CN117618549A - 一种基于黑猩猩腺病毒载体疫苗液体制剂及制备方法 - Google Patents
一种基于黑猩猩腺病毒载体疫苗液体制剂及制备方法 Download PDFInfo
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Abstract
本发明涉及一种疫苗辅料及其应用,该制剂包含有效成分和辅料;所述有效成分为表达抗原蛋白的重组黑猩猩腺病毒,所述辅料包括保护剂,所述保护剂包括乙醇、甘油或丙二醇中一种或多种;优选的,所述的保护剂包括乙醇和甘油;优选的,所述的保护剂包括丙二醇和甘油。本制剂中无动物源成分,安全性高。本发明制剂能够保持黑猩猩腺病毒载体疫苗液体制剂良好的稳定性。可以在2‑8℃稳定保存12个月以上,且其异常毒性试验合格,使用安全。
Description
技术领域
本发明属于病毒生物学领域,具体涉及一种基于黑猩猩腺病毒载体疫苗液体制剂。
背景技术
病毒性载体是指野生型病毒基因组经过基因改造后,减少或去除其病原性而保留高转染效率的特性,通过生物学感染途径就可将目的基因导人细胞内表达的一类缺陷型病毒。由于制备困难、目的基因容量较小及免疫原性和生物安全性问题,只有少数病毒能够改造成为基因治疗所需要的载体。根据病毒基因组类型可分类为DNA病毒载体(腺病毒载体、腺相关病毒载体和单纯疱疹病毒载体)、RNA病毒载体(反转录病毒载体和慢病毒载体)和嵌合型病毒载体。
腺病毒(adenovirus,Adv)为线性双链DNA病毒,直径约90-100nm,基因组全长约30~50kb,两端各有长约100bp的反向末端重复序列(ITR)。Adv载体的设计主要分为三代:第一代腺病毒载体中,病毒的El区(包括ElA、El B)和E3区被删除,El区常由目的基因取代,载人量7kb左右,由于ElA是病毒复制的重要元件,所以必须在体外由转染细胞系(如HEK293细胞)提供,随着科学技术的发展,一些新颖的细胞系如PER.C6和N52.E6已表现出更大的优势;第二代腺病毒载体是在第一代的基础上再删减了E2区和E4区,基因载入量增加到llkb,细胞毒性和免疫原性有所减弱,目的基因表达时间更长;第三代载体又被称为helper依赖型Adv载体,已经完全删减了病毒所有的开放阅读框,只保留了必要的顺式作用元件和包装信号序列,所以需要在helper的存在下,在转染细胞系中增殖。第三代载体的优点是可容纳较大的外源基因(最高可达32kb).安全性很高。
尽管腺病毒作为疫苗病毒具有很多优势,但这种研制疫苗的方法有一个重大缺陷。由于腺病毒如此普遍,约有三分之一的人群成年时对其已产生免疫性,这些人群的免疫系统会破坏疫苗而不是产生对抗携带插入基因的病毒的抗体。
考虑到大多数人从黑猩猩那里感染微生物的可能性要小的多,因此用黑猩猩的腺病毒可作为疫苗载体。
对于黑猩猩腺病毒载体疫苗,本身属于病毒载体疫苗,在液体状态下,疫苗含有的活性组分并不稳定,主要表现为储存条件变化及储存时间的延长会影响到疫苗本身的效力。因此,如何保证疫苗的稳定性是疫苗生产制造过程中最为核心的技术问题之一。而相较于人腺病毒,黑猩猩腺病毒更不容易控制其稳定性。专利申请CN114617972A公开了一种人腺病毒或黑猩猩腺病毒的辅料组合物,其包含甘露醇、蔗糖、氯化钠、氯化镁、HEPES、聚山梨酯80、甘油,本发明在是上述现有研究技术上的进一步改进。因此,开发一种安全性高、稳定性好、副作用少的疫苗制剂是非常有意义的。
发明内容
本发明的一个目的在于提供一种安全性高、稳定好的基于黑猩猩腺病毒载体疫苗液体制剂。
本发明的另一个目的在于提供一种黑猩猩腺病毒载体液体稳定剂。
本发明涉及一种疫苗制剂,所述疫苗为液体制剂,该制剂包含有效成分和辅料;所述有效成分为表达抗原蛋白的重组黑猩猩腺病毒,所述辅料包括保护剂,所述保护剂包括乙醇、甘油或丙二醇中一种或多种。
在一个实施方式中,所述的保护剂为乙醇。
在一个实施方式中,所述的保护剂为乙醇和甘油。
在一个实施方式中,所述的保护剂为丙二醇和甘油。
作为优选的,乙醇或丙二醇占制剂的体积百分比(v/v%)为0.1-10%。更优选的,乙醇或丙二醇占制剂的体积百分比(v/v%)为0.1-2%,例如是0.1%、0.5%、1%、2%。
作为优选的,制剂中甘油的浓度为0.5-10mg/ml。更优选的,制剂中甘油的浓度为0.1-6mg/ml,例如是0.1mg/ml、0.3mg/ml、0.5mg/ml、1.5mg/ml、2mg/ml、3mg/ml、4mg/ml、5mg/ml、6mg/ml。
作为优选的,所述的辅料还包括螯合剂、缓冲液、表面活性剂、糖类、盐中的一种或多种。
作为优选的,所述辅料还包括螯合剂;优选地,所述螯合物的浓度为0.01-1mM;优选地,螯合剂选自EDTA-Na2、EDTA-Na、枸橼酸钠、枸橼酸中的一种或几种,更优选地,为EDTA-Na2。
作为优选的,所述辅料还包括缓冲液,所述缓冲液选自氨基酸缓冲液、磷酸盐缓冲液或HEPES,更优选地,缓冲液浓度为1-20mM,更优选的,为氨基酸缓冲液,更优选地,为组氨酸缓冲液。优选的,所述的缓冲液浓度为2-15mM,例如,所述的缓冲液浓度为2、2.5、3、4、5、6、7、8、9、10、11、12、13、14、15mM。
作为优选的,所述疫苗辅料还包括表面活性剂,优选地,所述表面活性剂为选自非离子型表面活性剂、阴离子型表面活性剂、两性离子型表面活性剂和中的一种或多种;更优选地,选自十二烷基硫酸钠、聚乙烯醇、十二烷基磺酸钠、吐温80、司盘80、司盘20、吐温20中的一种或多种;优选地,所述表面活性剂浓度为0.01-1mg/ml。
作为优选的,所述疫苗辅料还包括糖类,所述糖类为蔗糖、甘露醇,优选地,浓度为20-80mg/ml。
作为优选的,所述疫苗辅料还包括盐,所述盐为氯化钠、氯化镁、氯化钙中的一种或多种,优选地,盐的浓度为30-70mM。
在本发明的具体实施方式中,所述的疫苗制剂中辅料包括缓冲液、蔗糖、甘露醇、氯化钠、氯化镁、吐温-80、EDTA-Na2,所述保护剂包括乙醇、甘油或丙二醇中一种或多种。优选的,所述辅料中蔗糖为25mg/ml;优选的,所述辅料中甘露醇为50mg/ml;优选的,所述辅料中氯化钠为50mM;优选的,所述辅料中氯化镁为2mM;优选的,所述辅料中吐温-80为0.1mg/ml;优选的,所述辅料中EDTA-Na2为0.1mM。
作为优选的,所述黑猩猩病毒选自AdC3、AdC6、AdC63、AdC68,Y25,优选为Y25。
作为优选的,所述抗原选自:SARS-CoV、SARS-CoV-2、埃博拉病毒、乙肝病毒、丙肝病毒、登革热病毒、带状疱疹病毒、狂犬病毒、人类免疫缺陷病毒,优选为水痘-带状疱疹病毒。
水痘-带状疱疹病毒(varicella-zoster virus,VZV)也被称为人疱疹病毒3型,是一个普遍存在的α疱疹病毒,为双股DNA病毒。VZV感染人有两种类型,即原发感染水痘(varicella)和复发感染带状疱疹(zoster)。VZV在自然状态下只感染人,没有动物宿主,主要靶标是T淋巴细胞、上皮细胞和神经节。初次感染引起水痘,恢复后病毒潜伏在神经节内。随着年龄的增长,细胞免疫逐渐衰退,或者在免疫缺陷病人中,病毒再发而引起带状疱疹。带状疱疹可并发慢性疼痛(带状疱疹后神经痛,PHN)和其他严重的神经和眼部疾病(例如,脑膜脑炎,脊髓炎,颅神经麻痹,血管病变,角膜炎和视网膜病变),以及多种内脏和胃肠道疾病,包括溃疡,肝炎和胰腺炎。使用针对带状疱疹的疫苗进行免疫接种,是预防该疾病的有效手段。
作为优选的,所述重组病毒载体的含量为1ⅹ109~1ⅹ1012VP/ml。
作为优选的,所述制剂为粘膜施用剂、口服施用剂、注射施用剂,优选地,所述注射施用剂为皮下注射、皮内注射、静脉注射或肌肉注射;所述粘膜施用剂为吸入制剂,优选地为雾化吸入制剂或干粉吸入剂。
肌肉注射剂型一般采用液体制剂或冻干制剂,其中液体制剂工艺简单,便于放大,是疫苗产品的优选剂型。
作为优选的,所述液体制剂的pH值为5-7,优选地,pH值为5.5-6.5,更优选地,6-6.5。
本发明涉及一种疫苗液体制剂的制备方法,包括以下步骤:
1)纯化重组腺病毒抗原原液;
2)按比例配置疫苗辅料;
3)配制半成品;
4)将半成品分装入管制瓶。
作为优选的,所述纯化步骤包括:病毒收获液经过裂解、离心、过滤等操作后得到澄清液,然后经过离子交换层析和复合模式层析两步层析后得到纯化病毒液,再经过超滤换液至指定配方中,最后通过无菌过滤得到疫苗原液。
本发明的有益效果是:
疫苗辅料是指疫苗制品调配处方时所用的保护剂、赋形剂和附加剂,是疫苗制剂中不可缺少的重要成分,对疫苗制剂的稳定性具有重要作用。合适的制剂配方对于疫苗产品的生物活性、开发新剂型与新品种、满足预防使用的要求等都有积极的关键性作用。本制剂中无动物源成分,安全性高。本发明制剂能够保持黑猩猩腺病毒载体疫苗液体制剂良好的稳定性。该疫苗制剂可有效避免抗原的聚集,可以在2-8℃稳定保存12个月以上,且其异常毒性试验合格,使用安全。
具体实施方式
除非另有定义,本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义。下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
附图说明
图1所示为0-12个月重组黑猩猩腺病毒载体疫苗长期稳定性试验-病毒感染滴度变化情况;
图2所示为0-12个月重组黑猩猩腺病毒载体疫苗长期稳定性试验-病毒颗粒数检测变化情况;
实施例1模型疫苗的制备
选择水痘-带状疱疹gE蛋白为模型抗原。
重组水痘-带状疱疹病毒的制备方法:通过对黑猩猩腺病毒Y25进行改造得到重组水痘-带状疱疹病毒。首先将Y25基因组左末端的两个同源臂LF1、LF2和右末端的一个同源臂RF插入到细菌人工染色体(bacterial artificial chromosome,BAC)系统,构建得到质粒pBACe3.6,随后将该质粒与Y25基因组共转化大肠杆菌,通过同源重组的方式,病毒基因组会整合到质粒上并删除掉E1区基因,通过氯霉素抗性和限制性酶切筛选得到正确的重组克隆,再利用引物E3delLH和E3delRH,E3区域被半乳糖激酶(Galactokinase,GalK)替换掉,,最后,两个GalK插入以替换掉E4区域开放阅读框ORF4,6,7,随后GalK基因被人腺病毒5型的E4区域替换掉,得到复制缺陷型的黑猩猩腺病毒载体。,该载体在E1缺失区有一独一的AsiSI酶切位点,插入了经过修饰的attR1 attR2 Gateway组件(Invitrogen),使用该组件,在其基因组中插入水痘-带状疱疹病毒gE蛋白基因,构建得到可表达水痘-带状疱疹病毒gE蛋白的复制缺陷型黑猩猩腺病毒载体,记为重组水痘-带状疱疹病毒。
重组水痘-带状疱疹疫苗原液的制备方法:使用重组水痘-带状疱疹病毒感染HEK293细胞,经扩增得到病毒收获液,病毒收获液经过裂解、离心、过滤等操作后得到澄清液,然后经过离子交换层析和复合模式层析两步层析后得到纯化病毒液,再经过超滤换液至指定配方中,最后通过无菌过滤得到疫苗原液。
实施例2复制缺陷型的黑猩猩腺病毒载体制剂稳定剂体系的筛选
不同稳定剂对制剂稳定性的影响
设置不同的缓冲液和不同醇类复配的稳定剂体系,分别放置在37℃条件下保存,于0天、2天、4天、7天、10天、14天取样检测病毒感染滴度;
病毒感染滴度检测;使用腺病毒检测试剂盒进行检测;
表1病毒感染滴度
注*:其余常规辅料为相同种类及浓度的蔗糖25mg/ml、甘露醇50mg/ml、氯化钠50mM、氯化镁2mM、吐温-80 0.1mg/ml、EDTA-Na20.1mM,其余为注射用水。
从表中数据可以看出,His缓冲液与乙醇、甘油复配的稳定剂体系能够起到对抗原成分更好的保护作用,可以替代明胶。同时,能够发挥一定的抗氧化作用。
实施例3长期稳定性试验
样品制备:
重组带状疱疹疫苗抗原原液适量;
把纯化的重组带状疱疹疫苗抗原原液按照下述配方配制成半成品;组氨酸10mM、蔗糖25mg/ml、甘露醇50mg/ml、氯化钠50mM、甘油1.5mg/ml、氯化镁2mM、吐温-80 0.1mg/ml、乙醇5mg/ml、EDTA-Na2 0.1mM,注射用水;
将半成品分装到2ml管制瓶,每管0.5ml。
长期稳定性试验方法:将疫苗放置在2~8℃的药品保存箱中储存,于0个月、1个月、2个月、6个月、9个月、12个月进行病毒感染滴度和病毒颗粒数的检测。
病毒颗粒数检测;使用分光光度计进行检测;
病毒感染滴度检测:使用腺病毒检测试剂盒进行检测;
研究结果:共制备了3批疫苗样品,将疫苗放置在2~8℃保存,于0个月、1个月、2个月、6个月、9个月、12个月将样品取出,分别进行病毒感染滴度和病毒颗粒数检测,检测结果如表2、表3、图1和图2所示。
表2长期稳定性试验-病毒感染滴度变化情况
批次\月 | 0 | 1M | 2M | 3M | 6M | 9M | 12M |
202012002 | 9.15 | 9.11 | 9.18 | 9.20 | 9.08 | 9.08 | 8.87 |
202012002 | 9.26 | 9.23 | 9.26 | 9.34 | 9.18 | 9.20 | 9.04 |
202012002 | 9.20 | 9.18 | 9.18 | 9.26 | 9.08 | 9.11 | 9.00 |
表3长期稳定性试验-病毒颗粒数检测变化情况
批次\月 | 0 | 1M | 2M | 3M | 6M | 9M | 12M |
202012002 | 11.08 | 11.08 | 11.11 | 11.15 | 11.08 | 11.11 | 11.04 |
202012002 | 11.11 | 11.11 | 11.08 | 11.15 | 11.04 | 11.11 | 11.11 |
202012002 | 11.11 | 11.08 | 11.11 | 11.08 | 11.04 | 11.08 | 11.11 |
从数据可以看出,利用本发明稳定剂体系制备的黑猩猩腺病毒载体疫苗液体制剂的长期稳定性良好。
实施例4
不同pH值对制剂稳定性的影响优选试验见表2,样品制备方法如下:
对照组配制方法如下:组氨酸10mM、HEPES 10mM、蔗糖25mg/ml、甘露醇50mg/ml、氯化钠50mM、甘油1.5mg/ml、氯化镁2mM、吐温-80 0.1mg/ml、乙醇5mg/ml、EDTA-Na2 0.1mM,注射用水。使用盐酸和氢氧化钠分别调整至不同的pH值。
实验组配置方法如下:组氨酸10mM、蔗糖25mg/ml、甘露醇50mg/ml、氯化钠50mM、甘油1.5mg/ml、氯化镁2mM、吐温-80 0.1mg/ml、乙醇5mg/ml、EDTA-Na2 0.1mM,注射用水。使用盐酸和氢氧化钠分别调整至不同的pH值。
病毒收获液经过裂解、离心、过滤等操作后得到澄清液,然后经过离子交换层析和复合模式层析两步层析后得到纯化病毒液,再经过超滤换液至不同pH值的缓冲液中,最后无菌过滤得到不同pH值的疫苗原液,用于研究不同pH值对病毒稳定性的影响。
表4:制剂不同pH值对病毒稳定性的影响
结果表明如表4所示:该疫苗液体制剂稳定性最佳的pH范围为5.4~7.0。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换等,均应包含在本发明的保护范围之内。
本发明中描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。
本发明中仅按一定顺序列出方法的步骤并不构成对方法步骤顺序的任何限制。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换等,均应包含在本发明的保护范围之内。
本发明中描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。
Claims (15)
1.一种疫苗制剂,其特征在于,所述疫苗为液体制剂,该制剂包含有效成分和辅料;所述有效成分为表达抗原蛋白的重组黑猩猩腺病毒,所述辅料包括保护剂,所述保护剂包括乙醇、甘油或丙二醇中一种或多种;优选的,所述的保护剂包括乙醇和甘油;优选的,所述的保护剂包括丙二醇和甘油。
2.根据权利要求1所述的疫苗制剂,其特征在于,所述乙醇或丙二醇占制剂的体积百分比(v/v%)为0.1-10%。
3.根据权利要求1-2任一项所述的疫苗制剂,其特征在于,所述制剂中的甘油的浓度为0.5-10mg/ml。
4.根据权利要求1-3任一项所述的疫苗制剂,其特征在于,所述辅料还包括螯合剂;优选地,所述螯合物的浓度为0.01-1mM;优选地,螯合剂选自EDTA-Na2、EDTA-Na、枸橼酸钠、枸橼酸中的一种或几种,更优选地,为EDTA-Na2。
5.根据权利要求1-4任一项所述的疫苗制剂,其特征在于,所述辅料还包括缓冲液,所述缓冲液选自氨基酸缓冲液、磷酸盐缓冲液或HEPES缓冲液,更优选地,缓冲液浓度为1-20mM,优选的,为氨基酸缓冲液,更优选地,为组氨酸缓冲液。
6.根据权利要求1-5任一项所述的疫苗制剂,其特征在于,所述疫苗辅料还包括表面活性剂,优选地,所述表面活性剂为选自非离子型表面活性剂、阴离子型表面活性剂、两性离子型表面活性剂和中的一种或多种;更优选地,选自十二烷基硫酸钠、聚乙烯醇、十二烷基磺酸钠、吐温80、司盘80、司盘20、吐温20中的一种或多种;优选地,所述浓度为0.01-1mg/ml。
7.根据权利要求1-6任一项所述的疫苗制剂,其特征在于,所述疫苗辅料还包括糖类,所述糖类为蔗糖、甘露醇,优选地,浓度为20-80mg/ml。
8.根据权利要求1-7任一项所述的疫苗制剂,其特征在于,所述疫苗辅料还包括盐,所述盐为氯化钠、氯化镁、氯化钙中的一种或多种,优选地,盐的浓度为30mM-70mM。
9.根据权利要求1-8任一项所述的疫苗制剂,其特征在于,所述黑猩猩病毒选自AdC3、AdC6、AdC63、AdC68,Y25,优选为Y25。
10.根据权利要求1-9任一项所述的疫苗制剂,其特征在于,所述抗原选自:SARS-CoV、SARS-CoV-2、埃博拉病毒、乙肝病毒、丙肝病毒、登革热病毒、带状疱疹病毒、狂犬病毒、人类免疫缺陷病毒,优选为水痘-带状疱疹病毒。
11.根据权利要求1-10任一项所述的疫苗制剂,其特征在于,所述重组病毒载体的含量为1ⅹ109~1ⅹ1012VP/ml。
12.根据权利要求1-11任一项所述的疫苗制剂,其特征在于,所述制剂为粘膜施用剂、口服施用剂、注射施用剂,优选地,所述注射施用剂为皮下注射、皮内注射、静脉注射或肌肉注射;优选地,所述粘膜施用剂为吸入制剂,更优选地,为雾化吸入制剂或干粉吸入剂。
13.根据权利要求1-12任一项所述的疫苗制剂,其特征在于,所述液体制剂的pH值为5-7,优选地,pH值为5.5-6.5,更优选地,6-6.5。
14.一种根据权利要求1-13任意一项所述疫苗液体制剂的制备方法,其特征在于,包括以下步骤:
1)纯化重组腺病毒抗原原液;
2)按比例配置疫苗辅料;
3)配制半成品;
4)将半成品分装入管制瓶。
15.根据权利要求14所述疫苗液体制剂的制备方法,其特征在于,所述纯化步骤包括:病毒收获液经过裂解、离心、过滤后得到澄清液,然后经过离子交换层析和复合模式层析两步层析后得到纯化病毒液,再经过超滤换液至指定配方中,最后通过无菌过滤得到疫苗原液。
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