CN117098552A - 流感疫苗 - Google Patents
流感疫苗 Download PDFInfo
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- CN117098552A CN117098552A CN202280025416.1A CN202280025416A CN117098552A CN 117098552 A CN117098552 A CN 117098552A CN 202280025416 A CN202280025416 A CN 202280025416A CN 117098552 A CN117098552 A CN 117098552A
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Abstract
提供在儿童、老年人中具有高的免疫原性,与以往的裂解疫苗相比有效性高的流感疫苗。组合物,其为向儿童及/或老年人施予的流感疫苗组合物,所述组合物含有用β‑丙内酯进行了灭活处理的灭活全毒粒作为病毒抗原。
Description
技术领域
本发明涉及对儿童或老年人有效性高的流感疫苗。
背景技术
人类的流感病毒是正粘病毒属的单链RNA病毒,根据内部抗原的抗原性分为A型、B型及C型。其中,已知以冬季为中心每年引起大流行的是A型及B型,推定在日本每年约1,000万人以上患病。对于这种每年引起大流行的流感病毒的预防而言最有效的手段是疫苗。日本的流感疫苗是以在1957年流行的亚洲流感为契机而推出的,当时为对纯化的流感病毒进行灭活处理后的灭活全毒粒疫苗。但是,为了减少之后的发热等副反应,批准了利用乙醚、表面活性剂处理解裂病毒粒子并除去脂质成分而得的裂解疫苗,现在,裂解疫苗在世界范围内广泛普及。
但是,已知裂解疫苗在儿童、老年人这样免疫应答弱的年龄层中免疫原性尤其低。因此,季节性流感病毒感染的约半数是儿童,虽然发生频率低,但与其它年龄层相比,儿童感染流感脑病的风险高,老年人感染症状容易呈重症化,死亡风险高。因此,在欧美,已经批准了鼻减毒活疫苗、佐剂制剂及高效价疫苗这样的用于儿童、老年人的有效性高的流感疫苗。
作为老年人的免疫应答弱的理由之一,可举出老年人的自然免疫降低。特别是已知吞噬细胞中的Toll样受体(TLRs)承担连接自然免疫和获得性免疫的重要作用(非专利文献1),但在老年人的巨噬细胞中,TLRs的表达显著降低,因此,作为抗原特异性反应的获得性免疫应答也降低(非专利文献2)。另外,在没有既往病史、疫苗接种史也少的儿童中,需要促进更强的基础免疫,因此,需要介由TLR7的浆细胞样树突状细胞的强的活化(非专利文献3)。
现有技术文献
非专利文献
非专利文献1:Vasselon T,Detmers PA.Toll receptors:a central element ininnate immune responses(Toll受体:固有免疫应答的中心要素).Infect Immun(感染与免疫).2002Mar;70(3):1033-41.
非专利文献2:Renshaw M,Rockwell J,Engleman C,Gewirtz A,Katz J,SambharaS.Cutting edge:impaired Toll-like receptor expression and function in aging(前沿:衰老过程中Toll样受体的表达和功能受损).J Immunol(免疫学杂志).2002Nov1;169(9):4697-701.
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发明内容
发明所要解决的课题
本发明涉及提供在儿童、老年人中具有高的免疫原性,与以往的裂解疫苗相比有效性高的流感疫苗。
用于解决课题的手段
本申请的发明人深入研究的结果发现,通过在流感病毒的灭活处理中使用β-丙内酯,能够制备与以往的福尔马林处理相比维持较高自然免疫活性的灭活全毒粒疫苗,该疫苗在儿童及老年人的模型动物中,具有比已经批准的裂解疫苗高的免疫原性。并且,在该β-丙内酯处理的灭活全毒粒疫苗中,能够对病毒增殖的鼻腔粘膜诱导病毒特异性抗体,在儿童及老年人的模型动物中,确认到相对于裂解疫苗而言的显著高的抗体诱导。
因此,本发明涉及以下的1)~6)。
1)组合物,其是向儿童及/或老年人施予的流感疫苗组合物,所述组合物含有用β-丙内酯进行了灭活处理的灭活全毒粒作为病毒抗原。
2)如1)所述的组合物,其中,病毒抗原包含由A/H1N1亚型及A/H3N2亚型组成的A型流感病毒株,以及由B/Victoria谱系及B/Yamagata谱系组成的B型流感病毒株。
3)如1)或2)所述的组合物,其不含佐剂。
4)如1)~3)中任一项所述的组合物,其被皮下施予。
5)免疫方法,其中,将含有用β-丙内酯进行了灭活处理的灭活全毒粒作为病毒抗原的组合物向儿童或老年人施予。
6)流感的预防方法,其中,将含有用β-丙内酯进行了灭活处理的灭活全毒粒作为病毒抗原的组合物向儿童或老年人施予。
发明效果
根据本发明,提供对免疫应答弱的儿童及/或老年人显示出比已经批准的裂解疫苗高的有效性的流感疫苗。本发明的流感疫苗组合物在儿童及老年人中,在血清及鼻腔粘膜的任一者中均促进高的抗体诱导,因此在感染、重症化的风险高的儿童及老年人中,能够提高病毒感染的防御活性,作为附加价值高的流感预防药的创制,能够对医药品产业作出巨大贡献。
附图说明
[图1]灭活处理对流感疫苗的自然免疫活性的影响。BPL:β-丙内酯。
[图2A]疫苗皮下施予21天后的血清中对于A/Singapore/GP1908/2015株的IgG效价。
[图2B]疫苗皮下施予21天后的血清中对于B/Phuket/3073/2013株的IgG效价。
[图3A]疫苗皮下施予42天后的血清中对于A/Singapore/GP1908/2015株的IgG效价。
[图3B]疫苗皮下施予42天后的血清中对于B/Phuket/3073/2013株的IgG效价。
[图4A]疫苗皮下施予42天后的血清中对于A/Singapore/GP1908/2015株的中和抗体效价。
[图4B]疫苗皮下施予42天后的血清中对于B/Phuket/3073/2013株的中和抗体效价。
[图5A]疫苗皮下施予42天后的鼻腔清洗液中对于A/Singapore/GP1908/2015株的IgG效价。
[图5B]疫苗皮下施予42天后的鼻腔清洗液中对于B/Phuket/3073/2013株的IgG效价。
具体实施方式
以下,对本发明的合适的实施方式进行详细说明。但是,本发明不限定于以下的实施方式。
本发明的流感疫苗组合物中的病毒抗原是用贝塔(β)丙内酯进行了灭活处理的流感病毒全毒粒。
本发明中,“流感病毒”是指A型流感病毒或B型流感病毒,或者其两者。另外,流感病毒还包含现在已知的全部的亚型以及将来被分离及鉴定的亚型。
本发明的病毒抗原至少包含A型流感病毒或B型流感病毒中的任一者。即,本发明的流感疫苗可以是包含A型流感病毒或B型流感病毒中的一者的病毒抗原的单价疫苗,也可以是包含这两者的多价疫苗。
作为病毒抗原,优选可举出包含由A/H1N1亚型及/或A/H3N2亚型组成的A型流感病毒株、和B/Victoria谱系及/或B/Yamagata谱系B型流感病毒株的病毒抗原,更优选可举出包含2株A型(A/H1N1亚型及A/H3N2亚型)、2株B型(B/Victoria谱系及B/Yamagata谱系)的病毒抗原。
流感病毒全毒粒能够通过使用发育鸡胚(日语为“発育鶏卵”)或培养细胞的方法制备。
基于发育鸡胚的制备方法是例如将病毒株接种于孵化鸡胚(日语为“孵化鶏卵”)并进行培养后,对病毒悬液进行澄清化、浓缩、纯化,得到包含病毒粒子的病毒溶液的方法。另外,基于培养细胞的制备方法是例如将病毒株接种于培养细胞并进行培养后,与上述发育鸡胚法同样地从培养上清液得到包含病毒粒子的病毒溶液的方法。
在此,对于培养而言,接种流感病毒株并于30~37℃培养1~7天左右,优选于33~35℃培养2天左右。培养结束后,回收病毒悬液(感染尿囊液或感染细胞培养上清液),为了澄清化,进行离心分离或过滤。接下来,为了浓缩,进行钡盐吸附洗脱反应、超滤。病毒纯化能够使用蔗糖密度梯度离心分离等超高速离心分离、液相色谱法等手段进行。
培养细胞只要是流感病毒显示增殖性的细胞,则没有特别限定,例如可举出MDCK(马丁达比犬肾,Madin-Darby Canine Kidney)、Vero、Caco-2、PER.C6、EB66及为了高表达用于病毒侵入的受体而重组的这些细胞。
这样得到的流感病毒全毒粒通过β-丙内酯进行了灭活处理。
即,本发明中,用β-丙内酯进行灭活处理来代替以往的使用甲醛的灭活处理(福尔马林处理)。
β-丙内酯是在多数的疫苗制备中用于灭活病毒而广泛使用的单烷化剂。
β-丙内酯的灭活处理是通过发育鸡胚或培养细胞进行培养时,在对回收的流感病毒悬液进行澄清化、浓缩或纯化中的任一时期进行。
作为β-丙内酯处理,可举出下述方法:在培养后回收的病毒溶液中,以终浓度成为0.0125~0.1vol%、优选为0.025~0.075vol%、更优选为0.05vol%的方式加入β-丙内酯,于2~8℃反应18小时以上、优选为20小时以上、更优选为24小时以上,并且50小时以下、优选为30小时以下。
作为更优选的方式,例如可举出于2~8℃以0.05%处理24小时。
如后述实施例所示,将用β-丙内酯进行了灭活处理的灭活全毒粒粒子作为抗原的流感疫苗与以往的通过福尔马林处理所制备的灭活全毒粒流感疫苗相比,自然免疫赋活化能力高,通过将其向儿童及老年人的模型动物施予,在第1次及2次施予后的血清中显示出与现有的裂解疫苗相比显著高的抗体诱导。另外,第2次施予后,该疫苗在鼻腔粘膜中也显示出高的病毒特异性IgG的诱导,在儿童的模型动物中,对于A型及B型中的任一病毒,均比裂解疫苗显著地高,在老年人的模型动物中,在B型的病毒中也显示出比现有的疫苗显著高的抗体诱导。
因此,包含将用β-丙内酯进行了灭活处理的流感病毒全毒粒作为病毒抗原的组合物在向儿童及/或老年人施予的情况下,作为发挥高的自然免疫赋活化能力的流感疫苗是有用的。另外,包含将用β-丙内酯进行了灭活处理的流感病毒全毒粒作为病毒抗原的组合物向儿童及/或老年人的施予作为用于在该在儿童及/或老年人中诱导针对流感病毒的抗体的免疫方法,以及作为流感的预防方法是有用的。
需要说明的是,自然免疫赋活化能力能够通过TLR活化能力评价,例如,如后述实施例所记载,能够通过测定对参入TLR7基因和分泌型碱性磷酸酶(SEAP)基因的RAW264.7细胞曝露流感抗原时的培养上清液中的SEAP活性(RLU值:相对光单位,Relative LightUnit)来进行。
本发明的流感疫苗组合物的病毒抗原例如使用如后述实施例所示使用重组RAW264.7细胞测定的RLU值优选为50以上,更优选为60以上。
本发明的流感疫苗组合物除了上述流感抗原以外,能够适当含有药学上可接受的载体,以规定形态被制剂化。
在此,作为载体,可举出在疫苗制造中通常使用的载体,具体而言,可例示出缓冲剂、乳化剂、保存剂(例如,硫柳汞)、等渗剂、pH调节剂、增稠剂、灭活剂(例如,福尔马林)、佐剂或免疫刺激剂等。佐剂是指通过与抗原一起施予,从而使对该抗原的免疫应答增强的物质,但是如上所述,本发明的疫苗组合物中疫苗抗原本身具有高的抗体诱导能力,因此并不是必需添加佐剂,能够制成不含有佐剂的组合物。
该流感疫苗组合物以固体、半固体或液体形态,以适合目的施予途径的方式适当地制剂。作为适当的施予途径,例如可举出肌肉内、经皮、皮下、皮内、鼻腔内、舌下、经口等,优选为皮下施予。作为肌肉内、经皮、皮下、皮内等的注射施予制剂,例如可举出液剂、乳剂(emulsion)、水溶性或疏水性的悬浮剂、添加液体使其溶解或悬浮进行使用的干燥粉末的剂型。
上述流感疫苗组合物中的流感抗原的含量是在1个施予单位中包含以血凝素量计为每1株病毒7.5μg以上、即7.5μgHA/株以上,优选为9~21μgHA/株,更优选为15μgHA/株。需要说明的是,血凝素含量是通过单向放射免疫扩散试验法(single radialimmunodiffusion)等由WHO、国家标准规定的试验法测定而得到的值。另外,疫苗中包含的抗原量可以根据病毒的种类或施予对象进行适当变更。
本发明的流感疫苗组合物的施予对象为儿童及/或老年人。本发明中,儿童是指0岁以上且不足15岁的人类,优选为3岁以上且不足12岁,老年人是指优选为50岁以上的人类,更优选为55岁以上,进一步优选为60岁以上。
本发明的流感疫苗组合物的施予次数为至少1次,但从有效性的观点考虑,优选至少2次。有时将进一步施予称为加强免疫,由此,能够发挥效果更高的感染防御效果。加强免疫的间隔推荐至少1周,优选为1~4周的间隔。
实施例
以下,通过实施例具体说明本发明,但本发明不受这些实施例的任何限定。
实施例1灭活处理对自然免疫赋活化能力的影响评价
在12日龄的发育鸡胚的绒毛膜尿囊腔(chorioallantoic cavity)内接种B/Phuket/3073/2013株的病毒,在培养3天后采集绒毛膜尿囊液(chorioallantoic fluid)。将所采集的绒毛膜尿囊液利用过滤器过滤而澄清化后,使其吸附于硫酸钡盐,利用12%柠檬酸钠溶液洗脱,回收流感病毒。回收的病毒进一步通过超滤置换为6.7mM磷酸缓冲生理盐水(pH7.2),在置换缓冲液后,通过利用蔗糖密度梯度离心回收包含流感病毒的级分,由此进行纯化。将得到的病毒溶液作为纯化流感病毒溶液。
向纯化流感病毒溶液以终浓度成为0.05%的方式添加作为灭活剂的β-丙内酯(BPL),通过4℃、24小时的反应来灭活流感病毒的感染性。在该灭活反应后,通过超滤(MWCO:100,000)将缓冲液置换为6.7mM磷酸缓冲生理盐水(pH7.2),将其作为β-丙内酯处理灭活全毒粒疫苗。
另外,将纯化流感病毒溶液调节为蛋白浓度为200μg/mL,向其中以福尔马林的终浓度成为0.01或0.02%的方式添加10%中性缓冲福尔马林液(富士胶片和光纯药、甲醛含量:3.8~4.1%),于4℃进行14天的反应。反应后,以终浓度成为10mM的方式添加甘氨酸来停止甲醛的反应,将其于4℃、以1,000,000×g离心分离4小时。离心分离后,弃上清液,使得到的病毒的沉淀物(pellet)在6.7mM磷酸缓冲生理盐水(pH7.2)中悬浮,将其作为甲醛处理灭活全毒粒疫苗。
相对于1.5×106细胞的NBP2-26261(Novus biologicals公司:在NFκB的转录应答元件的下游参入分泌型碱性磷酸酶(SEAP)基因而得的重组RAW264.7细胞,表达除TLR5以外的其它全部TLR。)而言,以按总蛋白量计为10μg的方式添加各种灭活处理疫苗,在37℃、5%CO2条件下培养24小时。培养后,回收上清液,利用SEAP报告检测试剂盒(SEAP ReporterAssay Kit)(商品名,Cayman公司)测定上清液的碱性磷酸酶活性。该测定值(RLU:相对光单位,Relative Light Unit)是介由TLR的自然免疫活性的指标,因此用本测定值对按照各灭活处理条件制备的疫苗的自然免疫活化能力进行比较。
测定值的比较如图1所示,作为病毒的灭活处理条件,在一般的用0.02%福尔马林于4℃反应14天的反应中,确认到明确的自然免疫赋活化能力的降低。另外,在0.01%福尔马林处理中,自然免疫赋活化能力也显示出比0.02%福尔马林处理高,但与β-丙内酯处理相比为低值。因此表明,与在1971年以前流通的利用福尔马林灭活的灭活全毒粒疫苗相比,β-丙内酯处理灭活全毒粒疫苗具有高的自然免疫赋活化能力。
实施例2在小鼠模型中的儿童及老年人的免疫原性评价
与实施例1同样地制备A/H1N1亚型(A/Singapore/GP1908/2015株)及B/Yamagata谱系(B/Phuket/3073/2013株)的β-丙内酯处理灭活全毒粒疫苗,以各株的血凝素每0.2mL成为15μgHA的方式用含有1w/w%蔗糖的6.7mM磷酸缓冲生理盐水(pH7.2)进行调节,作为灭活全毒粒疫苗。另外,对于裂解疫苗,使用流感HA疫苗的原液,同样以各株的血凝素每0.2mL成为15μgHA的方式用含有1w/w%蔗糖的6.7mM磷酸缓冲生理盐水(pH7.2)进行调节。
将如上所述制备的施予液(表1)以每1只间隔3周皮下施予2次的方式施予至1、3、6、12及18月龄的雄性C57BL/6小鼠(Charles River公司)。在第1次施予21天后(第21天),经尾静脉进行部分采血,在第2次施予21天后(第42天),在麻醉下进行全采血。对所采集的血液通过离心分离制备血清,供于各种抗体效价测定。
另外,在第42天的全采血后,经上颚的咽侧插入移液器,流入含有0.175%BSA及蛋白酶抑制剂(Thermo Fisher Scientific公司)的D-PBS,将从外鼻孔回收的溶液作为鼻腔清洗液。该鼻腔清洗液也供于病毒特异性IgG效价测定。
[表1]
已知1、3、6、12及18月龄的C57BL/6小鼠中,1月龄为未成熟个体(按人类相当于12岁),3及6月龄为成熟个体(按人类相当于20~30岁),12月龄为中年个体(相当于人类的42岁),18月龄为老年个体(相当于人类的56岁)(Charles River公司技术信息、用于研究的老龄C57BL/6J小鼠、https://www.crj.co.jp/cms/crj/pdf/product/rm/brochure/White_Paper_B6-Aged.pdf)。因此,1月龄为儿童,18月龄为老年人的模型动物。
确认到这些模型动物的设定在流感疫苗的免疫原性中也适当,因此用1~18月龄的小鼠比较已经批准的裂解疫苗(S.V.)的抗体诱导时,第1次施予后的血清的病毒特异性IgG效价如图2A(A型病毒)及图2B(B型病毒)所示,结果为:对于任一菌株而言,作为成熟个体的3月龄均为最高的抗体效价,1月龄及18月龄与3月龄相比,抗体诱导低。另外可知,第2次施予后的病毒特异性IgG效价(图3A(A型病毒)及图3B(B型病毒))及中和抗体效价(图4A(A型病毒)及图4B(B型病毒))的结果均与第1次施予后的病毒特异性IgG效价的结果相同,与作为抗体效价的峰值的3月龄相比,在1月龄及18月龄的小鼠中抗体诱导低。因此,与人类同样,在作为儿童模型的1月龄小鼠、作为老年人模型的18月龄小鼠中,确认到抗体诱导的降低,认为在流感疫苗的免疫原性方面,这些模型也适当。
作为这些模型中的免疫原性试验的结果,可知对于第1次施予后的血清的病毒特异性IgG效价(图2A(A型病毒)及图2B(B型病毒)),对于任一病毒株而言,在1月龄及18月龄的小鼠中,与裂解疫苗施予组(S.V.)相比,灭活全毒粒疫苗施予组(W.V.)的抗体诱导均显著地高。另外,第2次施予后的血清的病毒特异性IgG效价也与第1次施予后的结果同样地在灭活全毒粒疫苗施予组(W.V.)中显示出显著高的抗体效价(图3A(A型病毒)及图3B(B型病毒))。对于第2次施予后的血清也测定了中和抗体效价,如图4A(A型病毒)及图4B(B型病毒)所示,在1月龄及18月龄的小鼠中,灭活全毒粒疫苗施予组(W.V.)显示出显著高的抗体诱导。
另外,在第2次施予后的第42天,回收鼻腔清洗液,并评价了感染流感病毒的鼻腔粘膜中的抗体诱导。图5A中示出针对A/Singapore/GP1908/2015株的鼻腔的病毒特异性IgG效价,但在1月龄的小鼠中,与裂解疫苗施予组(S.V.)相比,在灭活全毒粒疫苗施予组(W.V.)显示出显著高的抗体诱导。但是,在18月龄中,施予任一疫苗时,抗体效价均为同等程度。图5B中示出针对B/Phuket/3073/2013株的鼻腔的病毒特异性IgG效价,在1月龄及18月龄的小鼠的任一者中,与裂解疫苗施予组(S.V.)相比,在灭活全毒粒疫苗施予组(W.V.)确认到显著高的抗体效价。
根据上述的结果,在儿童及老年人的模型动物中,对于血清的抗体诱导而言,与已经批准的裂解疫苗相比,在灭活全毒粒疫苗中确认到显著高的抗体诱导。另外,对于作为病毒感染部位的鼻腔粘膜的抗体诱导而言,在儿童的模型动物中,对于本实施例中评价的A型及B型病毒中的任一者,在灭活全毒粒疫苗施予组(W.V.)中均比裂解疫苗施予组(S.V.)显著地高,在老年人模型动物中,在A型病毒中为同等程度,但在B型病毒中,在灭活全毒粒疫苗中显示出显著高的抗体诱导。即,在儿童及老年人中的任一模型动物中均显示出免疫原性的显著提高,认为β-丙内酯处理灭活全毒粒疫苗比已经批准的裂解疫苗显示出高的有效性。
Claims (6)
1.组合物,其是向儿童及/或老年人施予的流感疫苗组合物,所述组合物含有用β-丙内酯进行了灭活处理的灭活全毒粒作为病毒抗原。
2.如权利要求1所述的组合物,其中,病毒抗原包含由A/H1N1亚型及A/H3N2亚型组成的A型流感病毒株,以及由B/Victoria谱系及B/Yamagata谱系组成的B型流感病毒株。
3.如权利要求1或2所述的组合物,其不含佐剂。
4.如权利要求1~3中任一项所述的组合物,其被皮下施予。
5.免疫方法,其中,将含有用β-丙内酯进行了灭活处理的灭活全毒粒作为病毒抗原的组合物向儿童或老年人施予。
6.流感的预防方法,其中,将含有用β-丙内酯进行了灭活处理的灭活全毒粒作为病毒抗原的组合物向儿童或老年人施予。
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