CN1097467C - 疫苗组合物 - Google Patents
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- CN1097467C CN1097467C CN95195504A CN95195504A CN1097467C CN 1097467 C CN1097467 C CN 1097467C CN 95195504 A CN95195504 A CN 95195504A CN 95195504 A CN95195504 A CN 95195504A CN 1097467 C CN1097467 C CN 1097467C
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Abstract
本发明涉及一种适用于粘膜给药，特别是鼻腔内给药的疫苗组合物，该组合物包括流感病毒抗原，诸如血细胞凝集素和神经氨酸酶的流感病毒抗原以及一种有效佐剂量的脱乙酰几丁质。该组合物可用来免疫宿主以预防流感感染的，而脱乙酰几丁质则是用于增强对保护性的IgA粘膜免疫应答和IgG全身性免疫应答的刺激。
Description
本发明涉及一种包含流感病毒抗原和粘膜佐剂的鼻腔内给药的疫苗组合物。本发明还涉及一种通过给病人施用该组合物而免疫病人以预防流感的方法，以及在鼻腔内给药时通过与该佐剂协同给药而增强流感病毒抗原的免疫原性的方法。此外，本发明提供了利用流感病毒抗原和脱乙酰几丁质结合制备鼻腔内给药以免疫病人预防流感的疫苗组合物。
目前的流感疫苗或者由灭活的整个病毒，破裂的病毒(割裂疫苗)或者由纯化的膜糖蛋白血细胞凝集素(HA)和神经氨酸酶(NA)亚单位疫苗制剂所组成。血细胞凝集素和神经氨酸酶是保护性抗体应答所涉及的抗原，并且血细胞凝集素是主要的保护性抗原。这些非肠胃给药的疫苗的效力的估价值变化很大。已知该疫苗主要通过诱生渗入下呼吸道的循环抗血细胞凝集素的IgG抗体而起作用。
M.L.Clements等人，《临床微生物学杂志》24，157-160，1986，曾报道分泌性IgA和血清IgG都参与了对流感病毒的免疫。而且，已发表的一些研究成果已证明了呼吸道IgA对小鼠预防流感感染的重要性。另外还发现了激起对流感的局部IgA应答的好处是它通常比血清应答具有更广泛的特异性并从而可以提供交叉保护以拮抗那些具有不同于疫苗中已存在的血细胞凝集素的病毒。相应，诱发局部分泌性和血清抗血细胞凝集素应答的流感疫苗应该都能提供比目前的疫苗更优良的免疫性。然而，肠胃外接种疫苗(肌内，皮下等)如果没有事先粘膜暴露(如注射)则对诱生局部抗体产生无效。为了刺激粘膜免疫系统，该疫苗必须局部给药于粘膜表面。
该流感疫苗的粘膜给药法较之于常规的肠胃外免疫方法具有许多的优越性。最重要的是更有效地刺激呼吸道的局部粘膜免疫系统，而又因为避免了和注射相关的畏惧和不适，所以疫苗的摄入率可能会提高。相应地，已进行了许多尝试以开发粘膜流感疫苗。然而缺点是灭活的疫苗通常在粘膜给药时免疫原性差。为了解决这个问题，改进口腔或鼻腔内给药的流感疫苗免疫原性的各种方法包括作为佐剂的霍乱毒素B亚单位(CTB)的使用，疫苗在微球体中的胶囊化，以及减毒活菌株的使用。然而至今依然没有开发出实用的方法以增强粘膜给药的流感疫苗的免疫原性。
本申请人已发现了在鼻腔给药的制剂中通过和特定的一起施用脱乙酰几丁质衍生物，该流感血细胞凝集素和神经氨酸酶抗原有可能取得良好的IgG和IgA应答。
脱乙酰几丁质是几丁质或聚-N-乙酰-D-葡糖胺的衍生物，其中大部分N-乙酰基团通过水解除去。
脱乙酰几丁质以前用于药物配方并且曾在EP-A-0460020中作为粘膜吸收增强剂公开，然而EP-A-0460020没有公开或建议该脱乙酰几丁质可在疫苗组合物中于给药时提供佐剂的作用。
本申请人现已发现如果将脱乙酰几丁质掺入含有流感病毒的神经氯酸酶和血细胞凝集素抗原的鼻腔内的疫苗组合物则可以产生良好的全身性和局部免疫应答。
相应地，本发明的第一方面提供了适用于粘膜给药的疫苗组合物；该组合物包括流感病毒抗原；以及有效佐剂量的脱乙酰几丁质。
本疫苗组合物优选地适用于鼻腔内给药。
优选地，本组合物包括血细胞凝集素和神经氨酸酶流感病毒抗原。
在一个优选的实施方案中，本发明提供了适用于鼻腔内给药的疫苗组合物；该组合物包括纯化的血细胞凝集素和神经氨酸酶流感病毒抗原；以及有效佐剂量的乙酰几丁质。
优选的，该纯化的血细胞凝集素和神经氨酸酶抗原以玫瑰花结形式存在。优选地，该玫瑰花结是半径在10-25纳米(nm)范围内的颗粒。
优选地，该玫瑰花结基本上不含脂类，此外，纯化的血细胞凝集素和神经氨酸酶抗原制剂作为整体也优选地基本不含脂类。
一个适用于本发明的组合物的血细胞凝集素/神经氨酸酶制剂的实例是英国西派克，莫日塞德的Evars医学有限公司生产和销售的Fluvirin”产品，并且还可见于S.Renfrey和A.Watts，《疫苗》，1994，12卷，第八期，第747-752页。
该组合物可包括来自单一病毒株或来自多个病毒株的流感病毒抗原。例如，该组合物可包含取自于多达三个或三个以上病毒株的抗原。仅仅作为例子，该组合物可含有来自一株或者更多株流感A的抗原以及来自一株或更多株流感B的抗原。
优选地，该脱乙酰几丁质是水溶性的。
该脱乙酰几丁质最好是一种至少有80％脱乙酰的脱乙酰几丁质。
优选地，该脱乙酰几丁质至少有85％脱乙酰，而更优选地则有88％到90％脱乙酰。
一个特别的脱乙酰几丁质是购自挪威Drammer Protan Biopoly-mer A/S的“Sea Cure+”脱乙酰几丁质谷氨酸盐。
此外，本发明提供了免疫宿主以预防流感感染的方法，该方法包括给宿主粘膜表面(优选地是鼻腔内)施用如前文所述的疫苗组合物，而该疫苗组合物则包括诸如纯化的血细胞凝集素和神经氨酸酶抗原的流感病毒抗原以及有效佐剂量的脱乙酰几丁质。
另外，本发明提供了增强保护性IgA粘膜免疫应答和IgG全身性免疫应答的方法，它是通过给病人的粘膜表面(优选地是鼻腔内)施用如前文定义的包括诸如纯化的血细胞凝集素和神经氨酸酶的流感病毒抗原以及有效佐剂量的脱乙酰几丁质的疫苗组合物而进行的。
还有，本发明通过与前文所述的脱乙酰几丁质协同给药提供了增强对诸如纯化的血细胞凝集素和神经氨酸酶的流感病毒抗原的免疫应答的方法(如当鼻腔内给药时)。
本发明的组合物，特别是鼻腔内给药的组合物可配成液体或干粉从而作为气雾剂或滴剂给药。
滴鼻给药的组合物可含有一种或多种通常包括在这样的组合物中类型的赋形剂，例如防腐剂，粘度调节剂，张度调节剂，缓冲剂及其它类似物。
为了确保该脱乙酰几丁质在水性介质中持续可溶以及该血细胞凝集素不受过酸性的pH的不利影响，优选地，溶液(如用于鼻腔内给药)的pH值在5.5到6.5之间，最优选地约为pH6。
本发明也考虑了提供用于分配诸如纯化的表面抗原的流感病毒抗原以及脱乙酰几丁质的鼻腔内给药的配方的装置。例如，分配装置可以采用气雾剂释放系统的形式，并可布置成仅是单剂量的或者是多剂量的形式。
该疫苗按有效剂量对病人给药以便刺激病人体内的防护性免疫应答。例如，该疫苗可以对人体按单—或者多剂量给药，每剂量包含1-250微克(μg)，或者更优选地5-50微克(μg)制备于每一病毒株的蛋白。例如，当血细胞凝集素和神经氨酸酶制剂制备于三种病毒株，如2X流感A和1X流感B时，那么给药的病毒蛋白总剂量可以在15-150微克的范围内。
附图简介
图1说明了用纯化的表面抗原(PSA)免疫的小鼠的血清IgG抗血细胞凝集素应答。每一柱代表四只小鼠的几何平均效价。误差柱代表平均值的1标准误差。作为检测下限的截断值是50。
图2表示用纯化的表面抗原(PSA)免疫的小鼠的鼻IgA抗血细胞凝集素应答。如图1，每一柱代表四只小鼠的几何平均效价，并且误差柱代表平均值的1标准误差。
图3a和3b表明使用ELISPOT法测定用PSA免疫的小鼠的鼻腔和肺的抗血细胞凝集素分泌细胞。图3a使用的是对数标度而图3b使用的是直线标度。
实施例1
制备流感B纯化的表面抗原/脱乙酰几丁质谷氨酸盐制剂
1A.将脱乙酰几丁质谷氨酸盐溶于0.8％的氯化钠中制成中等粘度的约含11％残留N-乙酰基团的1％的脱乙酰几丁质谷氨酸盐溶液。所用的脱乙酰几丁质谷氨酸盐的等级是购自挪威Drammen的Protan Biopolymer A/S的“Sea Cure+210”。
1B.将购自英国Merseyside，Speke的Evans医学有限公司的商标为“Fluvirin”的含有流感A和流感B蛋白的流感的纯化表面抗原(PSA)溶于磷酸盐缓冲盐水中制成浓度约为1mg/ml的蛋白溶液。虽然PSA也含有一些神经氨酸酶，但其几乎全部由血细胞凝集素(HA)的刺突蛋白所组成。
1C.将脱乙酰几丁质谷氨酸基溶液和PSA溶液的1∶1混合物制成含有0.5％的脱乙酰几丁质谷氨酸盐(11％乙酰化)，0.8％NaCl，0.1％PSA和pH为6的磷酸盐缓冲液的鼻腔内给药的疫苗组合物。
1D.制备含相同浓度的PSA但却没有脱乙酰几丁质谷氨酸盐和含相同浓度的脱乙酰几丁质谷氨酸盐却不含PSA的对照溶液。此外，还制备了含有相同浓度的吸附于已知的佐剂铝胶(氢氧化铝)上的PSA的组合物。
该PSA于4℃在铝胶上吸附过夜。
实施例2
小鼠免疫研究
2A.将如实施例1中所述制备的四种组合物对12只成熟的(6-8周)雌BALB/C小鼠组给药如下：
第1组：鼻腔内给药20μl(每鼻孔10μl)PSA/脱乙酰几丁质溶液。PSA剂量＝10μg。
第2组：鼻腔内给药20μlPSA(总PSA剂量＝10μg)。
第3组：皮下给药200μlPSA/铝胶(PSA剂量＝10μg)。
第4组：鼻内给药20μl脱乙酰几丁质溶液。
第5组：连续3天，每天给药20μlPSA(每鼻孔10μl)(此项研究中使用四只小鼠为一组)。
2B.该免疫步骤除了第5组的小鼠连续三天每天免疫外都是每隔一月进行一次，共进行三次。该免疫和采样方法如表1所示。免疫和采样方法表1
| 免疫 | 天 | 样品 | 天 |
| 1 | 1 | 1 | 21 |
| 2 | 30 | 2 | 44 |
| 3 | 57 | 3 | 71+72 |
在每次取样时，每组中的四只小鼠最终是通过穿心脏取血，切除头并用1毫升PBS+1％牛血清白蛋白灌洗鼻道。第5组的四只小鼠在前两次取样时只是通过尾静脉穿刺取血而只是在第3次取样时进行鼻腔的灌洗。抗体测定：
在所有的检测中，将整个流感疫苗(WIV)用作抗原。虽然WIV只是～50％HA，此检测被认为是主要测定抗HA抗体。此项推测通过用PSA(～100％HA)代替WIV并重复一些捡测而证实。无论用哪种抗原，该结果却是相似的，通过用酶联免疫吸附测定法(ELISA)测定HA特异性的血清IgG和鼻腔IgA抗体。校正去背景后，给出单个光密度(OD)稀释度曲线并测定出该效价值。该效价确定为OD值为0.2的血清稀释度或者OD值为0.1的鼻腔洗涤液稀释度。
在第3次采样中除了取鼻腔洗涤液外，还从鼻腔和肺粘膜中分离淋巴细胞并且用ELISPOT测定局部免疫应答。结果1.血清抗HA血清应答
纯化的表面抗原(图1和表2)
通过用PSA+铝胶皮下(S/C)免疫法诱发了预料中的良好的血清应答。在初次免疫后，所测试的全部动物都有血清转变发生并且几何平均效价(GMT)良好。在每次加强免疫后，该应答增强，而在第三剂后，该GMT值很高(～800,000)。相反地，血清对鼻腔内单独给药PSA的应答则不良：在首剂后，四只小鼠中仅有两只有血清转变发生，在第二剂后，无一试验小鼠有血清HA抗体(这些小鼠是从那些首次免疫后受试小鼠中分出的)并且虽然全部试验动物在第3剂后却有血清转变出现，但其GMT却比那些接受了一剂PSA+铝胶的动物的还要低。脱乙酰几丁质增强了鼻腔内给药PSA的血清应答，在第3次接种后，鼻腔内(I/N)接受PSA+脱乙酰几丁质的小鼠的抗体应答要比单独I/N接受PSA的要强360倍。在PSA+脱乙酰几丁质小鼠中，血清应答的强度非常相似于S/C免疫的小鼠；事实上，这两组GMT在任何取样点都没有统计学上的差异(t检验P＞0.01)。
单独用PSA鼻腔内给药以连续的天数免疫一些小鼠三次以研究此方法是否比每月一次更有优越性。虽然此组中所有小鼠在首剂后21天都可测出血清抗体而且此时的GMT也比鼻腔内接受的单剂PSA的小鼠的要高，但是尽管GMT没有降低，血清阳性的小鼠数在研究过程中却降低了(此组中相同的小鼠在每一时刻取样)，在最后时刻，每月方案中的小鼠的GMT要比每天方案中的高一个数量级。
表2
PSA免疫小鼠的血清IgG抗HA应答
a阳性数/试验数b几何平均效价
| 组 | 1剂后血清转变GMT | 2剂后血清转变GMT | 3剂后血清转变GMT |
| PSA+脱乙酰几丁质 | 4/4 557 | 4/4 40504 | 4/4 653113 |
| PSA鼻腔给药 | 2/4 67 | 0/4 ＜50 | 4/4 1818 |
| PSA皮下给药 | 4/4 2339 | 4/4 35196 | 4/4 816552 |
| PSA每天3剂 | 4/4 182 | 3/4 229 | 2/4 180 |
2.
鼻腔洗液IgA抗HA应答
纯化的表面抗原(图2和表3)
皮下给药PSA+铝胶的诱发鼻腔IgA应答的效果非常差，这和我们以前的以及其它一些研究成果一致。虽然按照应答动物数来看，鼻腔内单独给药PSA的粘膜免疫原性比皮下免疫的稍好，但它仍然是不良粘膜免疫原。虽然该应答在首剂后依然是低的，但是脱乙酰几丁质的加入大大增强了该IgA应答，HA特异性IgA可在四只小鼠的三只中检出。通过第二次免疫可大大增强这些小鼠的IgA应答。最后的免疫几乎没有效果；事实上该平均特异性IgA水平有轻微的下降。
表3
PSA免疫小鼠的鼻腔IgA抗HA应答
a阳性数/试验数b几何平均效价
| 组 | 1剂后粘膜转变GMT | 2剂后粘膜转变GMT | 3剂后粘膜转变GMT |
| PSA+脱乙酰几丁质 | 3/4 2.26 | 4/4 282.81 | 4/4 184.47 |
| PSA鼻腔给药 | 0/4 ＜1 | 1/4 1.20 | 3/4 2.31 |
| PSA皮下给药 | 0/4 ＜1 | 0/4 ＜1 | 2/4 1.32 |
| PSA每天三剂 | 0/4 ＜1 |
单独脱乙酰几丁质应答
在全部测定中，单独用脱乙酰几丁质免疫的对照小鼠的血清和鼻腔灌洗液都是阴性的。
鼻和肺组织中局部抗HA抗体分泌细胞应答(ASC)
在第三取样点，从每组的四只小鼠的鼻粘膜和肺实质中分离淋巴细胞。汇集来自单个小鼠的淋巴细胞并用ELISPOT法检测分泌IgA，IgG和IgM抗流感抗体的细胞。结果如图3a和3b所示。
全部试验组的鼻和肺组织中都检出了分泌HA特异性抗体的B细胞。而在PSA+脱乙酰几丁质组中则有非常大数量的这种细胞且这在直线标度的结果图中最明显(图3b)。在全部试验例中，除了皮下免疫的小鼠外，IgA抗体分泌细胞(ASC)在鼻腔中占优势而IgG或IgM则在肺中占优势。PSA+脱乙酰几丁质免疫的小鼠的肺和鼻中应答强度是相近的。
前述的实施例只是本发明的示范而无任何意图于局限本发明的范围，该范围是由附于此的权利要求书限定的。
Claims (13)
1、一种适用于粘膜给药的疫苗组合物；该组合物包括一种流感病毒抗原；以及一种有效佐剂量的脱乙酰几丁质，且该脱乙酰几丁质是至少有80％脱乙酰的脱乙酰几丁质。
2、按照权利要求1的疫苗组合物，其中的脱乙酰几丁质至少有85％脱乙酰。
3、按照权利要求2的疫苗组合物，其中的脱乙酰几丁质有88％到90％脱乙酰。
4、按照前述任何一个权利要求的疫苗组合物，其适用于鼻腔给药。
5、按照前述任何一个权利要求的疫苗组合物，其包括血细胞凝集素和神经氨酸酶流感病毒抗原。
6、按照权利要求1的适用于鼻腔给药的疫苗组合物；该组合物包含纯化的血细胞凝集素和神经氨酸酶流感病毒抗原；以及有效佐剂量的权利要求1-3任一项所述的脱乙酰几丁质。
7、按照权利要求5或者权利要求6的疫苗组合物，其中的血细胞凝集素和神经氨酸酶流感病毒抗原以半径在10到25nm范围内的玫瑰花结形式存在。
8、按照前述的任何一个权利要求的疫苗组合物，其中的脱乙酰几丁质是水溶性的。
9、按照前述的任何一个权利要求的疫苗组合物，其中组合物的pH在5.5到6.5的范围内。
10、按照权利要求9的疫苗组合物，其中的pH约为6。
11、一种包括适用于鼻腔给药组合物的分配装置的医药产品，其结合了如前文任何一个权利要求所述的疫苗组合物。
12、按照权利要求11的医药产品，其中的分配装置是一种气雾剂分送系统。
13、使用如前文任何一个权利要求所述的脱乙酰几丁质制备鼻腔内佐剂组合物以便在鼻腔内给药时增强诸如纯化的血细胞凝集素和神经氨酸酶的流感病毒抗原的免疫原性。
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| DE60042704D1 (de) | 2000-01-14 | 2009-09-17 | Whitehead Biomedical Inst | Induktion zytotoxischer lymphozyten durch hitzeschockprotein-fusionsproteine hängt von der atp-bindungsdomäne in hsp ab und is cd4+ unabhängig |
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| EP1620732A2 (en) * | 2003-04-30 | 2006-02-01 | Nastech Pharmaceutical Company Inc. | Claudins' underexpression as markers of tumor metastasis |
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| GB9202464D0 (en) * | 1992-02-05 | 1992-03-18 | Danbiosyst Uk | Composition for nasal administration |
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| GB9525083D0 (en) * | 1995-12-07 | 1996-02-07 | Danbiosyst Uk | Vaccine compositions |
-
1994
- 1994-10-04 GB GB9419979A patent/GB9419979D0/en active Pending
-
1995
- 1995-09-21 AT AT95932078T patent/ATE229816T1/de active
- 1995-09-21 MX MX9702336A patent/MX9702336A/es unknown
- 1995-09-21 JP JP51148896A patent/JP4240237B2/ja not_active Expired - Lifetime
- 1995-09-21 DE DE69529224T patent/DE69529224T2/de not_active Expired - Lifetime
- 1995-09-21 AU AU35269/95A patent/AU710930B2/en not_active Expired
- 1995-09-21 EP EP95932078A patent/EP0784485B8/en not_active Expired - Lifetime
- 1995-09-21 WO PCT/GB1995/002231 patent/WO1996010421A1/en active IP Right Grant
- 1995-09-21 US US08/817,417 patent/US6048536A/en not_active Expired - Lifetime
- 1995-09-21 KR KR1019970702172A patent/KR100373593B1/ko not_active IP Right Cessation
- 1995-09-21 CA CA002201598A patent/CA2201598C/en not_active Expired - Lifetime
- 1995-09-21 BR BR9509190A patent/BR9509190A/pt not_active IP Right Cessation
- 1995-09-21 ES ES95932078T patent/ES2192582T3/es not_active Expired - Lifetime
- 1995-09-21 CN CN95195504A patent/CN1097467C/zh not_active Expired - Lifetime
- 1995-09-21 DK DK95932078T patent/DK0784485T3/da active
- 1995-09-21 NZ NZ292953A patent/NZ292953A/en not_active IP Right Cessation
- 1995-10-17 TW TW084110887A patent/TW426521B/zh not_active IP Right Cessation
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| US4659569A (en) * | 1981-02-09 | 1987-04-21 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Process for the production of virus vaccine |
| EP0506326A2 (en) * | 1991-03-27 | 1992-09-30 | Pronova Biopolymer As | Diequitorially bound beta 1-4 polyuronates and use of same for cytokine stimulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101450208B (zh) * | 2008-12-31 | 2011-08-31 | 中国人民解放军军事医学科学院微生物流行病研究所 | 喷鼻免疫流感多价疫苗的制备及其方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| ATE229816T1 (de) | 2003-01-15 |
| DK0784485T3 (da) | 2003-04-07 |
| EP0784485B8 (en) | 2003-05-02 |
| EP0784485A1 (en) | 1997-07-23 |
| MX9702336A (es) | 1997-06-28 |
| CN1159761A (zh) | 1997-09-17 |
| US6048536A (en) | 2000-04-11 |
| AU3526995A (en) | 1996-04-26 |
| WO1996010421A1 (en) | 1996-04-11 |
| NZ292953A (en) | 2001-03-30 |
| JP4240237B2 (ja) | 2009-03-18 |
| KR100373593B1 (ko) | 2003-05-09 |
| ES2192582T3 (es) | 2003-10-16 |
| CA2201598A1 (en) | 1996-04-11 |
| TW426521B (en) | 2001-03-21 |
| KR970706018A (ko) | 1997-11-03 |
| DE69529224T2 (de) | 2003-07-24 |
| AU710930B2 (en) | 1999-09-30 |
| CA2201598C (en) | 2006-12-12 |
| JPH10506405A (ja) | 1998-06-23 |
| EP0784485B1 (en) | 2002-12-18 |
| GB9419979D0 (en) | 1994-11-16 |
| BR9509190A (pt) | 1997-10-21 |
| DE69529224D1 (de) | 2003-01-30 |
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