CN109806390A - 一种SamRNA疫苗及其制备方法 - Google Patents
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Abstract
本发明公开了一种SamRNA疫苗,所述的疫苗包括重组病毒载体,所述的重组病毒载体包括:i)病毒基因复制复合体,所述的病毒基因复制复合体包括编码病毒基因复制相关蛋白nsP1、nsP2、nsP3和nsP4的核苷酸序列,和ii)编码至少一种抗原的核苷酸序列。本发明所述SamRNA疫苗除了修饰化腺病毒载体本身的启动子可以转录抗原基因形成mRNA之外,所述的nsP1‑4病毒基因复制相关蛋白以RNA为模板,大量合成mRNA,极大的提高目标抗原的免疫效果。
Description
技术领域
本发明属于疫苗技术领域,具体涉及修饰化腺病毒载体生产mRNA疫苗的工艺技术及其制备方法,而且该腺病毒载体所生产的mRNA疫苗,可以RNA为模板进行持续的扩增形成更多的mRNA,简称samRNA(self-amplifying mRNA)。
背景技术
mRNA疫苗是具有免疫性、安全性、灵活性的基因疫苗,mRNA疫苗能够刺激免疫系统产生平衡、长效的保护。部分mRNA疫苗本身具有疫苗佐剂特性,通过产生多种细胞因子等不同方式刺激免疫系统,增强免疫机体反应能力,缩短免疫应答时间,加大抗体合成释放能力。
1990年,科学家将体外转录的信使RNA(mRNA)注射入小鼠体内,通过检测发现其可在小鼠体内表达活性,产生相关蛋白且具有剂量依赖性。这种直接注射mRNA的方法能够通过表达特定蛋白,产生免疫反应,这就是mRNA疗法的雏形。
相比传统疫苗,mRNA的安全性更有优势,不会插入基因突变,可以被正常细胞降解,通过调节序列修饰和递送载体可以改变其半衰期等。更重要的是,传统疫苗对很多新型病毒有心无力,更别提像癌症这种严重威胁人类健康的疾病了。而mRNA的作用机理使它就像一本餐谱一样,只要编好RNA序列,就可以将细胞变成小型的药物工厂,mRNA引导细胞自己产生特定蛋白发挥系统药效。
mRNA疫苗作用机理:mRNA参与DNA转录和蛋白质生成的中间步骤。目前用于制造疫苗的有两种RNA,非复制型(non-replicating)mRNA和自我扩增型(self-amplifying)mRNA(SamRNA)。传统mRNA疫苗编码的抗原包含5′和3′的未翻译区(UTRs),而自我扩增型RNA不仅能编码抗原,还有类似病毒复制过程的序列,使其可以在细胞内复制,提高蛋白表达量。
mRNA可以通过体外cDNA模板转录而成,转录后期在mRNA增加蛋白质编码的开放阅读框(open reading frame,ORF),使合成的mRNA具有编码蛋白质的功能。开放阅读框至少由两个重要元素组成:5’端的“帽子”结构和一条多聚A(poly A)的“尾巴”。此外,增加不转录区域(untranslated regions,UTRs)及其他复合物协助mRNA的稳定转录。
但是,裸露的mRNA直接进入体内会被降解,而高效的mRNA递送是疫苗药效的保证,因此开发高效的mRNA递送载体是确保疫苗有效的关键因素。目前mRNA的给药方式多以皮内或者节内注射为主,但是这种注射方式由于体内mRNA的降解,因此需要大量给药才能激发机体产生有效的免疫应答。有文献报道可以用鱼精蛋白,以及其他的高分子,比如脂质体来包裹mRNA,从而避免机体内蛋白酶对mRNA的大量破坏。虽然这种包裹方式相比较直接注射可以有效增加机体对抗原的吸收量,但是仍然存在一些缺陷需要克服,比如有效的包裹量,包裹后的mRNA在体内的释放时间,以及mRNA在体内的释放和转移等。
目前,腺病毒(adenovirus,Ad)载体系统已经大量的被应用于基因治疗药物以及疫苗的开发,临床中也有腺病毒载体系统的大量报道,其安全性和作为基因递送载体的可靠性已经充分证实。根据其能否复制,将腺病毒载体分为复制型和复制缺陷型。目前复制缺陷型腺病毒载体更为常用,与复制型腺病毒载体相比,前者的安全性更好,载体自身的免疫原性更低。腺病毒载体疫苗是指以腺病毒作为载体,将保护性抗原基因重组到病毒基因组中,腺病毒载体中的抗原基因有病毒衣壳蛋白保护,可以避免宿主体内各种蛋白酶对携带基因的降解,有效解决了mRNA从注射部位到宿主细胞被降解风险,腺病毒载体在感染宿主细胞后,所携带的抗原基因或者目标基因就可以表达蛋白。
mRNA疫苗除了易于降解、生物利用度低之外,还有一个问题就是拷贝数。无论是直接注射,还是常用的鱼精蛋白包裹的mRNA,都是一个mRNA只能在生物体内有效的翻译一次,这极大的限制了mRNA作为疫苗的利用度。因此,为解决此现象,需要设计一个可复制的系统,保证在宿主细胞内能不断的产生mRNA。该腺病毒载体感染宿主细胞后,将携带基因注入宿主细胞,这些基因可以利用宿主细胞的各碱基对合成mRNA。更为关键的是腺病毒为DNA病毒,DNA病毒在宿主体内的基因扩增能力远高于RNA病毒。因此以腺病毒作为载体将极大提高mRNA的拷贝数。
腺病毒载体疫苗感染宿主细胞后,目的基因的拷贝数通过腺病毒载体本身的启动子强弱来决定,尤其对复制缺陷型腺病毒载体而言,其复制功能还是比较弱。为了解决这个问题,在本发明中,发明人对腺病毒基因进行修饰,实现腺病毒载体本身的启动子与修饰基因共同作用,极大提高了目标抗原的表达率。也可以在携带mRNA基因的腺病毒载体中加入佐剂的DNA,如此构建的腺病毒载体系统不仅可以提高机体免疫原性,也可以产生佐剂的效果。
发明内容
本发明提供一种SamRNA疫苗,所述的疫苗包括重组病毒载体,所述的重组病毒载体包括:i)病毒基因复制复合体,所述的病毒基因复制复合体包括编码病毒基因复制相关蛋白nsP1、nsP2、nsP3和nsP4的核苷酸序列和ii)编码至少一种抗原的核苷酸序列。
优选的,所述SamRNA疫苗还包括iii)转录抗原基因的启动子。
优选的,所述的重组病毒载体为重组腺病毒、黑猩猩型腺病毒、重组水疱性口炎病毒、重组痘病毒、重组登革热病毒、重组昆津病毒、重组仙台病毒或重组犬瘟热病毒。更优选的,所述的重组病毒载体为重组腺病毒和黑猩猩型腺病毒载体,更优选的,所述的腺病毒可以为Ad1-Ad52中任意一种。
本发明所述的抗原引起针对细菌、病毒、真菌或寄生虫的免疫应答。
在本发明的一个实施方式中,所述的抗原为人带状疱疹病毒gE蛋白、轮状病毒VP4或VP7、HPV-L1蛋白或埃博拉病毒的gP蛋白。
本发明所述的抗原还可以为肿瘤特异抗原,例如所述肿瘤特异抗原选自NY-ESO-1、SSX2、SCP1、RAGE、BAGE、GAGE、MAGE家族多肽、p53、p21/Ras、CDK4、MUM1、caspase-8、CIA0205、HLA-A2-R1701、β-联蛋白、TCR、BCR-abl、磷酸甘油醛异构酶、KIA0205、CDC-27、LDLR-FUT、Galectin 4、Galectin 9、蛋白酶3、WT 1、碳酸酐酶、醛缩酶A、PRAME、HER-2/neu、乳腺珠蛋白、甲胎蛋白、KSA、胃泌素、端粒酶催化蛋白、MUC-1、G-250、p53、癌胚抗原、黑素瘤-黑素细胞分化抗原、PAP、PSA、PSMA、PSH-P1、PSM-P1、PSM-P2、p15、Hom/Mel-40、H-Ras、E2A-PRL、H4-RET、IGH-IGK、MYL-RAR、EB病毒抗原、EBNA、人乳头瘤病毒抗原、乙型和丙型肝炎病毒抗原、人类嗜T淋巴细胞病毒抗原、TSP-180、p185erbB2、p180erbB-3、c-met、mn-23H1、TAG-72-4、CA 19-9、CA 72-4、CAM 17.1、NuMa、K-ras、p16、TAGE、PSCA、CT7、43-9F、5T4、791Tgp72、β-HCG、BCA225、BTAA、CA 125、CA 15-3(CA 27.29\BCAA)、CA 195、CA 242、CA-50、CAM43、CD68\KP1、CO-029、FGF-5、Ga733(EpCAM)、HTgp-175、M344、MA-50、MG7-Ag、MOV18、NB/70K、NY-CO-1、RCAS1、SDCCAG16、TAAL6、TAG72、TLP、TPS。
优选的,所述的重组病毒载体由修饰化腺病毒骨架质粒与含有抗原基因的穿梭质粒共转染得到。所述修饰化腺病毒骨架质粒上包括病毒基因复制复合体,所述病毒基因复制复合体为来自于RNA病毒编码病毒基因复制的相关蛋白,更优先的,所述病毒基因复制复合体为来自于alphavirus的nsP1、nsP2、nsP3和nsP4的核苷酸序列。所述腺病毒骨架质粒选自:pAdEasy-1、pAdEasy-2、pBHG11、pBHG-fiber5或pBHG-fiber35。
在本发明的一个实施方式中,所述的重组病毒载体还包括:iv)编码至少一种佐剂的核苷酸序列,例如,所述的编码至少一种佐剂的核苷酸序列选自编码GM-CSF、IL-17、IFNg、IL-15、IL-21、抗PD1/2、乳铁蛋白、鱼精蛋白、IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-12、INF-α、INF-γ、Lymphotoxin-α、hGH的核苷酸序列。
本发明提供一种SamRNA疫苗的制备方法,包括:修饰化腺病毒骨架质粒的构建;抗原基因片段的克隆;穿梭质粒的构建;穿梭质粒与腺病毒骨架质粒共转染与包装。
优选的,所述修饰化腺病毒骨架质粒的构建包括所述病毒基因复制复合体和启动子的克隆,以及病毒基因复制复合体和启动子与腺病毒骨架质粒的连接。
优选的,所述腺病毒骨架质粒上包括病毒基因复制复合体,所述病毒基因复制复合体为编码病毒复制相关蛋白nsP1、nsP2、nsP3和nsP4的基因序列。所述的病毒复制相关蛋白nsP1、nsP2、nsP3和nsP4的氨基酸序列见SEQ ID NO.1、SEQ ID NO.2、SEQ ID NO.3、SEQID NO.4。
优选的,所述腺病毒骨架质粒上还包括启动子,所述启动子为转录抗原基因的启动子,启动子的序列由于编码至少一种抗原的核苷酸序列的改变而不同,优选的,在本发明中,启动子的基因序列如SEQ ID NO.5。
所述腺病毒骨架质粒选自:pAdEasy-1、pAdEasy-2、pBHG11、pBHG-fiber5、pBHG-fiber35等。
优选的,含有抗原基因的穿梭质粒的构建方法采用行业内常规的实验方法,本技术领域都采用该方法,例如合成编码至少一种抗原的核苷酸序列,所合成的编码至少一种抗原的核苷酸序列两端设计引入和穿梭质粒相同的酶,分别双酶切目标抗原和穿梭质粒,回收核苷酸片段后,以T4DNA连接酶连接编码至少一种抗原的核苷酸序列和质粒即可。具体可以参考骨架质粒中引入病毒基因复制复合体和启动子的方法。
本发明提供的SamRNA疫苗的制备方法,只要在穿梭质粒中插入任何抗原基因(即编码至少一种抗原的核苷酸序列),就会开发出一个可预防该疾病的SamRNA疫苗。所述疫苗上述插入病毒基因复制复合体和启动子基因的腺病毒骨架质粒与含有抗原基因的穿梭质粒共转染重组得到,所述的疫苗包括重组病毒载体,所述的重组病毒载体包括:i)病毒基因复制复合体,所述的病毒基因复制复合体包括编码病毒基因复制相关蛋白nsP1、nsP2、nsP3和nsP4的核苷酸序列,和ii)编码至少一种抗原的核苷酸序列。
优选的,所述抗原基因为可编码任意抗原的DNA序列,任何已经发现或者公开报道的抗原基因都可以通过穿梭质粒,重组到腺病毒载体中,骨架质粒和穿梭质粒共感染后,即可得到本发明所述的SamRNA疫苗。
优选的,所述抗原基因选自:编码人带状疱疹病毒gE蛋白的DNA序列、轮状病毒VP4或VP7的DNA序列、HPV-L1蛋白的DNA序列,埃博拉病毒的gP蛋白的DNA序列等。
所述穿梭载体选自:pDC311、pDC312、pDC315、pDC316、p-Shuttle、p-Shuttle-CMV、pAdTrack、pAdTrack-CMV等。
本发明提供一种药物组合物,所述药物组合物包括SamRNA疫苗和药学上可接受的辅料。
所述药学上可接受的辅料包括:稀释剂、增溶剂、粘合剂、润滑剂、助悬剂等。
所述药物组合物的剂型包括但不限于:冻干制剂、液体制剂、乳剂等;
优选的,所述的药物组合物为冻干制剂,冻干制剂的辅料例如包括甘露醇、蔗糖、人白蛋白、PB缓冲液(用于维持制剂的pH)。在本发明的实施方式中,药物组合物中所述的甘露醇浓度为10-500mg/ml,蔗糖浓度为10-500mg/ml,人白蛋白浓度为25-100mg/ml,PB缓冲液浓度为1-100mM。
优选的,SamRNA疫苗为液体针剂,液体制剂中加入的辅料包括人白蛋白,和PB缓冲液。所述人白蛋白浓度为25-100mg/ml,PB缓冲液浓度为1-100mM。
本发明提供一种修饰化腺病毒骨架质粒,所述腺病毒骨架质粒上插入病毒基因复制复合体基因,所述病毒基因复制复合体为编码病毒基因复制相关蛋白nsP1、nsP2、nsP3和nsP4的基因序列。所述基因序列以nsP1--nsP2--nsP3--nsP4连接的方式插入腺病毒骨架质粒中,相邻两个蛋白基因之间加入一个或多个linker。所述linker包括但不限于G4S、LElinker1(序列TTAGAA)、LE linker 2(序列CTCGAA)或DEL(序列GATGAACTG)。编码病毒基因复制相关蛋白nsP1、nsP2、nsP3和nsP4的氨基酸序列分别为SEQ ID NO.1、SEQ ID NO.2、SEQID NO.3、SEQ ID NO.4。
优选的,所述腺病毒骨架质粒上还包括启动子,所述启动子为转录抗原基因的启动子,启动子的序列由于抗原基因的改变而不同;所述启动子可以来自于RNA病毒非结构蛋白复制时的启动子,也可以来自于各种表达载体上常见的启动子。优选的,在本发明中,启动子的基因序列如SEQ ID NO.5。
优选的,腺病毒骨架质粒上的启动子以及复制体基因经过密码子优化,密码子优化的目的是提高复制体在宿主细胞内的表达,从而促进转录形成更多拷贝的mRNA。nsP1、nsP2、nsP3和nsP4的氨基酸序列分别为SEQ ID NO.1、SEQ ID NO.2、SEQ ID NO.3、SEQ IDNO.4。启动子的基因序列见SEQ ID NO.5。
所述nsP1、nsP2、nsP3和nsP4和启动子的序列采用基因合成的方法,本领域掌握一般知识的技术人员都知道该合成方法。其中nsP1、nsP2、nsP3和nsP4直接合成为一个片段,并且相邻基因之间加入一个或多个linker。所合成的序列两端加入酶切位点,因此该基因片段通过T4DNA连接酶就可以很简单的插入腺病毒骨架质粒。
所述腺病毒骨架质粒选自:pAdEasy-1、pAdEasy-2、pBHG11、pBHG-fiber5、pBHG-fiber35。
本发明提供一种制备修饰化腺病毒骨架质粒的方法,包括如下步骤:
病毒基因复制复合体和启动子基因的克隆,所述nsP1、nsP2、nsP3和nsP4的氨基酸序列分别为SEQ ID NO.1、SEQ ID NO.2、SEQ ID NO.3、SEQ ID NO.4。启动子的基因序列见SEQ ID NO.5。
本领域掌握常规技术都可以提供该基因的合成业务;基因合成采用本领域常规的实验技术。合成的启动子基因片段,两端加入酶切位点。
优选的,病毒基因复制复合体nsP1、nsP2、nsP3和nsP4的氨基酸序列为SEQ IDNO.1、SEQ ID NO.2、SEQ ID NO.3、SEQ ID NO.4。四个蛋白基因采用nsP1—linker--nsP2—linker--nsP3—linker--nsP4顺序进行合成一个基因片段,两个蛋白基因之间加入一个或多个linker。所述linker包括但不限于G4S、LE linker 1(核苷酸序列TTAGAA)、LE linker2(核苷酸序列CTCGAA)或DEL(核苷酸序列GATGAACTG)。该基因片段的两侧加入酶切位点。
病毒基因复制复合体和启动子基因片段插入腺病毒骨架质粒:病毒基因复制复合体和启动子基因片段和腺病毒骨架质粒的连接采用行业内常规的实验方法,掌握本行业分子生物学一般知识的人都可以进行该操作。
优选的,将病毒基因复制复合体基因片段和腺病毒骨架质粒相连接,具体的操作为分别将腺病毒骨架质粒与病毒基因复制复合体进行双酶切,酶切在37℃进行;酶切结束后胶回收目的基因片段,目的基因片段的回收采用胶回收试剂盒,具体的操作可依据试剂盒的说明书进行即可。然后用DNA连接试剂盒/T4DNA连接酶将双酶切后的病毒基因复制复合体基因片段以及腺病毒骨架质粒进行连接,连接过夜。之后将连接产物转化DH5a感受态细胞。PCR鉴定阳性的克隆接种LB培养基,在37℃200-2250rpm条件下过夜。第二天回收菌体,同时用质粒抽提试剂盒回收质粒。
优选的,将启动子基因片段插入已经连接病毒基因复制复合体片段的腺病毒骨架质粒。启动子基因片段插入腺病毒骨架质粒和上述方法类似。分别将已经连接病毒基因复制复合体的腺病毒骨架质粒与启动子进行双酶切,酶切在37℃进行;酶切结束后胶回收目的基因片段,目的基因片段的回收采用胶回收试剂盒,具体的操作可依据试剂盒的说明书进行即可。然后用DNA连接试剂盒/T4DNA连接酶将双酶切后的病毒基因复制复合体基因片段以及腺病毒骨架质粒进行连接,连接过夜。之后将连接产物转化DH5a感受态细胞。PCR鉴定阳性的克隆接种LB培养基,在37℃200-2250rpm条件下过夜。第二天回收菌体,同时用质粒抽提试剂盒回收质粒。
优选的,构建好腺病毒骨架质粒以双酶切,以及PCR的方法进行鉴定。
本发明解决了mRNA疫苗在体内被大量降解的风险,现有的包裹技术尽管可以避免mRNA疫苗的大量降解,但是解决不了mRNA难以直接进入细胞的缺陷(生物利用度低)。本发明所述的samRNA疫苗为携带有抗原的腺病毒载体,腺病毒载体可以直接感染人和动物细胞,从而将目标抗原基因注入宿主细胞。常规的mRNA疫苗进入宿主细胞后只能翻译一次,而本发明所述的samRNA疫苗可以以RNA为模板,合成大量的mRNA,从而极大的提高抗原的表达量。
普通复制缺陷型腺病毒载体,只能在类似于HEK293这样的细胞中进行复制,对于人和动物而言,只能感染,不能复制,因此在生物体内的复制能力有限。但是本发明所提供的插入病毒基因复制复合体和启动子的腺病毒载体疫苗感染宿主细胞后,将核酸注入宿主细胞内。随后在宿主细胞内将发生一系列动态反应,首先是病毒基因复制复合体基因的转录以及蛋白质的翻译。同时抗原基因被转录为mRNA。随着nsP1,nsP2,nsP3,nsP4蛋白的翻译,四个蛋白将形成病毒基因组病毒基因复制复合体,随后在该病毒基因复制复合体的作用下,以抗原基因RNA为模板,大量合成mRNA,这些mRNA利用宿主细胞的各种蛋白酶,合成目标抗原。所述的病毒基因复制复合体以RNA为模板合成mRNA是一个持续的过程,抗原表达持续的时间更长,因此修饰化腺病毒载体SamRNA疫苗的作用更持久。
文献报道以病毒作为SamRNA的载体,但是缺点也很明显,首先用于samRNA的病毒均为RNA病毒,而且为正义RNA病毒,这些病毒的感染和复制能力都有限。宿主限制性导致以病毒为载体的SamRNA生产非常困难,严格的宿主细胞限制导致常规的生产工艺很难满足这类病毒的生产,此外扩增能力有限更是严重影响病毒的产量。此外以病毒为载体的SamRNA,在基因组重组构建的过程中,RNA病毒的外膜结构基因被抗原的基因替代。病毒外膜结构基因的删除的优点是病毒感染动物和人宿主细胞后不会组装形成病毒,降低在感染或者致病的风险。但是缺点显而易见,结构基因的缺失,导致该病毒载体疫苗常规条件下没有办法完成病毒颗粒的组装,商业化生产的技术难度较高。
附图说明
图1病毒基因复制复合体蛋白基因插入骨架质粒鉴定结果;
图2启动子序列插入骨架质粒鉴定结果;
图3修饰化的骨架质粒;
图4Ad-SamRNA-gE构建流程图;
图5Ad-SamRNA-gE双酶切检定;
图6CL-4B纯化Ad-SamRNA-gE图谱;
图7Ad-SamRNA-gE纯度分析;
图8不同载体的免疫原性,左侧为一免的免疫原性,右侧为二免的免疫原性;
图9不同载体gE基因的表达量;
图10分子佐剂增强Ad-SamRNA-gE的免疫原性,左侧为一免的免疫原性,右侧为二免的免疫原性。
具体实施方式
下面将对本发明实施例中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的部分实施例,而不是全部。基于本发明中的实施例,本领域普通技术人员在没有做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。
实施例1病毒基因复制复合体和启动子基因片段插入骨架质粒
病毒基因复制复合体和启动子基因片段的合成:
在具体实施过程中,病毒基因复制复合体nsP1、nsP2、nsP3和nsP4的基因序列分别为SEQ ID NO.6、SEQ ID NO.7、SEQ ID NO.8、SEQ ID NO.9,依据上述序列合成病毒基因复制复合体基因片段,四个抗原蛋白基因合成为一个大的基因片段。
启动子依据SEQ ID NO.5合成启动子基因片段,同时在启动子基因片段两端加入酶切位点。
以pAdEasy-1腺病毒骨架质粒为例,呈现病毒基因复制复合体和启动子插入pAdEasy-1的过程。
首先将病毒基因复制复合体基因片段插入pAdEasy-1腺病毒骨架质粒,合成的4个病毒基因复制复合体蛋白基因长片段两侧都含有pacI酶切位点。分别以pac I酶酶切pAdEasy-1和4个病毒基因复制复合体蛋白基因。胶回收后,用T4DNA连接酶进行连接。理论上病毒基因复制复合体蛋白基因有两种连接方式(倒着插入骨架质粒和顺着插入骨架质粒),转化DH5a后,分别挑单克,通过PCR的方法来鉴别按照预期插入骨架质粒的载体。PCR鉴定结果见图1,1号和2号克隆都正确插入病毒基因复制复合体蛋白基因片段,选择1号克隆进行启动子基因片段插入的操作。
将启动子基因和已经插入病毒基因复制复合体基因的骨架质粒,以ClaI进行酶切,胶回收后,用T4DNA连接酶进行连接。理论上启动子蛋白基因有两种连接方式(倒着插入骨架质粒和顺着插入骨架质粒),转化DH5a后,分别挑单克,通过PCR的方法来鉴别按照预期插入骨架质粒的载体。PCR鉴定结果见图2,该步操作中,3号、4号、5号克隆正确插入启动子序列。
经过以上两步,将得到加入病毒基因复制复合体和启动子序列的骨架质粒pAdEasy-13号,4号和5号,pAdEasy-1骨架质粒中启动子和病毒基因复制复合体的位置见图3。
根据同样的方法可以在其他骨架质粒上完成启动子和病毒基因复制复合体序列的插入。
实施例2:Ad-SamRNA-gE的构建
以带状疱疹的gE蛋白抗原为例,进行Ad(腺病毒)-SamRNA疫苗构建工艺的展示。
合成gE抗原基因,同时在基因片段的两侧加入酶切位点,具体的酶切位点根据所选择的重组系统以及穿梭质粒来定,本领域专业技术人员都掌握该方法。下面以Adeasy载体系统为例进行Ad-SamRNA疫苗构建工艺的展示。
首先将gE抗原基因连接到穿梭质粒pS-C中形成pS-C-gE,所述连接方法采用业内常用的实验方法。穿梭质粒pS-C以及gE抗原基因以KpnⅠ、XhoⅠ同时进行双酶切(酶切反应体系见下表1),酶切反应结束后,用胶回收试剂盒回收目的片段(回收方法见说明书)。然后以T4DNA连接酶连接线性化的抗原片段和质粒(反应体系见下表2)。
对于采用其他腺病毒载体系统的构建方法和上述类似。
表1:双酶切反应体系(50ul)
双酶切反应在37℃酶切至少4h以上。
表2酶连接反应体系(10ul)
连接反应在4℃进行,过夜连接。
含有抗原基因的穿梭质粒pS-C-gE和插入病毒基因复制复合体、启动子的腺病毒骨架质粒(如pAdEasy-1)共转染,两个质粒将发生同源重组,分离得到Ad-SamRNA-gE,所述Ad-SamRNA构建流程图见图4。
采用双酶切的方法对构建好Ad-SamRNA-gE进行检定,检定构建成功的载体将用于疫苗的生产和免疫原性的评价,双酶切的结果如下图5:泳道M为marker,1为腺病毒载体双酶切,2为Ad-SamRNA-gE双酶切。结果表明,gE抗原基因已经正确的整和到腺病毒载体系统中。
实施例3Ad-SamRNA-gE疫苗的制备
以带状疱疹的gE蛋白抗原为例,进行Ad-SamRNA疫苗制备工艺的展示。
腺病毒载体可在293细胞中大量繁殖,Admax腺病毒载体系统多采用HEK293细胞,而采用Adeasy重组腺病毒载体细胞则采用AD293细胞。
Ad-SamRNA-gE以MOI=5—10感染293细胞,感染至少40h后8000g离心10min收集细胞沉淀。细胞沉淀以PB或者裂解(2mM MgCl2,50mM HEPES,PH7.5)缓冲液溶解后,-80℃反复冻融三次裂解细胞,离心去除细胞碎片,上清过CL-4B,经一步层析就可以得到目标病毒。
细胞裂解液中除了细胞碎片,各种杂蛋白就是Ad-SamRNA-gE,细胞碎片通过离心就可以去除。相比较杂蛋白,Ad-SamRNA-gE分子量远大于杂蛋白,因此,离心上清液通过CL-4B一步工艺就可以得到纯病毒。
CL-4B纯化Ad-SamRNA-gE结果如图6,Ad-SamRNA-gE分子量最大,因此最先洗脱,图6中的峰1即为Ad-SamRNA-gE。
以HPLC分析收获的Ad-SamRNA-gE的纯度,实验选择TSK5000的柱子,HPLC结果见图7,可以看出收获的病毒看不到杂质峰,病毒液的纯度很高。
实施例4Ad-SamRNA-gE疫苗免疫原性研究
以带状疱疹的gE蛋白抗原为例,进行Ad-SamRNA疫苗免疫原性的展示。
实验组:实施例3制备的Ad-SamRNA-gE组;
对照组1:gE蛋白mRNA直接注射组,简称为mRNA-gE;
对照组2:普通腺病毒为载体的gE蛋白抗原基因疫苗,简称为Ad-gE;
阴性对照组:生理盐水免疫组
实验动物:取NIH小鼠,每组10只,体重为12-14g,
免疫方式:皮下注射,实验组、对照组1、对照组2药物单次注射剂量为1×108IFU,每只小鼠免疫两针,两针间隔4周,第二针免前眼眶采集一免血,最后一次免后28天摘眼球采集二免血清,ELISA法测定血清中的抗体滴度,结果如图8所示。
根据图8结果可以看出,Ad-SamRNA-gE的免疫原性优于Ad-gE,也明显优于mRNA-gE,差异显著。因此,证明本发明所制备的以修饰化腺病毒为载体的抗原基因疫苗,可极大提高mRNA疫苗的免疫原性。
实施例5Ad-SamRNA-gE和Ad-gE表达量的测定
将构建好Ad-SamRNA-gE和Ad-gE以MOI=10感染293细胞,37℃5%CO2培养箱培养40h后离心收集细胞上清和沉淀,细胞沉淀以裂解缓冲液(2mM MgCl2,50mM HEPES,PH7.5)裂解;通过SDS-PAGE分析两个载体中gE蛋白的表达量。结果见图9.
图9中说明相比较对照组Ad-gE,供试品Ad-SamRNA-gE感染细胞后gE蛋白的表达量明显高。和实施例4中Ad-SamRNA-gE的免疫原性远高于Ad-gE相对应。
实施例6分子佐剂对Ad-SamRNA-gE的免疫原性
以带状疱疹的gE蛋白抗原为例,进行Ad-SamRNA疫苗免疫原性的展示。
实验组:分别制备含有C3b和不含有C3b的Ad-SamRNA-gE;
阴性对照组:生理盐水免疫组
实验动物:取NIH小鼠,每组10只,体重为12-14g,
免疫方式:皮下注射,实验组、对照组1、对照组2药物单次注射剂量为1×108IFU,每只小鼠免疫两针,两针间隔4周,第二针免前眼眶采集一免血,最后一次免后28天摘眼球采集二免血清,ELISA法测定血清中的抗体滴度,结果如图10所示。
根据图10结果可以看出,C3b可增强Ad-SamRNA-gE的免疫原性。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
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Lys Val Leu Ser Asn Ile Pro Gln Gly Asn Phe Thr Ala Thr Leu Glu
435 440 445
Glu Trp Gln Glu Glu His Asp Lys Ile Met Lys Val Ile Glu Gly Pro
450 455 460
Ala Ala Pro Val Asp Ala Phe Gln Asn Lys Ala Asn Val Cys Trp Ala
465 470 475 480
Lys Ser Leu Val Pro Val Leu Asp Thr Ala Gly Ile Arg Leu Thr Ala
485 490 495
Glu Glu Trp Ser Thr Ile Ile Thr Ala Phe Lys Glu Asp Arg Ala Tyr
500 505 510
Ser Pro Val Val Ala Leu Asn Glu Ile Cys Thr Lys Tyr Tyr Gly Val
515 520 525
Asp Leu Asp Ser Gly Leu Phe Ser Ala Pro Lys Val Ser Leu Tyr Tyr
530 535 540
Glu Asn Asn His Trp Asp Asn Arg Pro Gly Gly Arg Met Tyr Gly Phe
545 550 555 560
Asn Ala Ala Thr Ala Ala Arg Leu Glu Ala Arg His Thr Phe Leu Lys
565 570 575
Gly Gln Trp His Thr Gly Lys Gln Ala Val Ile Ala Glu Arg Lys Ile
580 585 590
Gln Pro Leu Ser Val Leu Asp Asn Val Ile Pro Ile Asn Arg Arg Leu
595 600 605
Pro His Ala Leu Val Ala Glu Tyr Lys Thr Val Lys Gly Ser Arg Val
610 615 620
Glu Trp Leu Val Asn Lys Val Arg Gly Tyr His Val Leu Leu Val Ser
625 630 635 640
Glu Tyr Asn Leu Ala Leu Pro Arg Arg Arg Val Thr Trp Leu Ser Pro
645 650 655
Leu Asn Val Thr Gly Ala Asp Arg Cys Tyr Asp Leu Ser Leu Gly Leu
660 665 670
Pro Ala Asp Ala Gly Arg Phe Asp Leu Val Phe Val Asn Ile His Thr
675 680 685
Glu Phe Arg Ile His His Tyr Gln Gln Cys Val Asp His Ala Met Lys
690 695 700
Leu Gln Met Leu Gly Gly Asp Ala Leu Arg Leu Leu Lys Pro Gly Gly
705 710 715 720
Ile Leu Met Arg Ala Tyr Gly Tyr Ala Asp Lys Ile Ser Glu Ala Val
725 730 735
Val Ser Ser Leu Ser Arg Lys Phe Ser Ser Ala Arg Val Leu Arg Pro
740 745 750
Asp Cys Val Thr Ser Asn Thr Glu Val Phe Leu Leu Phe Ser Asn Phe
755 760 765
Asp Asn Gly Lys Arg Pro Ser Thr Leu His Gln Met Asn Thr Lys Leu
770 775 780
Ser Ala Val Tyr Ala Gly Glu Ala Met His Thr Ala Gly Cys
785 790 795
<210> 3
<211> 482
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Ala Pro Ser Tyr Arg Val Lys Arg Ala Asp Ile Ala Thr Cys Thr Glu
1 5 10 15
Ala Ala Val Val Asn Ala Ala Asn Ala Arg Gly Thr Val Gly Asp Gly
20 25 30
Val Cys Arg Ala Val Ala Lys Lys Trp Pro Ser Ala Phe Lys Gly Ala
35 40 45
Ala Thr Pro Val Gly Thr Ile Lys Thr Val Met Cys Gly Ser Tyr Pro
50 55 60
Val Ile His Ala Val Ala Pro Asn Phe Ser Ala Thr Thr Glu Ala Glu
65 70 75 80
Gly Asp Arg Glu Leu Ala Ala Val Tyr Arg Ala Val Ala Ala Glu Val
85 90 95
Asn Arg Leu Ser Leu Ser Ser Val Ala Ile Pro Leu Leu Ser Thr Gly
100 105 110
Val Phe Ser Gly Gly Arg Asp Arg Leu Gln Gln Ser Leu Asn His Leu
115 120 125
Phe Thr Ala Met Asp Ala Thr Asp Ala Asp Val Thr Ile Tyr Cys Arg
130 135 140
Asp Lys Ser Trp Glu Lys Lys Ile Gln Glu Ala Ile Asp Met Arg Thr
145 150 155 160
Ala Val Glu Leu Leu Asn Asp Asp Val Glu Leu Thr Thr Asp Leu Val
165 170 175
Arg Val His Pro Asp Ser Ser Leu Val Gly Arg Lys Gly Tyr Ser Thr
180 185 190
Thr Asp Gly Ser Leu Tyr Ser Tyr Phe Glu Gly Thr Lys Phe Asn Gln
195 200 205
Ala Ala Ile Asp Met Ala Glu Ile Leu Thr Leu Trp Pro Arg Leu Gln
210 215 220
Glu Ala Asn Glu Arg Ile Cys Leu Tyr Ala Leu Gly Glu Thr Met Asp
225 230 235 240
Asn Ile Gly Ser Lys Cys Pro Val Asn Asp Ser Asp Ser Ser Thr Pro
245 250 255
Pro Arg Thr Val Pro Cys Leu Cys Arg Tyr Ala Met Thr Ala Glu Arg
260 265 270
Ile Ala Arg Leu Arg Ser His Gln Val Lys Ser Met Val Val Cys Ser
275 280 285
Ser Phe Pro Leu Pro Lys Tyr His Val Asp Gly Val Gln Lys Val Lys
290 295 300
Cys Glu Lys Val Leu Leu Phe Asp Pro Thr Val Pro Ser Val Val Ser
305 310 315 320
Pro Arg Lys Tyr Ala Ala Ser Thr Thr Asp His Ser Asp Arg Ser Leu
325 330 335
Arg Gly Phe Asp Leu Asp Trp Thr Thr Asp Ser Ser Ser Thr Ala Ser
340 345 350
Asp Thr Met Ser Leu Pro Ser Leu Gln Ser Cys Asp Ile Asp Ser Ile
355 360 365
Tyr Glu Pro Met Ala Pro Ile Val Val Thr Ala Asp Val His Pro Glu
370 375 380
Pro Ala Gly Ile Ala Asp Leu Ala Ala Asp Val His Pro Glu Pro Ala
385 390 395 400
Asp His Val Asp Leu Glu Asn Pro Ile Pro Pro Pro Arg Pro Lys Arg
405 410 415
Ala Ala Tyr Leu Ala Ser Arg Ala Ala Glu Arg Pro Val Pro Ala Pro
420 425 430
Arg Lys Pro Thr Pro Ala Pro Arg Thr Ala Phe Arg Asn Lys Leu Pro
435 440 445
Leu Thr Phe Gly Asp Phe Asp Glu His Glu Val Asp Ala Leu Ala Ser
450 455 460
Gly Ile Thr Phe Gly Asp Phe Asp Asp Val Leu Arg Leu Gly Arg Ala
465 470 475 480
Gly Ala
<210> 4
<211> 614
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Tyr Ile Phe Ser Ser Asp Thr Gly Ser Gly His Leu Gln Gln Lys Ser
1 5 10 15
Val Arg Gln His Asn Leu Gln Cys Ala Gln Leu Asp Ala Val Gln Glu
20 25 30
Glu Lys Met Tyr Pro Pro Lys Leu Asp Thr Glu Arg Glu Lys Leu Leu
35 40 45
Leu Leu Lys Met Gln Met His Pro Ser Glu Ala Asn Lys Ser Arg Tyr
50 55 60
Gln Ser Arg Lys Val Glu Asn Met Lys Ala Thr Val Val Asp Arg Leu
65 70 75 80
Thr Ser Gly Ala Arg Leu Tyr Thr Gly Ala Asp Val Gly Arg Ile Pro
85 90 95
Thr Tyr Ala Val Arg Tyr Pro Arg Pro Val Tyr Ser Pro Thr Val Ile
100 105 110
Glu Arg Phe Ser Ser Pro Asp Val Ala Ile Ala Ala Cys Asn Glu Tyr
115 120 125
Leu Ser Arg Asn Tyr Pro Thr Val Ala Ser Tyr Gln Ile Thr Asp Glu
130 135 140
Tyr Asp Ala Tyr Leu Asp Met Val Asp Gly Ser Asp Ser Cys Leu Asp
145 150 155 160
Arg Ala Thr Phe Cys Pro Ala Lys Leu Arg Cys Tyr Pro Lys His His
165 170 175
Ala Tyr His Gln Pro Thr Val Arg Ser Ala Val Pro Ser Pro Phe Gln
180 185 190
Asn Thr Leu Gln Asn Val Leu Ala Ala Ala Thr Lys Arg Asn Cys Asn
195 200 205
Val Thr Gln Met Arg Glu Leu Pro Thr Met Asp Ser Ala Val Phe Asn
210 215 220
Val Glu Cys Phe Lys Arg Tyr Ala Cys Ser Gly Glu Tyr Trp Glu Glu
225 230 235 240
Tyr Ala Lys Gln Pro Ile Arg Ile Thr Thr Glu Asn Ile Thr Thr Tyr
245 250 255
Val Thr Lys Leu Lys Gly Pro Lys Ala Ala Ala Leu Phe Ala Lys Thr
260 265 270
His Asn Leu Val Pro Leu Gln Glu Val Pro Met Asp Arg Phe Thr Val
275 280 285
Asp Met Lys Arg Asp Val Lys Val Thr Pro Gly Thr Lys His Thr Glu
290 295 300
Glu Arg Pro Lys Val Gln Val Ile Gln Ala Ala Glu Pro Leu Ala Thr
305 310 315 320
Ala Tyr Leu Cys Gly Ile His Arg Glu Leu Val Arg Arg Leu Asn Ala
325 330 335
Val Leu Arg Pro Asn Val His Thr Leu Phe Asp Met Ser Ala Glu Asp
340 345 350
Phe Asp Ala Ile Ile Ala Ser His Phe His Pro Gly Asp Pro Val Leu
355 360 365
Glu Thr Asp Ile Ala Ser Phe Asp Lys Ser Gln Asp Asp Ser Leu Ala
370 375 380
Leu Thr Gly Leu Met Ile Leu Glu Asp Leu Gly Val Asp Gln Tyr Leu
385 390 395 400
Leu Asp Leu Ile Glu Ala Ala Phe Gly Glu Ile Ser Ser Cys His Leu
405 410 415
Pro Thr Gly Thr Arg Phe Lys Phe Gly Ala Met Met Lys Ser Gly Met
420 425 430
Phe Leu Thr Leu Phe Ile Asn Thr Val Leu Asn Ile Thr Ile Ala Ser
435 440 445
Arg Val Leu Glu Gln Arg Leu Thr Asp Ser Ala Cys Ala Ala Phe Ile
450 455 460
Gly Asp Asp Asn Ile Val His Gly Val Ile Ser Asp Lys Leu Met Ala
465 470 475 480
Glu Arg Cys Ala Ser Trp Val Asn Met Glu Val Lys Ile Ile Asp Ala
485 490 495
Val Met Gly Glu Lys Pro Pro Tyr Phe Cys Gly Gly Phe Ile Val Phe
500 505 510
Asp Ser Val Thr Gln Thr Ala Cys Arg Val Ser Asp Pro Leu Lys Arg
515 520 525
Leu Phe Lys Leu Gly Lys Pro Leu Thr Ala Glu Asp Lys Gln Asp Glu
530 535 540
Asp Arg Arg Arg Ala Leu Ser Asp Glu Val Ser Lys Trp Phe Arg Thr
545 550 555 560
Gly Leu Gly Ala Glu Leu Glu Val Ala Leu Thr Ser Arg Tyr Glu Val
565 570 575
Glu Gly Cys Lys Ser Ile Leu Ile Ala Met Thr Thr Leu Ala Arg Asp
580 585 590
Ile Lys Ala Phe Lys Lys Leu Arg Gly Pro Val Ile His Leu Tyr Gly
595 600 605
Gly Pro Arg Leu Val Arg
610
<210> 5
<211> 193
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
gagtggacct gtgtcgcgta aatctaaaag taagagtgag gcagaatctt tttcggatag 60
tggcgcttct gagccactaa gttcataatc aagatgtctt actctacttc tggtttgcgt 120
tctttgcctg catatactaa gtctttttgt ccttattatg ctttgtatga tctgttggtg 180
tcagcccaag gtg 193
<210> 6
<211> 1614
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
atggccgcca aagtgcatgt tgatattgag gctgacagcc cattcatcaa gtctttgcag 60
aaggcatttc cgtcgttcga ggtggagtca ttgcaggtca caccaaatga ccatgcaaat 120
gccagagcat tttcgcacct ggctaccaaa ttgatcgagc aggagactga caaagacaca 180
ctcatcttgg atatcggcag tgcgccttcc aggagaatga tgtctacgca caaataccac 240
tgcgtatgcc ctatgcgcag cgcagaagac cccgaaaggc tcgatagcta cgcaaagaaa 300
ctggcagcgg cctccgggaa ggtgctggat agagagatcg caggaaaaat caccgacctg 360
cagaccgtca tggctacgcc agacgctgaa tctcctacct tttgcctgca tacagacgtc 420
acgtgtcgta cggcagccga agtggccgta taccaggacg tgtatgctgt acatgcacca 480
acatcgctgt accatcaggc gatgaaaggt gtcagaacgg cgtattggat tgggtttgac 540
accaccccgt ttatgtttga cgcgctagca ggcgcgtatc caacctacgc cacaaactgg 600
gccgacgagc aggtgttaca ggccaggaac ataggactgt gtgcagcatc cttgactgag 660
ggaagactcg gcaaactgtc cattctccgc aagaagcaat tgaaaccttg cgacacagtc 720
atgttctcgg taggatctac attgtacact gagagcagaa agctactgag gagctggcac 780
ttaccctccg tattccacct gaaaggtaaa caatccttta cctgtaggtg cgataccatc 840
gtatcatgtg aagggtacgt agttaagaaa atcactatgt gccccggcct gtacggtaaa 900
acggtagggt acgccgtgac gtatcacgcg gagggattcc tagtgtgcaa gaccacagac 960
actgtcaaag gagaaagagt ctcattccct gtatgcacct acgtcccctc aaccatctgt 1020
gatcaaatga ctggcatact agcgaccgac gtcacaccgg aggacgcaca gaagttgtta 1080
gtgggattga atcagaggat agttgtgaac ggaagaacac agcgaaacac taacacgatg 1140
aagaactatc tgcttccgat tgtggccgtc gcatttagca agtgggcgag ggaatacaag 1200
gcagaccttg atgatgaaaa acctctgggt gtccgagaga ggtcacttac ttgctgctgc 1260
ttgtgggcat ttaaaacgag gaagatgcac accatgtaca agaaaccaga cacccagaca 1320
atagtgaagg tgccttcaga gtttaactcg ttcgtcatcc cgagcctatg gtctacaggc 1380
ctcgcaatcc cagtcagatc acgcattaag atgcttttgg ccaagaagac caagcgagag 1440
ttaatacctg ttctcgacgc gtcgtcagcc agggatgctg aacaagagga gaaggagagg 1500
ttggaggccg agctgactag agaagcctta ccacccctcg tccccatcgc gccggcggag 1560
acgggagtcg tcgacgtcga cgttgaagaa ctagagtatc acgcaggtgc ataa 1614
<210> 7
<211> 2400
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
atgggggtcg tggaaacacc tcgcagcgcg ttgaaagtca ccgcacagcc gaacgacgta 60
ctactaggaa attacgtagt tctgtccccg cagaccgtgc tcaagagctc caagttggcc 120
cccgtgcacc ctctagcaga gcaggtgaaa ataataacac ataacgggag ggccggcggt 180
taccaggtcg acggatatga cggcagggtc ctactaccat gtggatcggc cattccggtc 240
cctgagtttc aagctttgag cgagagcgcc actatggtgt acaacgaaag ggagttcgtc 300
aacaggaaac tataccatat tgccgttcac ggaccgtcgc tgaacaccga cgaggagaac 360
tacgagaaag tcagagctga aagaactgac gccgagtacg tgttcgacgt agataaaaaa 420
tgctgcgtca agagagagga agcgtcgggt ttggtgttgg tgggagagct aaccaacccc 480
ccgttccatg aattcgccta cgaagggctg aagatcaggc cgtcggcacc atataagact 540
acagtagtag gagtctttgg ggttccggga tcaggcaagt ctgctattat taagagcctc 600
gtgaccaaac acgatctggt caccagcggc aagaaggaga actgccagga aatagttaac 660
gacgtgaaga agcaccgcgg gaaggggaca agtagggaaa acagtgactc catcctgcta 720
aacgggtgtc gtcgtgccgt ggacatccta tatgtggacg aggctttcgc ttgccattcc 780
ggtactctgc tggccctaat tgctcttgtt aaacctcgga gcaaagtggt gttatgcgga 840
gaccccaagc aatgcggatt cttcaatatg atgcagctta aggtgaactt caaccacaac 900
atctgcactg aagtatgtca taaaagtata tccagacgtt gcacgcgtcc agtcacggcc 960
atcgtgtcta cgttgcacta cggaggcaag atgcgcacga ccaacccgtg caacaaaccc 1020
ataatcatag acaccacagg acagaccaag cccaagccag gagacatcgt gttaacatgc 1080
ttccgaggct gggcaaagca gctgcagttg gactaccgtg gacacgaagt catgacagca 1140
gcagcatctc agggcctcac ccgcaaaggg gtatacgccg taaggcagaa ggtgaatgaa 1200
aatcccttgt atgcccctgc gtcggagcac gtgaatgtac tgctgacgcg cactgaggat 1260
aggctggtgt ggaaaacgct ggccggcgat ccctggatta aggtcctatc aaacattcca 1320
cagggtaact ttacggccac attggaagaa tggcaagaag aacacgacaa aataatgaag 1380
gtgattgaag gaccggctgc gcctgtggac gcgttccaga acaaagcgaa cgtgtgttgg 1440
gcgaaaagcc tggtgcctgt cctggacact gccggaatca gattgacagc agaggagtgg 1500
agcaccataa ttacagcatt taaggaggac agagcttact ctccagtggt ggccttgaat 1560
gaaatttgca ccaagtacta tggagttgac ctggacagtg gcctgttttc tgccccgaag 1620
gtgtccctgt attacgagaa caaccactgg gataacagac ctggtggaag gatgtatgga 1680
ttcaatgccg caacagctgc caggctggaa gctagacata ccttcctgaa ggggcagtgg 1740
catacgggca agcaggcagt tatcgcagaa agaaaaatcc aaccgctttc tgtgctggac 1800
aatgtaattc ctatcaaccg caggctgccg cacgccctgg tggctgagta caagacggtt 1860
aaaggcagta gggttgagtg gctggtcaat aaagtaagag ggtaccacgt cctgctggtg 1920
agtgagtaca acctggcttt gcctcgacgc agggtcactt ggttgtcacc gctgaatgtc 1980
acaggcgccg ataggtgcta cgacctaagt ttaggactgc cggctgacgc cggcaggttc 2040
gacttggtct ttgtgaacat tcacacggaa ttcagaatcc accactacca gcagtgtgtc 2100
gaccacgcca tgaagctgca gatgcttggg ggagatgcgc tacgactgct aaaacccggc 2160
ggcatcttga tgagagctta cggatacgcc gataaaatca gcgaagccgt tgtttcctcc 2220
ttaagcagaa agttctcgtc tgcaagagtg ttgcgcccgg attgtgtcac cagcaataca 2280
gaagtgttct tgctgttctc caactttgac aacggaaaga gaccctctac gctacaccag 2340
atgaatacca agctgagtgc cgtgtatgcc ggagaagcca tgcacacggc cgggtgttaa 2400
<210> 8
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atggcaccat cctacagagt taagagagca gacatagcca cgtgcacaga agcggctgtg 60
gttaacgcag ctaacgcccg tggaactgta ggggatggcg tatgcagggc cgtggcgaag 120
aaatggccgt cagcctttaa gggagcagca acaccagtgg gcacaattaa aacagtcatg 180
tgcggctcgt accccgtcat ccacgctgta gcgcctaatt tctctgccac gactgaagcg 240
gaaggggacc gcgaattggc cgctgtctac cgggcagtgg ccgccgaagt aaacagactg 300
tcactgagca gcgtagccat cccgctgctg tccacaggag tgttcagcgg cggaagagat 360
aggctgcagc aatccctcaa ccatctattc acagcaatgg acgccacgga cgctgacgtg 420
accatctact gcagagacaa aagttgggag aagaaaatcc aggaagccat tgacatgagg 480
acggctgtgg agttgctcaa tgatgacgtg gagctgacca cagacttggt gagagtgcac 540
ccggacagca gcctggtggg tcgtaagggc tacagtacca ctgacgggtc gctgtactcg 600
tactttgaag gtacgaaatt caaccaggct gctattgata tggcagagat actgacgttg 660
tggcccagac tgcaggaggc aaacgaacgg atatgcctat acgcgctggg cgaaacaatg 720
gacaacatcg gatccaaatg tccggtgaac gattccgatt catcaacacc tcccaggaca 780
gtgccctgcc tgtgccgcta cgcaatgaca gcagaacgga tcgcccgcct taggtcacac 840
caagttaaaa gcatggtggt ttgctcatct tttcccctcc cgaaatacca tgtagatggg 900
gtgcagaagg taaagtgcga gaaggttctc ctgttcgacc cgacggtacc ttcagtggtt 960
agtccgcgga agtatgccgc atctacgacg gaccactcag atcggtcgtt acgagggttt 1020
gacttggact ggaccaccga ctcgtcttcc actgccagcg ataccatgtc gctacccagt 1080
ttgcagtcgt gtgacatcga ctcgatctac gagccaatgg ctcccatagt agtgacggct 1140
gacgtacacc ctgaacccgc aggcatcgcg gacctggcgg cagatgtgca ccctgaaccc 1200
gcagaccatg tggacctcga gaacccgatt cctccaccgc gcccgaagag agctgcatac 1260
cttgcctccc gcgcggcgga gcgaccggtg ccggcgccga gaaagccgac gcctgcccca 1320
aggactgcgt ttaggaacaa gctgcctttg acgttcggcg actttgacga gcacgaggtc 1380
gatgcgttgg cctccgggat tactttcgga gacttcgacg acgtcctgcg actaggccgc 1440
gcgggtgcat aa 1452
<210> 9
<211> 1908
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
atgtatattt tctcctcgga cactggcagc ggacatttac aacaaaaatc cgttaggcag 60
cacaatctcc agtgcgcaca actggatgcg gtccaggagg agaaaatgta cccgccaaaa 120
ttggatactg agagggagaa gctgttgctg ctgaaaatgc agatgcaccc atcggaggct 180
aataagagtc gataccagtc tcgcaaagtg gagaacatga aagccacggt ggtggacagg 240
ctcacatcgg gggccagatt gtacacggga gcggacgtag gccgcatacc aacatacgcg 300
gttcggtacc cccgccccgt gtactcccct accgtgatcg aaagattctc aagccccgat 360
gtagcaatcg cagcgtgcaa cgaataccta tccagaaatt acccaacagt ggcgtcgtac 420
cagataacag atgaatacga cgcatacttg gacatggttg acgggtcgga tagttgcttg 480
gacagagcga cattctgccc ggcgaagctc cggtgctacc cgaaacatca tgcgtaccac 540
cagccgactg tacgcagtgc cgtcccgtca ccctttcaga acacactaca gaacgtgcta 600
gcggccgcca ccaagagaaa ctgcaacgtc acgcaaatgc gagaactacc caccatggac 660
tcggcagtgt tcaacgtgga gtgcttcaag cgctatgcct gctccggaga atattgggaa 720
gaatatgcta aacaacctat ccggataacc actgagaaca tcactaccta tgtgaccaaa 780
ttgaaaggcc cgaaagctgc tgccttgttc gctaagaccc acaacttggt tccgctgcag 840
gaggttccca tggacagatt cacggtcgac atgaaacgag atgtcaaagt cactccaggg 900
acgaaacaca cagaggaaag acccaaagtc caggtaattc aagcagcgga gccattggcg 960
accgcttacc tgtgcggcat ccacagggaa ttagtaagga gactaaatgc tgtgttacgc 1020
cctaacgtgc acacattgtt tgatatgtcg gccgaagact ttgacgcgat catcgcctct 1080
cacttccacc caggagaccc ggttctagag acggacattg catcattcga caaaagccag 1140
gacgactcct tggctcttac aggtttaatg atcctcgaag atctaggggt ggatcagtac 1200
ctgctggact tgatcgaggc agcctttggg gaaatatcca gctgtcacct accaactggc 1260
acgcgcttca agttcggagc tatgatgaaa tcgggcatgt ttctgacttt gtttattaac 1320
actgttttga acatcaccat agcaagcagg gtactggagc agagactcac tgactccgcc 1380
tgtgcggcct tcatcggcga cgacaacatc gttcacggag tgatctccga caagctgatg 1440
gcggagaggt gcgcgtcgtg ggtcaacatg gaggtgaaga tcattgacgc tgtcatgggc 1500
gaaaaacccc catatttttg tgggggattc atagtttttg acagcgtcac acagaccgcc 1560
tgccgtgttt cagacccact taagcgcctg ttcaagttgg gtaagccgct aacagctgaa 1620
gacaagcagg acgaagacag gcgacgagca ctgagtgacg aggttagcaa gtggttccgg 1680
acaggcttgg gggccgaact ggaggtggca ctaacatcta ggtatgaggt agagggctgc 1740
aaaagtatcc tcatagccat gaccaccttg gcgagggaca ttaaggcgtt taagaaattg 1800
agaggacctg ttatacacct ctacggcggt cctagattgg tgcgttaata cacagaattc 1860
tgattatagc gcactattat agcaccatga attacatccc tacgctaa 1908
Claims (14)
1.一种SamRNA疫苗,所述的疫苗包括重组病毒载体,所述的重组病毒载体包括:i)病毒基因复制复合体,所述的病毒基因复制复合体包括编码病毒基因复制相关蛋白nsP1、nsP2、nsP3和nsP4的核苷酸序列,和ii)编码至少一种抗原的核苷酸序列。
2.根据权利要求1所述的SamRNA疫苗,其特征在于,所述的重组病毒载体为重组腺病毒、黑猩猩型腺病毒、重组水疱性口炎病毒、重组痘病毒、重组登革热病毒、重组昆津病毒、重组仙台病毒或重组犬瘟热病毒。
3.根据权利要求1所述的SamRNA疫苗,其特征在于,所述的抗原引起针对细菌、病毒、真菌或寄生虫的免疫应答。
4.根据权利要求3所述的SamRNA疫苗,其特征在于,所述的抗原为人带状疱疹病毒gE蛋白、轮状病毒VP4或VP7、HPV-L1蛋白或埃博拉病毒的gP蛋白。
5.根据权利要求1所述的SamRNA疫苗,其特征在于,所述的抗原为肿瘤特异抗原,选自NY-ESO-1、SSX2、SCP1、RAGE、BAGE、GAGE、MAGE家族多肽、p53、p21/Ras、CDK4、MUM1、caspase-8、CIA0205、HLA-A2-R1701、β-联蛋白、TCR、BCR-abl、磷酸甘油醛异构酶、KIA0205、CDC-27、LDLR-FUT、Galectin 4、Galectin 9、蛋白酶3、WT1、碳酸酐酶、醛缩酶A、PRAME、HER-2/neu、乳腺珠蛋白、甲胎蛋白、KSA、胃泌素、端粒酶催化蛋白、MUC-1、G-250、p53、癌胚抗原、黑素瘤-黑素细胞分化抗原、PAP、PSA、PSMA、PSH-P1、PSM-P1、PSM-P2、p15、Hom/Mel-40、H-Ras、E2A-PRL、H4-RET、IGH-IGK、MYL-RAR、EB病毒抗原、EBNA、人乳头瘤病毒抗原、乙型和丙型肝炎病毒抗原、人类嗜T淋巴细胞病毒抗原、TSP-180、p185erbB2、p180erbB-3、c-met、mn-23H1、TAG-72-4、CA 19-9、CA 72-4、CAM 17.1、NuMa、K-ras、p16、TAGE、PSCA、CT7、43-9F、5T4、791Tgp72、β-HCG、BCA225、BTAA、CA 125、CA 15-3(CA 27.29\BCAA)、CA 195、CA 242、CA-50、CAM43、CD68\KP1、CO-029、FGF-5、Ga733(EpCAM)、HTgp-175、M344、MA-50、MG7-Ag、MOV18、NB/70K、NY-CO-1、RCAS1、SDCCAG16、TAAL6、TAG72、TLP、TPS。
6.根据权利要求1所述的SamRNA疫苗,其特征在于,所述的重组病毒载体由修饰化腺病毒骨架质粒与含有编码至少一种抗原的核苷酸序列的穿梭质粒共转染得到,所述修饰化腺病毒骨架质粒上包括病毒基因复制复合体,所述病毒基因复制复合体为编码病毒基因复制相关蛋白nsP1、nsP2、nsP3和nsP4的基因序列。
7.根据权利要求6所述的SamRNA疫苗,其特征在于,所述腺病毒骨架质粒选自:pAdEasy-1、pAdEasy-2、pBHG11、pBHG-fiber5或pBHG-fiber35。
8.根据权利要求1所述的SamRNA疫苗,其特征在于,所述的重组病毒载体还包括:iii)转录抗原基因的启动子。
9.根据权利要求1所述的SamRNA疫苗,其特征在于,所述的重组病毒载体还包括:iv)编码至少一种佐剂的核苷酸序列。
10.根据权利要求8所述的SamRNA疫苗,其特征在于,所述的佐剂选自C3b、GM-CSF、IL-17、IFN、IL-15、IL-21、IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-12、INF-α、INF-γ、CpG。
11.一种权利要求1所述的SamRNA疫苗的制备方法,包括:修饰化腺病毒骨架质粒的构建;抗原基因片段的克隆;穿梭质粒的构建;穿梭质粒与腺病毒骨架质粒共转染与包装,所述修饰化腺病毒骨架质粒上包括病毒基因复制复合体,所述病毒基因复制复合体为编码病毒基因复制相关蛋白nsP1、nsP2、nsP3和nsP4的基因序列。
12.一种药物组合物,其特征在于,所述药物组合物包括权利要求1-10任一所述的SamRNA疫苗和药学上可接受的辅料。
13.权利要求1-10任一所述的SamRNA疫苗或权利要求12所述的药物组合物在制备用于哺乳动物的疫苗中的应用。
14.一种修饰化腺病毒骨架质粒,其特征在于,所述腺病毒骨架质粒上包括病毒基因复制复合体,所述病毒基因复制复合体为编码病毒基因复制相关蛋白nsP1、nsP2、nsP3和nsP4的基因序列,所述腺病毒骨架质粒选自:pAdEasy-1、pAdEasy-2、pBHG11、pBHG-fiber5或pBHG-fiber35。
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CN110448689A (zh) * | 2019-08-06 | 2019-11-15 | 太仓美诺恒康生物技术有限公司 | mRNA疫苗及其试剂盒、应用 |
WO2020143634A1 (zh) * | 2019-01-07 | 2020-07-16 | 康希诺生物股份公司 | 一种SamRNA疫苗及其制备方法 |
CN111926042A (zh) * | 2020-06-09 | 2020-11-13 | 深圳豪石生物科技有限公司 | 一种治疗性树突状细胞癌症疫苗及其应用 |
CN112625095A (zh) * | 2021-01-13 | 2021-04-09 | 武汉科前生物股份有限公司 | 一种猪轮状病毒重组蛋白以及表达该蛋白的重组腺病毒和应用 |
CN116875520A (zh) * | 2023-07-12 | 2023-10-13 | 吉林农业大学 | 表达核糖体失活蛋白的乳酸菌及其在抗轮状病毒中的应用 |
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WO2020143634A1 (zh) * | 2019-01-07 | 2020-07-16 | 康希诺生物股份公司 | 一种SamRNA疫苗及其制备方法 |
CN110448689A (zh) * | 2019-08-06 | 2019-11-15 | 太仓美诺恒康生物技术有限公司 | mRNA疫苗及其试剂盒、应用 |
CN111926042A (zh) * | 2020-06-09 | 2020-11-13 | 深圳豪石生物科技有限公司 | 一种治疗性树突状细胞癌症疫苗及其应用 |
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CN112625095A (zh) * | 2021-01-13 | 2021-04-09 | 武汉科前生物股份有限公司 | 一种猪轮状病毒重组蛋白以及表达该蛋白的重组腺病毒和应用 |
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