，前提是其能产生与天然蛋白基本相同的免疫应答。联合运用2D-结构预测和抗原指数预测两种方法鉴定表面暴露且具有抗原性的肽，由此可以迅速确定蛋白质序列中潜在的B-细胞表位的位置。用PSIPRED程序能进行2D-结构预测(来自David Jones，BrunelBioinforrnatics Group，Dept.Biological Sciences，Brunel University，UxbridgeUB8 3PH，UK)。可以在Jameson和Wolf(CABIOS4：181-186[1988])说明的方法基础上计算抗原指数。
本发明在下述方面优于肺炎链球菌多糖疫苗：本发明的复合肺炎链球菌蛋白(免疫原性的)组合物可能包括对多种血清型的更大的交叉保护作用，能进一步抑制粘着和集落形成，还能潜在地增加能够中和病原体毒性/酶作用的抗体。而且，另外的表面抗原还提供一种进一步刺激调理吞噬的方式。
本发明也考虑预防一系列不同病原体的组合疫苗。目前许多儿科疫苗以组合疫苗的形式给予，以减少儿童的注射次数。因此对于儿科疫苗来说，来自其它病原体的其它抗原可以与本发明的疫苗一起制备。例如本发明的疫苗可以用公知的“三价”组合疫苗配制(或同一时间分别服用)，该三价组合疫苗包含白喉类毒素(DT)，破伤风类毒素(TT)和百日咳成分[通常是脱毒的百日咳类毒素(PT)和丝状血凝素(FHA)，任选pertactin(PRN)和/或凝集素1+2]，例如市售疫苗INFANRIX-DTPaTM(SmithKlineBeecham Biologicals)包含DT、TT、PT、FHA和PRN抗原，或带有完整百日咳细胞成分，例如：SmithKlineBeecham Biologicals s.a.销售的TritanrixTM。该组合疫苗也可以包含其它抗原，如乙型肝炎表面抗原(HBsAg)、脊髓灰质炎病毒抗原(例如灭活的三价脊髓灰质炎病毒-IPV)、卡他莫拉菌(Moraxella Catarrhalis)外膜蛋白、非典型流感嗜血杆菌蛋白、脑膜炎奈瑟氏球菌B外膜蛋白。
可以包含在组合疫苗中(特别是用于预防中耳炎)的卡他莫拉菌蛋白抗原的优选实例为：OMP106[WO 97/41731(Antex)和WO 96/34960(PMC)]；OMP21；LbpA和/或LbpB[WO 98/55606(PMC)]；TbpA和/或TbpB[WO97/13785和WO 97/32980(PMC)]；CopB[Helminen ME，等，(1993)Infect.Immun.61：2003-2010]；UspA1和/或UspA2[WO 93/03761(University ofTexas)]；OmpCD；HasR(PCT/EP99/03824)；PilQ(PCT/EP99/03823)；OMP85(PCT/EP00/01468)；lipo06(GB 9917977.2)；lipo10(GB 9918208.1)；lipo11(GB 9918302.2)；lipo18(GB 9918038.2)；P6(PCT/EP99/03038)；D15(PCT/EP99/03822)；OmplA1(PCT/EP99/06781)；Hly3(PCT/EP99/03257)和OmpE。可以包含在组合疫苗中(特别是用于预防中耳炎)的非典型流感嗜血杆菌抗原优选实例为：Fimbrin蛋白[(US 5766608-OhioState Research Foundation)]和含来自该蛋白的肽的融合体[例如LB1(f)肽融合体；US 5843464(OSU)或WO99/64067]；OMP26[WO97/01638(Cortecs)；P6[EP281673(State University of New York)]；TbpA和/或TbpB；Hia；Hsf；Hin47；Hif；Hmw1；Hmw2；Hmw3；Hmw4；Hap；D15(WO94/12641)；蛋白质D(EP594610)；P2和P5(WO94/26304)。
另一实施方案中，以上引用的多种抗原可以包含在本发明的免疫原性组合物中，作为抗原出现在由细菌制成的外膜囊(泡)的表面。
其它考虑的组合物是本发明的肺炎链球菌蛋白与病毒抗原的组合，所述病毒抗原例如来自流感病毒(减毒的、解体的(split)或其亚单位)[例如表面糖蛋白神经氨酸酶(NA)和血凝素(HA)，参见例如：Chaloupka I.等，Eur.Journal Clin.Microbiol.Infect.Dis.1996，15：121-127]，RSV(例如F和G抗原或F/G融合体，参见例如：Schmidt A.C.等，J Virol，May 2001，p4594-4603)，PIV3(例如HN和F蛋白，参见Schmidt等，同上)，水痘病毒(例如减毒的，糖蛋白I-V等)和MMR(麻疹，流行性腮腺炎，风疹)的任意(或全部)组分。
本发明的多糖抗原
本申请也考虑带有两种或两种以上肺炎链球菌蛋白的组合疫苗，该肺炎链球菌蛋白与肺炎链球菌以外的多糖组合。这样的多糖可以从例如流感嗜血杆菌，流感嗜血杆菌B型(Hib)，脑膜炎奈瑟氏球菌A、C、W、Y族(group)，肺炎链球菌以外的链球菌(例如B族链球菌，酿脓链球菌(S.pyrogenes)等)，葡萄球菌属(例如金黄色葡萄球菌，表皮葡萄球菌)，大肠杆菌，肠球菌属(例如粪肠球菌(E.faecalis)屎肠球菌(E.faecium))等。优选多糖选自流感嗜血杆菌B型(Hib)，和/或脑膜炎奈瑟氏球菌A、C、W135和/或Y族。
如上所述，用于接种的多糖的问题是多糖本身为弱免疫原。为克服此问题，可以将多糖与提供旁路T细胞辅助的蛋白载体结合。因此优选将本发明所用多糖与这样的蛋白载体结合，目前常用于生产多糖免疫原的此种蛋白载体的例子包括白喉和破伤风类毒素(分别为DT、DT CRM197、其它DT突变体：例如第148位Glu的突变体等[参见例如US4,709,017，WO93/25210，WO95/33481等]和TT(和TT截短物C))，匙孔血蓝蛋白(KLH)，来自脑膜炎奈瑟氏球菌的OMPC和结核菌素的纯蛋白衍生物(PPD)。
另一种用于基于多糖的免疫原性组合物(或疫苗)的载体是来自于流感嗜血杆菌(EP 594610-B)的蛋白D或其片段。适用的片段包括包含T-辅助细胞表位的那些片段。具体是蛋白D片段优选包含该蛋白N-末端的1/3。
可以利用任何公知的方法将该多糖连接到载体蛋白上(例如用Likhite，美国专利号4,372,945和Armor等，美国专利号4,474,757)。优选执行CDAP偶联(WO 95/08348)。为增强免疫原性，可以控制多糖分子大小(解聚)，加入佐剂，冷冻干燥或连接到不同的载体蛋白上。
本发明的TH1佐剂
本发明疫苗优选配有佐剂。合适的佐剂包括铝盐，例如氢氧化铝凝胶(明矾)或磷酸铝，也可以是钙盐、镁盐、铁盐或锌盐，或也可以是酰化酪氨酸不溶性悬浮液，或酰化糖，阳离子或阴离子衍生多糖，或聚磷腈。
优选地，该佐剂是诱导TH1型应答的优先诱导物。如此高水平的Th1型细胞因子有助于诱导对给定的细胞介导的免疫应答，而高水平的Th2型细胞因子有助于诱导对该抗原的体液免疫应答。
Th1型免疫应答和Th2型免疫应答的区别不是绝对的，记住这一点很重要。现实中，个体可能表现为以Th1为主或以Th2为主的免疫应答，但是通常用Mosmann和Coffman在鼠CD4+ve T细胞克隆中所描述的来考虑该细胞因子家族比较方便(Mosmann，T.R和Coffman，R.L(1989)TH1 andTH2 cells：different patterns of lymphokine secretion lead to different functionalproperties.Annual Review of Immunology，7，p145-173)。Th1型应答与T淋巴细胞产生INF-γ和IL-2细胞因子有关。通常与Th1型免疫应答诱导直接有关的其它细胞因子不由T细胞产生，例如IL-12。比较而言，Th2型应答与II-4，IL-5，IL-6和IL-10的分泌有关。激发以TH1应答为主的应答的合适佐剂系统包括：单磷酰脂A或其衍生物，特别是3-去氧酰化单磷酰脂A(3-de-O-acylated monophosphoryl lipid A)(3D-MPL)(其制备参见GB2220211A)；和单磷酰脂A的组合，优选3-去氧酰化单磷酰脂A与铝盐(例如磷酸铝或氢氧化铝)或水包油型乳剂组合。在这样的组合中，抗原和3D-MPL被包含在同一颗粒结构中，允许抗原和免疫刺激信号更有效地传递。研究表明3D-MPL能进一步加强明矾吸附抗原的免疫原性[Thoelen等，Vaccine(1998)16：708-14；EP 689454-B1]。
强化系统包括单磷酰脂A和皂苷(saponin)衍生物的组合，特别是WO94/00153中公开的QS21和3D-MPL的组合，或WO 96/33739中公开的反应原性稍弱的组合，其中QS21用胆固醇猝灭。
特别有效的佐剂制剂包括QS21，3D-MPL和生育酚的水包油型乳剂，公开于WO 95/17210，并且为优选制剂。
疫苗优选含有皂苷，更优选QS21。该制剂也可以含有水包油型乳剂和生育酚(WO 95/17210)。
本发明还提供一种疫苗制剂的制备方法，该方法包括将本发明的一种蛋白与可药用赋形剂例如3D-MPL的混合。
包含寡核苷酸的非甲基化CpG(WO 96/02555)也是诱导TH1应答的优先诱导物，并且适用于本发明。
本发明另一方面提供一种医用疫苗。一个实施方案中提供了一种预防或改善老年人肺炎的方法，包括给所述老年患者服用安全而有效剂量的本发明疫苗，且任选服用一种Th1佐剂。
另一实施方案提供了一种预防或改善婴儿(24个月以下)或幼儿(24个月～5岁)中耳炎的方法，包括给所述婴儿或幼儿服用安全而有效剂量的疫苗，该疫苗包含本发明的肺炎链球菌蛋白，且任选服用一种Th1佐剂。
本发明的疫苗制品
本发明的疫苗制剂可以用于预防或治疗哺乳动物(优选人类患者)的感染，其方法是通过全身或粘膜给药途径给予所述疫苗。给药方式包括肌肉注射、腹膜内注射、皮内注射或皮下注射，或口腔/消化道、呼吸道和泌尿生殖道粘膜给药。治疗肺炎或中耳炎优选鼻内给与疫苗(由于能更有效地阻止肺炎双球菌的鼻咽运送，因此能在最早期阶段减弱感染)。本发明的疫苗可以单剂给药，其组分也可以同时或不同时联合服用(例如：如果疫苗中有多糖，则多糖可以与细菌蛋白组合物在同一时间分开服用，或在服用细菌蛋白组合物后1～2周服用，以使二者发挥最佳免疫应答协同作用)。除单一给药途径之外，还能采用两种不同的给药途径。例如：病毒抗原能以ID(皮内)方式给药，而细菌蛋白能以IM(肌肉)或IN(鼻内)方式给药。如果有多糖，则多糖能以IM(或ID)方式给药，细菌蛋白能以IN(或ID)方式给药。另外，本发明的疫苗能以IM方式给予初次免疫、以IN方式给予加强免疫。
单剂疫苗剂量中偶联物抗原的量是能诱导免疫保护应答，但在通常的疫苗中又无明显副作用的量，此量随特异性免疫原的使用及其被呈递的方式而改变。蛋白抗原在疫苗中的通常含量范围为1～100μg，优选5～50μg，最常见的范围为5～25μg。如果含有多糖，预计一般单剂包含0.1～100μg多糖，优选0.1～50μg，更优选0.1～10μg，其中1～5μg为最优选范围。
特殊抗原中各成分的最佳量可以通过标准试验确定，包括观察受试者适当的免疫应答。初次接种后，患者可以在适当的时间间隔内接受一次或多次加强性免疫接种。通常，疫苗包含抗原(蛋白)、佐剂、赋形剂或可药用载体。
疫苗制剂通常公开于Vaccine Design(″The subunit and adiuvantapproach″(Powell M.F.和Newman M.J.编)(1995)Plenum Press New York)。脂质体胶囊公开于Fullerton的美国专利4,235,877。
虽然本发明的疫苗能以任何途径给药，所述疫苗皮内给药(ID)构成了本发明的一个实施例。人的皮肤包含一层外部“角质”表皮层，称之为角质层，它覆盖了表皮。此表皮下是真皮层，真皮层依次覆盖了皮下组织。研究者们已发现皮内注射，特别是真皮内注射疫苗能刺激免疫应答，还伴随其它好处。此处所述的皮内接种疫苗构成了本发明的一个优选特征。
皮内注射的常规技术“芒图操作(mantoux procedure)”包括下述步骤：清洗皮肤，伸出一只手，然后使小号针的斜面朝上(26～31号)，以10-15°的角度将针插入。一旦针斜面被插入后，针筒下降，施予轻微压力进一步推进，使其在皮下抬起。然后液体缓慢注入，导致皮肤表面形成包或隆起，最后缓慢抽出针。
近来，皮内或通过皮肤给与液体制剂的特定装置已被公开，例如：该装置公开于WO 99/34850和EP 1092444，喷射注射装置公开于WO 01/13977，US 5,480,381，US 5,599,302，US 5,334,144，US 5,993,412，US 5,649,912，US5,569,189，US 5,704,911，US 5,383,851，US 5,893,397，US 5,466,220，US5,339,163，US 5,312,335，US 5,503,627，US 5,064,413，US 5,520,639，US4,596,556，US 4,790,824，US 4,941,880，US 4,940,460，WO 97/37705和WO97/13537。该疫苗制剂的真皮内给药替代方法包括常规注射器和针，或固体疫苗的弹道式给药装置(WO 99/27961)，或经皮贴剂(WO 97/48440；WO98/28037)；或皮肤表面给药(经皮的给药WO 98/20734；WO 98/28037)。
当本发明的疫苗是给至皮肤时，更具体地说是真皮时，给与小体积量的疫苗，具体地说大约为0.05ml和0.2ml。
本发明皮肤或皮内疫苗中抗原含量可以类似于肌内疫苗所用的常规剂量。因此，皮内疫苗中的蛋白抗原含量范围可以为1～100μg，优选5～50μg。同样，如果有多糖偶联物抗原，则预计其在单剂疫苗中的含量通常为0.1～100μg多糖，优选0.1～50μg，更优选0.1～10μg，可以为1～5μg。但是，皮肤或皮内疫苗的一个特点是其制剂可以为“低剂量”。因此，“低剂量”疫苗中的蛋白抗原含量则为每剂0.1～10μg，优选0.1～5μg；如果有多糖偶联物抗原，则其在单剂疫苗中的含量范围通常为0.01～1μg多糖，优选0.01～0.5μg。
此处所用的术语“皮内给药”是指将疫苗给至皮肤的真皮区域，但疫苗不一定仅存在于真皮内。真皮层是距离人体皮肤表面约1.0mm和约2.0mm的皮层，但个体之间和同一个体的不同部位之间存在差异。一般地，预计疫苗可以通过距离表面皮肤1.5mm的深度达到真皮层。真皮上面为角质层和表皮，下面为皮下层。通过设计给药模式，可以使该疫苗最终仅存在于或主要存在于真皮内，或最终分布于表皮和真皮。
本发明另一方面可以包含编码一个或多个肺炎链球菌蛋白的DNA，以便在原位产生蛋白质。该DNA可以包含在本领域常规技术中公知的任何给药系统中，包括核酸表达系统，细菌和病毒表达系统。本领域中许多基因给药技术已公知，例如：Rolland，(Crit.Rev.Therap.Drug Carrier Systems15：143-198，1998)中所描述的及本文参考文献中所引用的。合适的核酸表达系统包含在患者体内表达所必需的DNA表达序列(如适当的启动子和终止信号)。当表达系统为活体重组微生物时，例如病毒或细菌，目的基因可以插入活的重组的病毒或细菌基因组中。用此活载体进行接种和体内感染会导致抗原体内表达和诱导免疫应答。用于此目的的病毒和细菌包括痘病毒(例如牛痘(caccima)，鸟痘(fowlpox)和金丝雀痘病毒(canarypox))，甲病毒(alphaviruses)(辛德毕斯病毒(Sindbis virus)，塞姆利基森林病毒(SemlidiForest virus)，委内瑞拉马脑炎病毒(Venezuelian Equine Enecphalitis Virus)，腺病毒，腺相关病毒，微小RNA病毒(picomavimses)(脊髓灰质炎病毒，鼻病毒)，疱疹病毒(水痘-带状疱疹病毒等)，李司忒菌属(Listeria)，沙门菌属(Salmonella)，志贺菌属(Shigella)，奈瑟菌属(Neisseria)和BCG。上述病毒和细菌可以具有毒性，或通过多种途径减毒以获得活疫苗。这样的活疫苗也构成本发明的一部分。
本发明另一方面提供一种制备此处说明的疫苗制剂的方法，根据本发明，该方法包括混合要进行组合的蛋白。
含有上文所述多糖的抗原性组合物(和疫苗)使用前优选一直是冷冻的，使用时用稀释剂临时配制。更优选地，在3D-MPL存在的条件下冷冻，用盐溶液临时配制。
疫苗冷冻在本领域已公知。通常，液体疫苗在抗结块剂，例如蔗糖或乳糖等糖类(起始浓度为10～200mg/mL)存在的条件下冻干。冷冻包含一系列典型步骤，例如：-69℃开始循环，再逐渐升温至-24℃，升温时间为3小时，保持此温度18小时。再逐渐升温至-16℃，升温时间为1小时，保持此温度6小时。然后逐渐升温至+34℃，升温时间为3小时，最后保持此温度9小时。
本发明的免疫组合物和疫苗可以用多种动物模型或人血清进行评价。例如：下列动物模型可以用于评价肺炎球菌感染，皮下给与以50μl CFA为佐剂的15μg蛋白免疫C3H/HeJ小鼠(6～8周大小)，随后3～4周用带IFA的15μg蛋白加强免疫。为证明小鼠对系统感染的被动和主动防护，腹腔注射15～90 LD50的肺炎双球菌进行攻击之前，可以在8～10周腹腔给与小鼠免疫血清或蛋白。另外，蛋白质可以用小鼠鼻咽部菌群定居模型进行检测(Wu等Microbial Pathogenesis 1997；23：127-137)。
除小鼠外，大鼠幼鼠对肺炎链球菌的定居和感染敏感。在被动保护试验中，2～5天大小的大鼠幼鼠在鼻腔给与肺炎链球菌(10μl)进行攻击前，可以给与小鼠免疫血清(100μl i.p.或10μl i.n.)。可以用鼻流出物的铺板培养(20～40μl输入，10μl流出)确定菌群定居。
组合疫苗中的蛋白成分间的有利相互作用可以通过每次给与疫苗中的一种蛋白来证明，该疫苗作为单价疫苗具有亚保护性。组合疫苗的预防效力较单价疫苗升高，这归结于各成分之间的有利相互作用。
本发明用下列附加实施例用来举例说明。除另有详细说明外，用本领域技术中公知和常规的标准技术实施实施例。实施例仅用于举例说明，但不限制本发明。
实施例
实施例1 抗原的构建和表达
NR1xR2
CbpA是一种由若干区域组成的74kDa的表面暴露蛋白。其N-末端区域包含两个高度保守的重复单元(R1和R2)，C-末端区域包含10个串联的具有20个氨基酸的直接重复序列。制备CbpA截短物用于产生NR1XR2(没有胆碱结合区域)。
NR1XR2基因是从来自肺炎链球菌血清型4菌株的DNA通过PCR扩增而来的(参见例如WO97/41157或WO99/51266)。用Expand High FidelityPCR系统或Hi-Fi(Roche)进行PCR。所述系统由包含Taq聚合酶和校正性的聚合酶的混合物组成。由于固有的3’-5’核酸外切酶校正活性，用Hi-Fi使DNA合成的忠实性比用Taq聚合酶提高3倍。
PCR片段被克隆到来自pGEM-T Vector Systems(Promega)的pGEM-T载体中，这一步对用限制性内切酶消化PCR片段以进行进一步的连接来说是必需的。pGEM-T载体为线性的，并且包含3’-T突出端。这些突出端促进耐热聚合酶产生的PCR产物插入，该耐热聚合酶以不依赖于模板的方式添加单个脱氧腺苷至扩增片段的3’末端。
根据Benore-Parsons等的文章(Nucletic Acids research，23，4926-4927，1995)，将所述片段和载体在酶消化后纯化(NdeI和Xbal消化)。3～4小时内将琼脂糖薄片完全冻干。把1∶1的乙醇-TE溶液加入冻干凝胶中。样品轻微混合一小时，压紧琼脂糖，然后通过离心沉淀完全除去。用乙醇沉淀方法从洗脱液中回收DNA。
编码NR1xR2的DNA克隆到包含噬菌体λ的长启动子L的载体中。当出现在AR58大肠杆菌菌株中时，目的蛋白能被热诱导，或出现在AR120大肠杆菌菌株中时，能被萘啶酮酸诱导。
在30℃进行细菌隔夜预培养，将该预培养液稀释约40倍，至总体积为20ml，30℃下放置至O.D.为0.4-0.6，然后在42℃下进行热诱导。分别在不同时间点取样，1ml培养液以7000rpm的转速离心5分钟。培养物上清液在-20℃下存放，沉淀物(全部提取物)重新悬浮在500μl样品缓冲液(蛋白印迹或十二烷基硫酸钠聚丙稀酰胺凝胶电泳分析)或500μl裂解缓冲液中，37℃下温育30分钟(ELISA)。裂解缓冲液的组分为：十二烷基硫酸钠0.1％，去氧胆酸盐0.1％，枸橼酸钠0.015M。
样品进行十二烷基硫酸钠聚丙稀酰胺凝胶电泳，上样至4～20％的凝胶上(Novex Invitrogen)，200V下进行迁移。用考马斯蓝染色。上样至4～20％的凝胶上(Novex，Invitrogen)进行蛋白印迹，200V下进行迁移。将凝胶转移到硝酸纤维上，用兔α-NR1XR2多克隆抗体(第一抗体)和与碱性磷酸酯酶偶联的α-兔抗体(第二抗体)进行显影。
在十二烷基硫酸钠聚丙稀酰胺凝胶电泳分析中发现一条约为55kDa的带。在十二烷基硫酸钠聚丙稀酰胺凝胶电泳分析分析基础上选择一个28B2克隆并转移后进行发酵。该克隆被测序且其序列得到确认(第39(即信号序列之后)～446位的氨基酸＝406个氨基酸)。
对隔夜诱导的细菌进行裂解，然后离心，进行NR1XR2可溶性研究。再进行SDS-PAGE分析和ELISA试验，NR1XR2似乎主要(＞95％)回收自可溶性组分。
R1xR2，PhtD，Sp91，(N)R1xR2-Sp91[C-末端区域]和Ply
上述基因也以与NR1xR2相似的方式克隆、测序和表达。R1xR2包含CbpA(肺炎链球菌血清型4N)的第177～443位的氨基酸，PhtD包含第21位(即信号序列之后)至末端(肺炎链球菌血清型4N的第839位氨基酸)的氨基酸，Sp91以第20位的氨基酸(VAA)开始直至末端。对于融合体蛋白，R1xR2-Sp91Cterm包含CbpA的第177～443位氨基酸和翻译终点之前的271个氨基酸。对于两种融合蛋白，(N)R1xR2和Sp91Cterm序列之间发现两个附加的氨基酸(GS)。对于所有结构，ATG引入基因起始的5’端以允许转录和翻译，这就意味着上述各序列前面都有一个附加的N-末端蛋氨酸。
实施例2 血清学
使用来自临床研究的血清，对肺炎链球菌蛋白自然产生的抗体应答进行ELISA检测。
2.1实验步骤
血清采样
当婴儿为2～4个月和6～12个月大小时分别收集两份血清(N＝20，研究DTPa HBV)。
～20岁成人血清(N＝50)。
65岁以上老年人血清(N＝140)。
ELISA步骤
4℃下各种蛋白均以1μg/ml覆盖免疫反应板，放置过夜。连续两倍稀释的血清(从1/10th的稀释液开始)在室温(RT)下振荡温育一小时。用稀释了4000倍的过氧化物酶偶联的抗人IgG单克隆抗体(Strateck，HP6043)，在RT下振荡温育30分钟进行免疫检测。显色后用SoftMaxPro算出中点滴度。滴度≥10的血清视为阳性。用几何平均值计算，滴度为5的(截留值的一半)被主观定为阴性血清。
通过比较样品光密度(OD)和生色IgG纯品(chromopure IgG)(Jackson)的OD曲线，确定IgG浓度(表示为μg/ml)。该IgG纯品被多克隆抗人IgG羊抗体捕获到反应板中，然后用与上述相同的过氧化物酶标记的抗体进行显色。
2.2结果
2.2.1婴儿链球菌蛋白血清学
受检的2～4个月婴儿血清中，PhtD，PsaA，Sp128和NR1xR2的抗体滴度和血清阳性反应率最高，Sp91和Ply次之。Sp101和Sp130无应答或有低应答。Sp46和PhtA未检测(材料获得性问题)。
相同受试者在6～12个月时收集的血清中抗体应答总体下降，这表明上述高滴度主要由被动转移的母体抗体所导致。
但是，某些婴儿对相同蛋白质的免疫应答随年龄增加，可能是自然暴露于肺炎双球菌的结果。主要与此血清转变相关的抗原确定为PsaA。有些受试者对PhtD，NR1xR2，Sp128，Sp91和Ply的抗体水平也增加，对Sp101和Sp130的体液应答仅发现有微弱变化。(参见图1和2)。
2.2.2年轻成人链球菌蛋白血清学
根据滴度的几何平均值可知，被评价的年轻成人群体中，PhtD，PhtA和NR1xR2是最具免疫原性的蛋白，Sp128，Ply和Sp91次之。所有受试者都能检测到对这些蛋白质的抗体。对Sp46，特别是对Sp130和Sp101的应答较弱。PsaA未检测(血清不够)。(参见图3和4)。
2.2.3老年人链球菌蛋白血清学
老年人链球菌蛋白的抗体水平比年轻成人明显降低。老年人最好的免疫原为PhtD，其次为Sp128、NR1xR2、Sp91、Ply和PsaA。Sp130和Sp101仅有微弱应答。Sp46和PhtA未检测(材料获得性问题)。(参见图5和6)。
表1 老年人的IgG几何平均浓度(GMC)(μg/ml)
| 蛋白 | IgG(GMC，μg/ml) |
| PhtDNR1xR2Sp91Ply | 193.52.52.3 |
此说明书中引用的所有出版物包括但不限于专利和专利申请在此引入作为参考，就如同各个出版物全文内容在此引入并全部公开。
本发明的优选实施方案已经在上文中作了举例说明，应该理解：本发明不限于此处公开的精确教导，本发明权利要求的范围包括对上述说明作出的所有改变。
Claims (12)
1.一种免疫原性组合物，含有至少两种肺炎链球菌蛋白，所述蛋白选自多组氨酸三联体家族(PhtX)，胆碱结合蛋白家族(CbpX)、CbpX截短物、LytX家族、LytX截短物、CbpX截短物-LytX截短物嵌合蛋白，肺炎球菌溶血素(Ply)、PspA、PsaA、Sp128、Sp101、Sp130、Sp125和Sp133的肺炎链球菌蛋白。
2.权利要求1的免疫原性组合物，含有一种源自多组氨酸三联体家族(PhtX)的蛋白和另一种选自胆碱结合蛋白家族(CbpX)、CbpX截短物、LytX家族、LytX截短物、CbpX截短物-LytX截短物嵌合蛋白，肺炎球菌溶血素(Ply)、PspA、PsaA、Sp128、Sp101、Sp130、Sp125和Sp133的蛋白。
3.权利要求1的免疫原性组合物，含有一种选自胆碱结合蛋白家族(CbpX)，CbpX截短物和CbpX截短物-LytX截短物嵌合蛋白的蛋白和另一种选自多组氨酸三联体家族(PhtX)，LytX家族，肺炎球菌溶血素(Ply)，PspA，PsaA，Sp128，Sp101，Sp130，Sp125和Sp133的蛋白。
4.权利要求1～3的免疫原性组合物，其中PhtX为PhtA、PhtB或PhtD。
5.权利要求1～4的免疫原性组合物，其中CbpX为CbpA或PspC。
6.权利要求1～5的免疫原性组合物，其还含有佐剂。
7.一种含有权利要求6的免疫原性组合物的疫苗。
8.一种引发免疫应答的方法，其通过用权利要求1～6的免疫原性组合物免疫哺乳动物。
9.一种预防或改善55岁以上患者链球菌感染的方法，包括给与所述患者安全且有效量的权利要求7的疫苗。
10.权利要求7的疫苗在制备预防55岁以上患者肺炎的药物中的应用。
11.一种预防或改善婴儿中耳炎的方法，包括给与所述患者安全且有效量的权利要求7的疫苗。
12.一种制备权利要求7的疫苗的方法，包括下述步骤：选择和分离两种不同的肺炎链球菌蛋白，然后将所述蛋白与可药用载体混合。
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