CN106456585B - 疫苗组合物 - Google Patents
疫苗组合物 Download PDFInfo
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- CN106456585B CN106456585B CN201580030764.8A CN201580030764A CN106456585B CN 106456585 B CN106456585 B CN 106456585B CN 201580030764 A CN201580030764 A CN 201580030764A CN 106456585 B CN106456585 B CN 106456585B
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- influenza
- excipient
- antigen
- adjuvant
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Abstract
Description
技术领域
本发明涉及特定的二烷基甘氨酸和三烷基甘氨酸赋形剂用于增加流感抗原的免疫原性的用途,以及涉及用于增加流感抗原的免疫原性的方法,涉及使用该方法可获得的疫苗组合物,以及涉及该疫苗组合物在患者的疫苗接种中的用途。
背景技术
流感病毒是正黏病毒科(Orthomyxoviridae family)的成员。存在三种流感病毒的亚型,命名为感染人类的A、B、和C。
流感的季节性流行可以快速传遍世界各地并在医院和其它医疗保健成本以及损失的生产力方面造成显著的经济负担。世界卫生组织估计,在每年的流感流行中,存在三至五百万的严重疾病的病例以及每年在世界各地大约250,000至500,000例死亡。
流感大流行会在具有高致病性和抗原新颖性的种群中出现新的流感病毒株时发生。在一年中,全球大流行可以折磨世界人口的20%至40%。例如1918-19年的大流行在世界范围内影响了2亿人,致死3000万以上。虽然,从那之后,医疗保健已显著改善,开发了疫苗和抗病毒治疗,但估计现今的大流行将导致全球二到七百万的死亡。
在流感大流行将发生的情况下,一个可能出现的问题是,可能难以在所需时间内制造需要用于疫苗的足够量的流感抗原。另一个可能出现的问题是,流感疫苗可以需要数个星期来赋予免疫性,其可能不足够快以防止或减少高度感染菌株的传播。
因此存在对于具有增加的免疫原性(其可以比现有抗原更小量使用和/或更快速地赋予免疫性)的流感抗原的需要。
WO 2011/121301、WO 2011/121306和WO 2013/050780涉及特定赋形剂,包括二烷基甘氨酸和三烷基甘氨酸如二甲基甘氨酸(DMG),用于稳定病毒颗粒和/或多肽的用途。WO2011/121305涉及类似的赋形剂用于在冷冻或干燥过程中稳定铝盐佐剂的用途。这些参考文献均没有涉及增加流感抗原的免疫原性。
Reap等人的Journal of Laboratory and Clinical Medicine(1990),115(4),481-6描述了在兔模型中二甲基甘氨酸(DMG)的免疫调节能力。在用流感抗原接种之前和之后,兔被强迫喂食DMG。Reap等人并没有描述在给予兔之前在DMG的存在下冷冻、冷冻干燥或加热流感抗原。
发明内容
本发明出乎意料的发现是,可以在二烷基甘氨酸和三烷基甘氨酸如二甲基甘氨酸(DMG)的存在下,通过冷冻、冷冻干燥或加热流感抗原来增加流感抗原的免疫原性。相比于未修饰的流感抗原,得到的修饰的流感抗原具有增加的免疫原性。相比于已与二烷基甘氨酸/三烷基甘氨酸混合但没有经历冷冻、冷冻干燥或加热的流感抗原,得到的修饰的流感抗原也具有增加的免疫原性。
存在相关于修饰的流感抗原的增加的免疫原性的两个显著的优点。
首先,修饰的流感抗原可以使用比未修饰的流感抗原低得多的剂量来在患者中激发(illicit)相同的免疫应答(immune response)。这种“抗原节约(antigen sparing)”的性能是非常有利的,特别是在其中数百万患者需要接种疫苗的大流行情况下。
第二,修饰的流感抗原能够比未修饰的流感抗原更快速地赋予患者免疫性。免疫性的更快起效也是非常有利的,特别是在其中重要的是试图停止大流行的传播的大流行情况下。
因此,本发明提供了赋形剂用于增加流感抗原的免疫原性的用途,该赋形剂是化学式(I)的化合物或其生理学上可接受的盐或酯:
其中:
R1表示氢或C1-6烷基;
R2表示C1-6烷基;并且
R3表示C1-6烷基,
该用途包括(a)冷冻,(b)热处理,和/或(c)冷冻干燥包含流感抗原和赋形剂的水性组合物。
本发明进一步提供了用于增加流感抗原的免疫原性的方法,所述方法包括(a)冷冻、(b)热处理、和/或(c)冷冻干燥包含流感抗原和赋形剂的水性组合物,该赋形剂是化学式(I)的化合物或其生理学上可接受的盐或酯:
其中:
R1表示氢或C1-6烷基;
R2表示C1-6烷基;并且
R3表示C1-6烷基。
本发明进一步提供了可以通过所述方法可获得的疫苗组合物。
本发明进一步提供了所述疫苗组合物,用于在人或动物患者中预防流感感染。
本发明进一步提供了所述疫苗组合物在制造用于在人或动物患者中预防流感感染的药物中的用途。
本发明进一步提供了在人或动物患者中预防流感感染的方法,该方法包括将所述疫苗组合物给予所述患者。
附图说明
图1示出了在实施例2中对在第1和24天给予组合物A至F的小鼠,在不同的时间点测量的血细胞凝集抑制试验(HIA)滴度。组合物A至C没有用赋形剂处理。组合物A含有正常剂量的抗原,而组合物B和C含有1/100剂量的抗原。组合物D至F含有1/100剂量的抗原,但与赋形剂混合然后热处理。组合物D至F的HIA滴度比用对照组合物B和C观测到的显著更高。
图2示出了在实施例3中对在第1和24天给予组合物G至N的小鼠在不同的时间点测量的血细胞凝集抑制试验(HIA)滴度。一旦HIA滴度大于50,认为小鼠具有获得免疫性。用赋形剂、佐剂和热处理的组合(组合物N)最快速地获得免疫性。
图3示出了在实施例4中对在第1和24天给予组合物O至R的小鼠在不同的时间点测量的血细胞凝集抑制试验(HIA)滴度。这些结果表明,用实施例3的组合物R中的二甲基甘氨酸也观测到了用实施例1和2的聚乙烯亚胺(polyethyleneimine)以及实施例3或组合物Q所观测到的对流感抗原的影响。
具体实施方式
概要
本发明涉及,使用化学式(I)的赋形剂或其生理学上可接受的盐或酯,如二甲基甘氨酸,来增加流感抗原的免疫原性。
通常将流感抗原与赋形剂混合以给出水性组合物,然后使水性组合物经受处理,如冷冻、加热和/或冷冻干燥,其增加流感抗原的免疫原性。相比于如果仅将流感抗原与赋形剂混合而没有冷冻、加热和/或冷冻干燥所观测到的,在赋形剂的存在下冷冻、加热和/或冷冻干燥流感抗原会增加抗原的免疫原性。
在处理过程中流感抗原和赋形剂相互作用,从而相比于在处理之前的流感抗原的免疫原性,增加了流感抗原的免疫原性。因此抗原的免疫原性在处理步骤过程中通常是增加的。
通常,该处理是冷冻或加热或冷冻干燥,优选冷冻或加热,更优选冷冻。可替换地,可以使用处理的组合,如冷冻随后加热或冷冻干燥,随后加热。在后一种情况下,通常在加热之前重构(reconstitute)冷冻干燥的组合物。
可以分别在冷冻、冷冻干燥或加热以后,解冻、重构或冷却得到的组合物,并作为疫苗组合物给予患者。
水性组合物
水性组合物包含赋形剂和流感抗原。水性组合物通常是悬浮液或溶液。水性组合物是通过在水性溶剂中混合赋形剂和流感抗原来制备的。可以使用任何适宜的水性溶剂体系。水性溶剂可以是缓冲水(buffered water)。水性溶剂通常是HEPES缓冲的水、Tris缓冲的水、磷酸盐缓冲的水或纯水。
可选地,在与赋形剂和流感抗原混合之前,将一种或多种糖与水溶剂混合。可替换地,可以在赋形剂和流感抗原以后,将一种或多种糖与水溶剂混合。
可选地,在与赋形剂和流感抗原混合之前,将佐剂与水溶剂混合。可替换地,可以在赋形剂和流感抗原之后,将佐剂与水溶剂混合。
通常,如果存在佐剂,则将也存在一种或多种糖,因为该一种或多种糖将通常使佐剂稳定,特别是在处理步骤过程中。
在水性组合物中还可以存在其它成分。例如,还可以存在化学式(II)的化合物:
其中X表示-S(O)2-并且Ra和Rb独立地表示C1-6烷基。化学式(II)的优选化合物是甲基磺酰基甲烷(MSM),其中Ra和Rb均表示甲基。赋形剂和化学式(II)的化合物的组合可以在一起相互作用,从而在处理步骤过程中进一步增加流感抗原的免疫原性。
水性组合物中的赋形剂的浓度通常在0.001M或更大的范围内,优选0.01M或更大且更优选0.1M或更大的范围内,例如0.1M至5.0M,或约0.5M。
如果使用一种或多种糖,则水性组合物中糖的浓度或糖的总浓度通常是1M或更小,优选0.7M或更小,例如0.5M或更小或0.3M或更小。糖浓度或总浓度可以低至0.1mM或低至0.5mM。
采用的每种成分的具体浓度将取决于多种因素,包括流感抗原的性质;使用的赋形剂;是否使用一种或多种糖(并且如果是,糖的特性);是否存在佐剂;以及采取的具体的冷冻、冷冻干燥或热处理步骤。
流感抗原
适用于本发明的流感抗原包括流感(类型A、B或C)疫苗的任何免疫原性组分。
流感抗原可以是全灭活的流感病毒或活的减毒的流感病毒。流感抗原可以是流感(类型A、B或C)的表面蛋白。具体地,流感抗原可以是血凝素(HA)、神经氨酸酶(NA)、核蛋白、M1、M2、NS1、NS2(NEP)、PA、PB1、PB1-F2和或PB2蛋白、或任何这些蛋白质的免疫原性衍生物或片段。流感抗原可以是HA1、HA2、HA3、HA4、HA5、HA6、HA7、HA8、HA9、HA10、HA11、HA12、HA13、HA14、HA15和/或HA16、它们的任何免疫原性片段或衍生物、以及HA蛋白、片段或衍生物的任何组合。神经氨酸酶可以是神经氨酸酶1(N1)或神经氨酸酶2(N2)。
赋形剂
赋形剂是化学式(I)的化合物或其生理学上可接受的盐或酯。
生理学上可接受的盐通常是与生理上可接受的酸的盐,因而包括用无机酸如盐酸或硫酸或有机酸如柠檬酸、酒石酸、苹果酸、马来酸、扁桃酸、富马酸或甲磺酸形成的那些。盐酸盐是优选的。
酯通常是C1-6烷基酯,优选C1-4烷基酯。因此酯可以是甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基酯。乙基酯是优选的。
如在本文中所使用的,C1-6烷基基团优选是C1-4烷基基团。优选的烷基基团选自甲基、乙基、丙基、异丙基、丁基、异丁基和叔丁基。甲基和乙基是特别优选的。
为避免疑义,化学式(I)的化合物的定义还包括其中羧酸根阴离子是质子化的以产生-COOH并且铵阳离子结合药学上可接受的阴离子的化合物。另外,为避免疑义,以上定义的化合物可以以任何对映体形式来使用。
通常,R1表示氢或C1-4烷基,优选氢或C1-3烷基,更优选氢、乙基或甲基,最优选氢或甲基。
通常,R2表示C1-4烷基,优选C1-3烷基,更优选乙基或甲基,最优选甲基。
通常,R3表示C1-4烷基,优选C1-3烷基,更优选乙基或甲基,最优选甲基。
R2和R3可以是相同或不同的,但优选是相同的。当R1表示C1-6烷基时,那么R1、R2和R3可以是相同或不同的,但优选是相同的。
在优选的实施方式中,R1表示氢并且R2和R3是如以上所定义的。因此,特别优选的是,R1表示氢并且R2和R3表示甲基,使得化学式(I)的化合物是二甲基甘氨酸。
在可替换的优选的实施方式中,R1表示C1-6烷基并且R2和R3是如以上所定义的。因此,特别优选的是,R1至R3均表示甲基,使得化学式(I)的化合物是三甲基甘氨酸。
可替换地,赋形剂可以是聚合物,如聚乙烯亚胺(polyethyleneimine)(PEI),而非化学式(I)的化合物或其生理学上可接受的盐或酯。
PEI是脂肪族多胺,其特征在于表示为-(CH2-CH2-NH)-的重复化学单元。在本文中提及的PEI包括聚乙烯亚胺均聚物或共聚物。聚乙烯亚胺共聚物可以是无规或嵌段共聚物。例如,PEI可以由聚乙烯亚胺和另一种聚合物如聚乙二醇(PEG)的共聚物组成。聚乙烯亚胺可以是线性或支链的。
提及的PEI还包括聚乙烯亚胺的衍生形式。聚乙烯亚胺在不同位置含有氮原子。氮原子存在于末端氨基基团中,例如R-NH2,,并且存在于内部基团中,如在聚合物结构内中断烷基或亚烷基基团的基团,例如R-N(H)-R’,以及存在于聚合物分支的交叉处,例如R-N(-R’)-R”,其中R、R’和R”可以是例如亚烷基基团。除了或代替氢原子,烷基或芳基基团可以连接于氮中心。这样的烷基和芳基基团可以是取代的或未取代的。烷基基团通常是C1-C4烷基,例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基。芳基基团通常是苯基。
PEI可以是已共价连接于各种其它的聚合物如聚乙二醇的聚乙烯亚胺。已经生成了PEI的其它的改性形式并且一些是可商购的:支化的PEI 25kDa,LMW-PEI5.4kDa、伪树枝状PEI(pseudodendrimeric PEI)、PEI-SS-PEI、PEI-SS-PEG、PEI-接枝-PEG、PEG-共-PEI、PEG-接枝-PEI、PEI-共-L乳酰胺-共-琥珀酰胺、PEI-共-N-(2-羟乙基-乙烯亚胺)、PEI-共-N-(2-羟丙基)甲基丙烯酰胺、PEI-接枝-PCL-嵌段-PEG、PEI-SS-PHMPA、PEI-接枝-葡聚糖10 000和PEI-接枝-转铁蛋白-PEG、-接枝-PEI。PEI可以是全甲基化聚乙烯亚胺或聚乙烯亚胺-乙磺酸。
可以获得广范围的数均摩尔质量(Mn)的PEI,例如300Da和800kDa之间。优选地,数均摩尔质量是300和2000Da之间、500和1500Da之间、1000和1500Da之间、10和100kDa之间、20和100kDa之间、30和100kDa之间、在40和100kDa之间、50和100kDa之间、60和100kDa之间、50和70kDa之间或55和65kDa之间。大约60kDa的相对高Mn的PEI或1200Da的相对低Mn是适宜的。
优选地,PEI的重均摩尔质量(Mw)是500Da和1000kDa之间。最优选地,PEI的Mw是500Da和2000Da之间、1000Da和1500Da之间、或1和1000kDa之间、100和1000kDa之间、250和1000kDa之间、500和1000kDa之间、600和1000kDa之间、750和1000kDa之间、600和800kDa之间、700和800kDa之间。大约750kDa的相对较高Mw或大约1300Da的相对较低Mw是适宜的。
可以通过本领域技术人员众所周知的方法来确定PEI的重均摩尔质量(Mw)和数均摩尔质量(Mn)。例如,可以通过光散射、小角度中子散射(SANS)、X射线散射或沉降速度来确定Mw。可以例如通过凝胶渗透色谱法、粘度测定法(Mark-Houwink等式)和依数性方法(colligative method)如蒸气压渗透法或端基滴定,来确定Mn。
各种形式的PEI是可商购的(例如Sigma、Aldrich)。例如,本文中使用的具有约60kDa的Mn和约750kDa的Mw的支化的、相对高分子量形式的PEI是可商购的(Sigma P3143)。这种PEI可以由以下化学式来表示:
本文中使用的相对低分子量形式的PEI也是可商购的(例如Aldrich482595),其具有1300Da的Mw和1200Da的Mn。
糖
在水性组合物中可选地存在一种或多种糖。可以存在两种或更多种糖,例如两种、三种或四种糖。优选的是,存在一种或两种糖,最优选两种糖。赋形剂和糖的组合可以在一起相互作用,从而在处理步骤过程中进一步增加流感抗原的免疫原性。在处理步骤过程中,糖还帮助稳定佐剂(当存在时),特别是铝盐佐剂。
糖通常是单糖、二糖、三糖、四糖、糖醇或另一种寡糖。
通常,单糖是葡萄糖、果糖、阿拉伯糖、甘油醛、半乳糖或甘露糖。通常,二糖是蔗糖、海藻糖、乳糖、纤维二糖、松二糖、麦芽酮糖、蜜二糖、异麦芽糖、或麦芽糖。通常,三糖是棉子糖、松三糖或伞形糖。通常,四糖是水苏糖。通常,糖醇是甘露醇。寡糖的其它实例包括五糖毛蕊花糖。
通常,糖是非还原糖,例如蔗糖或棉子糖。
当在水溶液中存在一种糖时,该糖优选是甘露醇或蔗糖,优选甘露醇。
当在水悬浮液中存在两种糖时,该糖优选是蔗糖和棉子糖。
佐剂
在水性组合物中可选地存在佐剂。可以使用任何适宜的佐剂,但铝盐佐剂是优选的。当使用铝盐佐剂时,优选的是,在水性组合物中还存在一种或多种糖,以在处理步骤过程中稳定佐剂。
通常,铝盐是氢氧化铝(Al(OH)3)、磷酸铝(AlPO4)、盐酸铝、硫酸铝、铵矾、钾明矾或硅酸铝。优选地,使用的铝盐佐剂是氢氧化铝或磷酸铝。最优选地,铝盐佐剂是氢氧化铝(Al(OH)3)。
通常,铝盐佐剂采取由铝盐制成的水合凝胶的形式,该水合凝胶是水性介质中的颗粒悬浮液。铝盐佐剂的制备是本领域技术人员众所周知的。例如,如本领域技术人员已知的,通常通过在明确限定和受控的化学环境中将铝离子(通常作为硫酸盐或氯化物)的水溶液暴露于碱性条件来制备氢氧化铝和磷酸铝佐剂。这样的方法可以,例如用来制备氢氧化铝或磷酸铝水合凝胶。
冷冻
可以通过任何适宜的方法来进行水性组合物的冷冻。因此,可以通过浸没在液氮或液氮蒸汽中,置于冷冻器中或使用干冰和醇冷冻浴,来进行冷冻。
通常,将水性组合物冷冻至-4℃或以下,优选-10℃或以下,更优选至-20℃或以下,更优选至-30℃。通常不在-100℃以下冷冻水性组合物。可以将水性组合物冷冻至例如约-80℃。
通常将水性组合物在期望的温度下保持冷冻30分钟或更久,优选1小时或更久,例如2至24小时。
通常在用作疫苗以前,通过在室温下放置,使得冷冻的水性组合物解冻。
可以通过常规实验来适当优化冷冻和解冻条件。
冷冻干燥
可以按照标准程序来进行冷冻干燥。有三个主要阶段:冷冻,初次干燥(primarydrying)和二次干燥(secondary drying)。通常使用冷冻干燥机来进行冷冻。在此步骤中,重要的是,将生物材料冷却到低于其低共熔点(eutectic point),材料的固相和液相可以共存的最低温度。这确保在随后的步骤中将发生升华而不是熔化。可替换地,无定形材料不具有低共熔点,但确实具有必须将产物保持在其以下的临界点,以在初次和二次干燥过程中防止回熔(melt-back)或瓦解。
在初次干燥过程中,通过施加适当水平的真空来控制压力,同时供应足够的热量,以使得水能够升华。在此阶段,升华至少50%,通常60至70%的材料中的水。初级干燥可能是缓慢的,因为过多的热量可以降解或改变生物材料的结构。冷凝器室和/或冷凝板提供通过再凝固,在其上俘获水蒸气的表面。
在二次干燥过程中,通过进一步施加热量来除去水合的水。通常,还降低压力以促进进一步干燥。在冷冻干燥过程的完成以后,可以在密封之前用惰性气体如氮气来打破真空,或可以在真空下密封材料。
在用作疫苗以前,使用例如水或水性缓冲液,将冷冻干燥的组合物重构为水性组合物。
可以通过常规实验来适当优化冷冻干燥条件。
热处理
可以通过任何适宜的方法来进行水性组合物的加热处理。
通常,将水性组合物加热至大于30℃,优选大于40℃。更优选地,将水性组合物加热至30℃至80℃的温度,例如35℃至60℃或40℃至50℃。优选的温度是约45℃。
一旦已将水性组合物至加热期望的温度,优选将其保持在该温度下30分钟或更久,优选1小时或更久,例如2小时至2周或4小时至24小时。
典型的热处理包括加热至约45℃并保持在该温度下约7天。
在用作疫苗以前,通常使热处理的水性组合物返回到室温。
可以通过常规实验来适当优化热处理条件。
免疫原性的增加
流感抗原的免疫原性是抗原在人或动物的身体中引起免疫应答的能力。可以通过使用用于预测免疫应答的水平的标准试验,如血细胞凝集抑制试验,比较未修饰(对照)的流感抗原的免疫原性与根据本发明的修饰的流感抗原的免疫原性,来测量免疫原性的变化。
可以使用本领域技术人员已知的任何适宜的技术来测量流感抗原的免疫原性。优选的标准技术是血细胞凝集抑制试验。在以下实施例中,描述了用于此试验的示例性流程。
本发明的修饰的流感抗原的增加的免疫原性是指,用较小量的修饰的抗原可以获得相同的免疫应答。因此,如果给予患者剂量D的未修饰的抗原得到了一定水平的免疫原性,那么通常0.5D或更少,优选0.1D或更少,更优选0.01D或更少的剂量,将得到相同水平的免疫原性。通常在给予患者以后至少10天,例如在10天、15天或20天以后测量免疫原性。
本发明的修饰的流感抗原的增加的免疫原性是指,免疫性的引发比用未修饰的抗原更加快速地发生。因此,如果患者在给予给定剂量的未修饰的抗原以后需要时间T来获得免疫性,那么对于给予相同剂量的修饰的抗原的患者通常将需要0.75T或更少时间,优选0.5T或更少时间,最优选0.2T或更少时间,来获得免疫性。
疫苗组合物的使用
在冷冻、冷冻干燥、或加热以后,可以分别解冻、重构或冷却得到的组合物,然后用作疫苗组合物。在使用之前,根据需要可以用例如磷酸盐缓冲的盐水或注射用水来稀释疫苗组合物。
通常,疫苗组合物含有一种或多种不同的流感抗原,其至少一种是根据本发明制备的。在一种实施方式中,疫苗组合物含有两种、三种或四种不同的流感抗原,优选地其全部均是根据本发明制备的。
然后可以通过例如注射将得到的疫苗组合物给予需要疫苗接种的人或动物患者。通常,患者是人。
优选地,患者是具有“风险”群体的一部分的人。这样的患者包括儿童、老年患者和/或患有肺病、糖尿病、癌症、或肾或心脏问题的患者。特别优选用本发明的疫苗组合物来治疗此患者组,因为相比标准疫苗,用本发明疫苗所得到的免疫性的快速引发会降低患者在疫苗接种和免疫性引发之间的时间段中被感染的风险。
优选地,该患者以前已经遭受对流感疫苗的不良反应。特别优选用本发明的疫苗组合物来治疗此患者组,因为抗原节约效应意味着,需要对患者递送较少的疫苗组合物,因而降低对疫苗的过敏反应或其它不良反应的风险。
以下实施例举例说明本发明。
实施例1–疫苗组合物的制备
材料
均如获得自商业来源(Aldrich)地使用二甲基甘氨酸(DMG)、蔗糖、棉子糖、HEPES(4-(2-羟乙基)-1-哌嗪乙磺酸)缓冲剂、氯化钠和无菌水。如获得自商业来源(SourceBioscience)地使用AlhydrogelTM。如获得自商业来源(Sigma目录号:P3143-50%w/v在水中的溶液;Mn 60,000)地使用聚乙烯亚胺(PEI)。全灭活流感A/Solomon Islands/2006H1N1抗原获得自英国国家生物标准及控制研究所(National Institute for BiologicalStandards and Control)(NIBSC)。
组合物制备
150ml的HEPES缓冲液制备如下。在量筒中量出100ml的无菌水。用校准检查的天平称出2.5g NaCl,并使用磁力搅拌器和棒溶解于无菌水中。加入6ml的1M HEPES并搅拌。当完全溶解时,使用pH计和氢氧化钠将pH改变到7.9。用无菌水将最终体积补足至150ml。然后在生物安全柜中通过0.2μm过滤单元过滤最终的HEPES缓冲液混合物。
在称量所需要的在以下表1至3中描述的赋形剂组分以后,将它们放入50ml无菌烧瓶中。然后将大约6ml的HEPES缓冲液加入烧瓶并通过旋转来混合内含物。然后在+60℃水浴中加热烧瓶和内含物直到溶解。当溶解时,测量混合物的体积并用更多的HEPES缓冲液将最终体积补足至10ml。在生物安全柜中通过0.2μm过滤装置过滤赋形剂制剂。
使冷冻干燥的流感病毒抗原A/Solomon Islands/2006H1N1的小瓶从-20℃达到室温,然后制备抗原在无菌水中的工作储存液(working stock)。
如在以下表1至3中详细说明的,制备玻璃螺旋盖的小瓶(预先高压灭菌的)。每个小瓶最终含有1ml的总体积。在需要的情况下,将500μl的AlhydrogelTM储存液(2%w/v的浓度,以产生1%w/v的最终浓度)用移液管吸取到每个小瓶。然后将流感病毒抗原储存液用移液管吸取到每个小瓶,以在每个小瓶中产生2或0.2μg抗原的最终抗原浓度。将小瓶封盖并通过简单涡旋混合。
然后用下文描述的和如在表1至3中陈述的处理A至C之一来可选地处理小瓶。
·处理1–将小瓶存储在45℃下7天,然后使其返回到室温。
·处理2–将小瓶冷冻至-80℃,然后通过保持在室温下使其解冻。
·处理3–在商用冷冻干燥器中,通过冷冻至–80℃并在真空下干燥16小时来冷冻干燥小瓶。然后将小瓶存储在45℃下7天,接着重构回到1ml的总体积并使其返回室温。
表1
表2
表3
实施例2–抗原节约效应
在第0天和第24天,将在实施例1中制备的组合物A至F皮下给予BALB-c小鼠。通过在不同的时间点测量取自小鼠的血液的血细胞凝集抑制试验(HIA)滴度来确定组合物针对流感的保护效果。
血细胞凝集抑制试验包括以下步骤。
1.在56℃下灭活血清30分钟。
2.通过用1%CRBC来预温育血清30分钟以除去非特异性鸡红细胞(CRBC)凝集活性。除去CRBC并分离血清。
3.在PBS/0.5%BSA中连续稀释血清。
4.将流感病毒的HAU加入孔。
5.在室温下温育板30分钟。
6.将1%CRBC/PBS悬浮液加入孔。
7.在室温下温育板30-45分钟。
8.肉眼确定孔中的凝集。
9.记录和报告HIA滴度,其中HIA滴度是形成CRBC小粒的最大稀释系列的倒数。
结果描述于图1。组合物D至F的这些结果表明,相比于对照组合物A,赋形剂与热处理的组合导致相等或更好的HIA滴度。这是意想不到的,因为相比于对照(与用组合物B所获得的结果相比),组合物D至F仅含有按重量计1%的抗原。
实施例3–加速免疫性的引起
在第0天和第24天,将在实施例1中制备的组合物G至N皮下给予BALB-c小鼠。通过如在实施例2中描述的测量HIA滴度,在各个时间点确定组合物针对流感的保护效果。
结果描述于图2。一旦HIA滴度大于50,认为小鼠具有获得免疫性。用赋形剂、佐剂和热处理的组合(组合物N),最快速地获得免疫性。
实施例4–用不同的赋形剂观测到的类似结果
在第0天和第21天,将在实施例1中制备的组合物O至R皮下给予BALB-c小鼠。通过如在实施例2中描述的测量HAI滴度,在各个时间点确定组合物针对流感的保护效果。
结果描述于图3。这些结果表明,用二甲基甘氨酸也观测到了实施例1和2中用聚乙烯亚胺的所观测到的对流感抗原的效果。因此,用二甲基甘氨酸也观测到了用聚乙烯亚胺所观测到的免疫性引发的加速和抗原节约效应。
Claims (5)
1.赋形剂在制备用于增加流感抗原的免疫原性的水性组合物中的用途,所述赋形剂是二甲基甘氨酸或其生理学上可接受的盐或酯,
所述用途包括在40℃至50℃的温度下热处理包含所述流感抗原、所述赋形剂、一种或多种糖和佐剂的水性组合物2小时至2周,其中,所述一种或多种糖是蔗糖和棉子糖以及所述佐剂是铝盐佐剂。
2.一种疫苗组合物的制备方法,所述方法包括在40℃至50℃的温度下热处理水性组合物2小时至2周,所述水性组合物包含流感抗原、赋形剂、一种或多种糖和佐剂,其中所述赋形剂是二甲基甘氨酸或其生理学上可接受的盐或酯,其中所述一种或多种糖是蔗糖和棉子糖以及所述佐剂是铝盐佐剂。
3.一种通过权利要求2中限定的方法能够获得的疫苗组合物。
4.权利要求3中限定的疫苗组合物在制备用于预防人或动物患者中的流感感染的药物中的用途。
5.根据权利要求4所述的用途,其中,所述患者是(a)儿童、老年患者和/或患有肺病、糖尿病、癌症、或肾或心脏问题的患者、或(b)先前已经遭受对流感疫苗的不良反应的患者。
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AU2015245313B2 (en) | 2020-01-23 |
AU2015245313A1 (en) | 2016-11-03 |
US10806783B2 (en) | 2020-10-20 |
US10086064B2 (en) | 2018-10-02 |
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EP3129007A1 (en) | 2017-02-15 |
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