CN111701018A - 环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统 - Google Patents
环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统 Download PDFInfo
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Abstract
本发明涉及一种环二核苷酸修饰铝纳米粒疫苗佐剂‑传递系统，是一种基于铝纳米粒的疫苗载体，其是采用环二核苷酸(CDN)修饰铝纳米粒，用作疫苗佐剂‑传递系统(VADS)。所述的环二核苷酸为环二单磷酸鸟苷分子(c‑di‑GMP，cyclic dimeric guanosine monophosphate)，环二单磷酸腺苷分子(c‑di‑AMP，cyclic dimeric adenosine monophosphate)，或环单磷酸鸟‑单磷酸腺苷分子(cGAMP，cyclic GMP‑AMP)。
Description
技术领域
本发明属于生物制剂领域，是一种基于环二核苷酸修饰铝纳米粒构建的新型疫苗佐剂-传递系统，即一种环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，包括组成、制备方案和应用。
背景技术
疫苗是能够诱导机体产生抗体的免疫原物质，是用于防治传染性疾病、肿瘤、自身免疫性疾病的生物制剂。目前疫苗从主要成分性质上分类，包括如下5种类型。1)灭活疫苗：是采用物理或化学方法直接杀灭病原体，再添加适当辅助成分制成疫苗制剂。此种疫苗进入机体后不能生长繁殖，对机体刺激时间短，要获得持久免疫力需多次重复接种，或加入疫苗佐剂。2)减毒活疫苗：用人工定向诱变方法消除病原体致病性，或从自然界筛选出无毒力的活微生物制成活疫苗。如卡介苗(BCG，结核病)、麻疹疫苗、脊髓灰质炎疫苗(小儿麻痹症)等。接种后在体内有生长繁殖能力，接近于自然感染，可激发机体对病原的持久免疫力。减毒活疫苗的免疫诱导效果较好，但存在基因突变产生致病性的风险，安全性较差。3)核酸疫苗：包括RNA、DNA两种疫苗，是将蛋白抗原的表达基因克隆在表达载体上，注入体内，使其抗原在体内表达后激发机体产生免疫反应，也存在安全性较低等弱点。4)类毒素(外毒素)：是将细菌外毒素经处理消除毒性而保留免疫原性，成为类毒素，通常加适量磷酸铝和氢氧化铝制备为疫苗制剂。常用的类毒素疫苗有白喉、破伤风等类毒素制剂等，一般用作治疗目的。5)亚单位疫苗(纯抗原组分疫苗)：将诱导机体产生免疫的病原体抗原制备为疫苗。亚单位疫苗免疫原性低，需要疫苗佐剂-传递系统。
各种不同类型疫苗各具特点与优势，但也均存在自身缺陷，概括而言突出表现为以下两方面。1)安全性问题，主要表现在疫苗变异或恢复致病性，而发展亚单位疫苗是提高疫苗安全性有效措施，但亚单位疫苗免疫诱导效力较弱。2)效力问题，尤其是亚单位疫苗，由于只含有抗原成分，缺乏病原体原有的保护成分、病原体相关分子模式等，免疫诱导效力较弱。
针对上述安全性及效力两个问题，疫苗研究人员发展了一些应对策略。1)发展新型佐剂系统(adjuvant system,AS)：除传统佐剂铝盐外，皂角苷，角鲨烯，肠毒素，霍乱毒素，CpG-ODN，cGAMP，乳剂，脂质体等均为目前积极研究的新佐剂。多种成分组合形成的佐剂系统，正成为提高疫苗效力的新策略。2)发展疫苗佐剂-传递系统(Vaccine Deliverysystem,VDS)：即构建兼具佐剂、传递功能的疫苗载体，例如，采用能够激活固有免疫应对成分修饰的脂质体、乳剂、高分子/无机纳米粒、免疫刺激复合物、病毒样颗粒、外膜囊泡、病毒体，以及微针等。这些VADS有效地保护了疫苗抗原(Ag)，提高了疫苗免疫诱导效率。
综上所述，经过多年发展疫苗研究取得了显赫成果，有效地维护了人类健康，现有疫苗也存在一些不足，在安全性、疫苗诱导效力、稳定性方面，有待于进一步提高。有鉴于此，本专利以传统佐剂铝盐(Alum)为基础，发展一种多功能铝纳米粒(简称纳米铝)新型疫苗佐剂-传递系统(VADS)。
发明内容
本发明的目的是提供一种环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，为了克服一些疫苗免疫诱导效力较弱的问题，本发明采用环二核苷酸共修饰铝纳米粒，用作疫苗佐剂-传递系统。
本发明是采用如下技术方案实现的：一种环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，采用环二核苷酸(CDN)修饰铝纳米粒，用作疫苗佐剂-传递系统(VADS)；
所述的环二核苷酸为环二单磷酸鸟苷分子(c-di-GMP，cyclic dimericguanosine monophosphate)，环二单磷酸腺苷分子(c-di-AMP，cyclic dimeric adenosinemonophosphate)，或环单磷酸鸟-单磷酸腺苷分子(cGAMP，cyclic GMP-AMP)。
进一步的，所述的铝纳米粒是粒径在100纳米以下的氧化铝，磷酸铝，硫酸铝，氢氧化铝等纳米粒中的一种或多种。
再进一步的，所述的氧化铝为α结晶型氧化铝。
进一步的，环二核苷酸(CDN)修饰铝纳米粒的制备方法为先形成铝纳米粒，再与环二核苷酸混合均匀。
再进一步的，所述的铝纳米粒与环二核苷酸二者混合比例范围为10-60：1。
进一步的，所述的VADS运载不同类型疫苗，该疫苗包括灭活病原体，病原体表面抗原，编码病原体表面抗原的mRNA或DNA。
进一步的，该VADS制备的疫苗制成液体制剂或固体制剂，
再进一步的，所述的固体制剂为含有冻干保护剂的冻干品。
再进一步的，该VADS制备的疫苗采用粘膜部位接种或是注射接种。
再进一步的，该VADS制备的疫苗接种对象为哺乳动物，家禽类或鱼类。
本发明的有益效果：1、适于多途径接种：可以通过腔道粘膜接种，也可以通过皮下、皮内、肌肉注射接种。2、免疫诱导效力强：铝纳米粒激活免疫系统产生体液免疫，而环二核苷酸(CDN)能够激活STING通路，诱导Th1免疫反应，促进细胞免疫。
具体实施方式
本发明公开一种新型疫苗佐剂-传递系统，涉及生物药物技术领域，是一种环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统。本专利保护的一种功能铝纳米粒疫苗载体，是采用环二核苷酸分子修饰铝纳米粒，形成疫苗佐剂-传递系统(VADS)。由该VADS制备的疫苗可以采用多种方式进行接种，刺激机体产生形成抗原特异性抗体及细胞毒性T淋巴细胞，提高疫苗免疫诱导效力。
具体的，本发明的一种环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，是一种基于铝纳米粒的疫苗载体，其是采用环二核苷酸(CDN)修饰铝纳米粒，用作疫苗佐剂-传递系统(VADS)。所述的环二核苷酸为环二单磷酸鸟苷分子(c-di-GMP，cyclic dimeric guanosinemonophosphate)，环二单磷酸腺苷分子(c-di-AMP，cyclic dimeric adenosinemonophosphate)，或环单磷酸鸟-单磷酸腺苷分子(cGAMP，cyclic GMP-AMP)。
进一步的，所述的铝纳米粒是粒径在100纳米以下的氧化铝(进一步具体来说是α结晶型)，磷酸铝，硫酸铝，氢氧化铝等纳米粒中的一种或多种。
再进一步的，环二核苷酸共修饰铝纳米粒制备方法，即环二核苷酸(CDN)修饰铝纳米粒制备方法为先形成铝纳米粒，再与环二核苷酸混合均匀即可。
再进一步的，所述的铝纳米粒与环二核苷酸二者混合比例范围为10-60：1。
再进一步的，所述的VADS可以运载不同类型疫苗，该疫苗包括灭活病原体，病原体表面抗原，编码病原体表面抗原的mRNA或DNA。
再进一步的，该VADS制备的疫苗可以制成液体制剂；也可以是固体制剂，如含有冻干保护剂的冻干品。
再进一步的，该VADS制备的疫苗可以采用粘膜部位接种，也可以是注射接种。
再进一步的，该VADS制备的疫苗接种对象可以是哺乳动物(包括人)，也可以是家禽类，鱼类等。
本发明构建的疫苗传递佐剂系统具有两个显著优势：1、适于多途径接种：可以通过腔道粘膜接种，也可以通过皮下、皮内、肌肉注射接种。2、免疫诱导效力强：铝纳米粒激活免疫系统产生体液免疫，而环二核苷酸(CDN)能够激活STING通路，诱导Th1免疫反应，促进细胞免疫。
通过下列实施实例举例说明本发明的具体方案及方法及应用，但本发明的保护范围，不局限于此。
以下实施例c-di-GMP为环二鸟单磷酸苷；c-di-AMP，环二腺单磷酸苷；2’,3’-cGAMP，2’,3’-环鸟腺单磷酸苷；3’,3’-cGAMP，3’3’-环鸟腺单磷酸苷；下列实施例提及的氧化铝纳米粒均为α-晶型氧化铝)。
实施例1:c-di-GMP修饰磷酸铝纳米粒疫苗佐剂-传递系统
将磷酸铝纳米粒(平均粒径85纳米)与c-di-GMP水溶液(质量比Al/c-di-GMP为10:1)，40℃搅拌20min，按照Al/c-di-GMP/OVA(10:1:1,mass ratio)比例，加入卵清蛋白(ovalbumin,OVA)为模型抗原，室温下搅拌均匀，以NaCl调为等渗，即为疫苗产品。按照8μg/50μL OVA剂量，通过肌肉注射给小鼠接种。与两对照组(OVA+磷酸铝传统佐剂，等剂量同样方式接种；OVA+磷酸铝纳米粒，等剂量同样方式接种)相比较，3周后产生的抗原特异性抗体水平分别提高了1.5和1.7倍，细胞毒性T细胞(CTL)提高了3.3和3.5倍，IFN-γ水平提高了1.9和2.6倍，表明接种鼠产生Th1/Th2混合型免疫应答。
实施例2:c-di-AMP修饰氧化铝纳米粒疫苗佐剂-传递系统
将氢氧化铝纳米粒(平均粒径95纳米)与c-di-AMP水溶液混合(Al/c-di-AMP质量比40:1)，30℃搅拌25min，按照Al/MPLA/c-di-AMP/OVA(40:1:1,质量比)比例，加入OVA为模型抗原，室温下搅拌均匀，以NaCl调为等渗，即为疫苗产品。按照4μg/50μL OVA剂量，通过滴入鼻腔，由鼻腔黏膜给小鼠接种。与两对照组(OVA+氢氧化铝传统佐剂，等剂量同样方式接种；OVA+氢氧化铝纳米粒，等剂量同样方式接种)相比较，3周后产生的抗原特异性抗体分别提高了3.2和2.1倍，CTL提高了3.7和3.3倍；IFN-γ提高了3.8和2.9倍，表明接种鼠产生Th1/Th2混合型免疫应答；同时在小鼠鼻腔冲洗液检测到了IgA，其平均滴度水平是对照组的4.5倍，表明小鼠既产生了系统免疫应答，也产生了粘膜免疫应答。
实施例3:2’,3’-cGAMP修饰氧化铝纳米粒疫苗佐剂-传递系统
将氧化铝纳米粒(平均粒径35纳米)与2’,3’-cGAMP水溶液混合(Al/c-di-AMP质量比80:1)，25℃搅拌30min，按照Al/2’,3’-cGAMP/OVA(80:1:2,mass ratio)比例，加入OVA为模型抗原，室温下搅拌均匀，以NaCl调为等渗，即为疫苗产品。按照2μg/50μL OVA剂量，通过吸入肺部给小鼠接种。与两对照组(OVA+氢氧化铝传统佐剂，等剂量肌肉注射接种；OVA+氧化铝纳米粒，等剂量吸入肺部接种)相比较，3周后产生OVA特异性抗体提高了5.2和3.5倍，CTL提高了4.2和2.7倍，IgG1/IgG2a比值提高了2.3和1.8倍，IFN-γ提高了4.5和2.7倍；同时在小鼠肺洗液均检测到了IgA，其平均滴度水平分别是对照组的8.7和5.6倍，表明小鼠既产生了系统免疫应答，也产生了粘膜免疫应答。
实施例4:3’,3’-cGAMP修饰氧化铝纳米粒疫苗佐剂-传递系统
将氧化铝纳米粒(平均粒径50纳米)纳米粒与3’,3’-cGAMP水溶液混合(Al/c-di-AMP质量比100:1)，25℃搅拌30min，按照Al/3’,3’-cGAMP/OVA(100:1:1,mass ratio)比例，加入卵清蛋白(ovalbumin,OVA)为模型抗原，室温下搅拌均匀，以NaCl调为等渗，即为疫苗产品。按照2μg/50μL OVA剂量，通过雌性小鼠生殖道黏膜接种。与两对照组(OVA+氢氧化铝传统佐剂，等剂量同样方式接种；OVA+氧化铝纳米粒，等剂量同样方式接种)相比较，3周后产生OVA特异性抗体提高了4.2和3.3倍，CTL提高了4.9和3.7倍，IgG1/IgG2a比值提高了2.8和1.9倍，IFN-γ提高了4.2和2.5倍；同时在生殖道冲洗液均检测到了IgA，其平均滴度水平分别是对照组的7.7和5.1倍，表明小鼠既产生了系统免疫应答，也产生了粘膜免疫应答。
实施例5:2’,3’-cGAMP共修饰氧化铝纳米粒疫苗佐剂-传递系统冻干品
将氧化铝纳米粒(平均粒径35纳米)与2’,3’-cGAMP溶液混合(Al/c-di-AMP质量比60:1)，25℃搅拌30min，按照Al/2’,3’-cGAMP/HBsAg(60:1:2,mass ratio)比例，加入HBsAg抗原，室温搅拌均匀，加入蔗糖，浓度达到5％，通过冷冻干燥获得冻干品。加入与冻干之前相同体积的纯水，水化，再按照6μg/50μL HBsAg剂量，通过皮下注射给小鼠接种。与两对照组(OVA+氢氧化铝传统佐剂，等剂量同样方式接种；OVA+氧化铝纳米粒，等剂量同样方式接种)相比较，3周后产生OVA特异性抗体提高了4.1和3.5倍，CTL提高了4.2和3.7倍，IgG1/IgG2a比值提高了2.1和1.6倍，IFN-γ提高了3.9和2.5倍，表明接种鼠产生Th1/Th2混合型免疫应答。
对于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。
Claims (10)
1.一种环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，其特征在于：采用环二核苷酸(CDN)修饰铝纳米粒，用作疫苗佐剂-传递系统(VADS)；
所述的环二核苷酸为环二单磷酸鸟苷分子(c-di-GMP，cyclic dimeric guanosinemonophosphate)，环二单磷酸腺苷分子(c-di-AMP，cyclic dimeric adenosinemonophosphate)，或环单磷酸鸟-单磷酸腺苷分子(cGAMP，cyclic GMP-AMP)。
2.根据权利要求1所述的环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，其特征在于：所述的铝纳米粒是粒径在100纳米以下的氧化铝，磷酸铝，硫酸铝，氢氧化铝等纳米粒中的一种或多种。
3.根据权利要求2所述的环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，其特征在于：所述的氧化铝为α结晶型氧化铝。
4.根据权利要求1所述的环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，其特征在于：环二核苷酸(CDN)修饰铝纳米粒的制备方法为先形成铝纳米粒，再与环二核苷酸混合均匀。
5.根据权利要求1或4所述的环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，其特征在于：所述的铝纳米粒与环二核苷酸二者混合比例范围为10-60：1。
6.根据权利要求1所述的环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，其特征在于：所述的VADS运载不同类型疫苗，该疫苗包括灭活病原体，病原体表面抗原，编码病原体表面抗原的mRNA或DNA。
7.根据权利要求1所述的环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，其特征在于：该VADS制备的疫苗制成液体制剂或固体制剂。
8.根据权利要求7所述的环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，其特征在于：所述的固体制剂为含有冻干保护剂的冻干品。
9.根据权利要求1或6或7或8所述的环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，其特征在于：该VADS制备的疫苗采用粘膜部位接种或是注射接种。
10.根据权利要求9所述的环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统，其特征在于：该VADS制备的疫苗接种对象为哺乳动物，家禽类或鱼类。
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