CN111588843A - 一种病毒抗原-免疫共激活因子的双分子dna疫苗 - Google Patents

一种病毒抗原-免疫共激活因子的双分子dna疫苗 Download PDF

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CN111588843A
CN111588843A CN202010369825.6A CN202010369825A CN111588843A CN 111588843 A CN111588843 A CN 111588843A CN 202010369825 A CN202010369825 A CN 202010369825A CN 111588843 A CN111588843 A CN 111588843A
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余力
曾蓁
曾莲
张媚
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Sichuan Chengyu Biological Products Co ltd
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Abstract

本发明公开了一种病毒抗原‑免疫共激活因子的双分子DNA疫苗，涉及生物医药技术领域。所述表达载体为DNA质粒；所述病毒抗原为任一病毒免疫原性(抗原)分子；所述免疫活性因子为T细胞共激活因子。本发明公开的疫苗，将表达T细胞共激活因子的外源基因片段和病毒抗原分子的病毒基因片段共构建在一个DNA质粒中并同时表达于同一细胞内，利用此双分子激活T细胞对病毒的系统免疫反应。双分子DNA疫苗也是一类新型疫苗技术平台，适合用于开发多种传染性疾病的预防性疫苗。针对全球COVID‑19大流行，即可通过该技术平台，构建新冠病毒S抗原片段‑免疫共激活因子的双分子DNA疫苗，实现其免疫预防和控制。

Description

一种病毒抗原-免疫共激活因子的双分子DNA疫苗
技术领域
本发明涉及生物医药技术领域，具体涉及一种病毒抗原-免疫共激活因子的 双分子DNA疫苗，以用于预防传染性疾病。
背景技术
新冠肺炎疫情防控至关重要，为避免疫情扩散和蔓延，寻找快速有效的疫苗 帮助我们快速形成群体免疫力，防止病毒的传播从而阻止其大规模扩散，迫在眉 睫。
然而，传统疫苗开发，通过大量的传代和筛选鉴定来获得减毒株，过程漫长。 此外，另一个瓶颈是新冠肺炎疫苗开发中没有可用的动物模型，这使得传代和鉴 定所选择的减毒疫苗株是否有效更加困难。同时研发筛选这种高传染性病毒疫苗 需要相对安全的实验室，例如bsP3和P4，然而目前国内具有这种实验室条件的 少，因此，不难理解传统的疫苗开发需要数年时间，很难成为我们期待中的救星， 而疫苗的开发刻不容缓。
众所周知，抗原性是决定疫苗特异性和有效性的主要因素之一。这使得现代 基因工程技术使疫苗的开发可不再依赖于传统方法，同时基因工程疫苗可以大大 缩短疫苗开发的时间。基因工程疫苗通常包括DNA或RNA疫苗。与传统疫苗 方法相比，基因工程疫苗具有许多潜在的优势，包括刺激B细胞和T细胞反应， 提高疫苗的稳定性，基因工程疫苗主要优势是安全性好，不需处理有毒的病原体 或将病原体用于生产目的，而快速制造新的疫苗。在近30年的许多临床研究中， 至今都尚未发现使用基因工程疫苗会引起不良或毒性反应。
DNA疫苗在体内细胞中表达抗原来激活免疫系统对微生物的免疫应答。
DNA疫苗不仅能在大肠杆菌中大量生产，而且成本低廉、易于存储和运输。此 外，DNA疫苗可以大大缩短疫苗开发的时间。其主要优势是安全性好，不需处 理有毒的病原体，而快速制造新的疫苗。DNA疫苗以DNA质粒作为载体携带 特异性抗原来激活免疫系统。但是DNA疫苗在细胞中有限的抗原表达量往往不 足以刺激人体的免疫反应，因此尚未批准任何DNA疫苗人群使用。
由于低免疫原性一直是在人类中使用DNA疫苗的主要障碍，因此科学家们 研究了多种方法来增加DNA疫苗诱导免疫反应强度和持续时间。一种流行的 策略是创建疫苗混合物，其中包括DNA疫苗与编码免疫调节蛋白的质粒(例如 IL-2，IL-12等)，激活和/或增强APC活性的细胞因子的质粒(GM-CSF)，或 CXC趋化因子(IL-8)，以及CC趋化因子(如巨噬细胞炎性蛋白MIP-1α，MIP-3β) 的混合注射。此外，DNA疫苗的免疫原性也可以与质粒编码共刺激分子和粘附 分子通过共同传递来增强。所有这些DNA疫苗+免疫调节因子的共同应用证明， 合理设计的DNA疫苗和免疫疗法对于提高DNA疫苗的免疫原性大有可为。
虽然各种不同免疫调节因子都曾联合应用于DNA疫苗，但一般都将表达抗 原和表达免疫因子分别置于在两个DNA质粒中，并且是混合这两个DNA用于 局部给药。混合DNA疫苗不能有效地将两种信号集合地呈现给免疫细胞，因此 诱导对特异性抗原的免疫反应作用较低。
发明内容
为解决上述技术问题，本发明公开了一种病毒抗原-免疫共激活因子的双分 子DNA疫苗，该双分子DNA疫苗能降低免疫原性的阈值从而提高免疫应答的 能力。
该双分子DNA疫苗将两个基因片段：病毒特异性抗原和人源免疫活性因子 基因，共同装载在一个DNA质粒内，在同一细胞内表达用于激活免疫系统所必 须的双信号，激活对该病毒的系统免疫应答，保护机体免于该病毒的感染。
为实现以上发明目的，本发明提供以下技术方案：
一种病毒抗原-免疫共激活因子的双分子DNA疫苗，包括表达载体和装载在 同一表达载体上的病毒抗原分子基因片段、人源免疫活性因子基因片段，所述表 达载体为DNA质粒；所述病毒抗原分子基因片段为任一编码病毒抗原基因片段； 所述免疫活性因子基因为人源T细胞共激活因子。
在上述技术方案中，所述双分子DNA疫苗在细胞内表达人源T细胞共激活 因子和病毒抗原分子，通过此双信号共刺激，特异性激活对该病毒的系统免疫应 答，保护机体免于该病毒的感染。该免疫基因DNA疫苗也能够作为双分子表达 和增强激活免疫系统的技术平台，适合用于开发构建多种传染性疾病的预防性疫 苗。针对全球大流行的COVID-19的预防和控制，也可通过应用该技术平台，构 建含有新冠病毒S抗原片段-免疫共激活因子的双分子DNA疫苗实现其免疫预防。
在上述技术方案中，所述人源免疫活性因子基因片段和病毒抗原分子基因片 段通过基因工程插入在DNA质粒的起动子后，在细胞中能够同时转录表达非融 合的病毒抗原和人源免疫活性因子，该双分子(双信号)共同表达于同一细胞内， 特异性增强激活对该病毒的系统免疫。
进一步地，所述人源免疫活性因子基因片段在B细胞或抗原呈递细胞内表达 为T细胞共激活因子。
进一步地，所述T细胞共激活因子可特异激活不同类型的T细胞亚群；所 述Y细胞共激活因子包括CD80、CD86、ICOSL、OX40L、CD40、4-1BBL、CD70、 CD30L、CD48中的任一种。
进一步地，所述T细胞亚群包括CD4细胞、CD8细胞、NK细胞、细胞毒 性T细胞、淋巴因子T细胞、诱导性T细胞、辅助性T细胞中的任一种。
进一步地，所述T细胞共激活因子在细胞内表达为一个或多个活化T细胞 因子的同源或异源融合分子。
进一步地，所述人源免疫活性因子基因片段在细胞表达为有功能活性的蛋白 质或蛋白多肽。
所述人源T细胞共激活因子的功能活性对于激活T细胞提供了必须的第二 信号，并增强对共表达抗原的特异系统免疫反应。
进一步地，所述蛋白多肽经过剪接修饰或突变的活性蛋白多肽。
进一步地，由质粒DNA编码的病毒抗原分子和人源T细胞共激活因子两个 非融合分子同时表达在一个细胞内。
本发明还公开了上述双分子DNA疫苗的应用方法，该双分子DNA疫苗为 DNA生物大分子结构，并以DNA质粒形式接种体内，用于防控各种传染性疾病。
优选地，所述双分子DNA疫苗包括任一病毒特异性抗原片段和几种的人源 免疫因子的疫苗制定在一个治疗疗程组里，最大化的激活免疫系统。
所述发明使用包含抗原和T细胞共激活因子的DNA质粒作为免疫疫苗的技 术平台，其中任何特异性病毒抗原基因可以插入以构建此双分子DNA质粒(疫 苗)而产生增强地特异性免疫反应。因此，可以通过使用不同的特异性抗原基因 片段来获得不同的免疫双分子DNA疫苗。
附图说明
图1为本申请的双分子DNA疫苗降低免疫原性阈值提高免疫应答的能力 的示意图；
图2双分子DNA疫苗结构示意图.质粒DNA含有新冠状病毒S抗原基因和 人源免疫活性分子基因；
图3为双分子DNA疫苗在细胞中共表达SARS-CoV-2S抗原和T细胞共刺 激因子示意图。
具体实施方式
下面结合附图，对本申请实施例作详细的说明。
为了使本申请的目的、技术方案及优点更加清楚明白，以下结合附图及实施 例，对本申请进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用 以解释本申请，并不用于限定本申请。
本申请中人源免疫活性因子表达部位和功能与专利CN2019111493147中所 示，在本申请中不再一一详列。
如图1所示，本申请公开了一种病毒抗原-免疫共激活因子的双分子DNA疫 苗，包括表达载体和装载在同一表达载体上的病毒抗原分子基因片段、人源免疫 活性因子基因片段，所述表达载体为DNA质粒；所述病毒抗原分子基因片段为 任一病毒特异性抗原基因片段；所述人源免疫活性因子是人源T细胞共激活分 子。该双分子DNA疫苗能降低免疫原性的阈值从而提高免疫应答的能力。
以针对COVID-19的DAN双分子疫苗为例，所述病毒抗原分子为 SARS-CoV-2的S抗原。SARS-CoV-2的S抗原基因片段和人T细胞共激活因子 基因片段构建在同一DNA质粒中使其成为双分子DNA疫苗，用于对COVID-19 的免疫预防。
如图2所示，本申请下述实施例中，采用的表达载体为DNA质粒，表达人 源免疫活性因子的基因片段和SARS-CoV-2S抗原基因(GenBank:MN988713.1) 通过常规的基因工程方法插入DNA质粒载体中。
双分子DNA疫苗具体构建和鉴定方法如下：
采用PCR合成人或鼠源T细胞共激活因子的基因片段和新冠状病毒S抗原 或者GFP基因片段，将这些基因片段分别连接于相同酶切割的DNA质粒上，且 紧随在DNA质粒的起动子后，如图2所示；酶切和序列分析筛选出阳性克隆， 用免疫荧光法检测插入的外源基因在转染细胞中表达，如图3所示。
本发明并不局限于前述的具体实施方式。本发明扩展到任何在本说明书中披 露的新特征或任何新的组合，以及披露的任一新的方法或过程的步骤或任何新的 组合。
序列表
<110> 四川骋誉生物制品有限公司
<120> 一种病毒抗原-免疫共激活因子的双分子DNA疫苗
<150> PCT/CN2020/087720
<151> 2020-04-29
<160> 9
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370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Thr Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Lys His Ile Asp Ala Lys Glu Gly Gly Asn
435 440 445
Phe Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ala Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro Cys
465 470 475 480
Asn Gly Gln Thr Gly Leu Asn Cys Tyr Tyr Pro Leu Tyr Arg Tyr Gly
485 490 495
Phe Tyr Pro Thr Asp Gly Val Gly His Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Ala Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Arg Ser Val Ala Ser Gln Ser Ile
675 680 685
Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser
690 695 700
Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr
705 710 715 720
Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met
725 730 735
Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr
740 745 750
Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala Val
755 760 765
Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile
770 775 780
Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Leu Pro
785 790 795 800
Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu
805 810 815
Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu
820 825 830
Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly
835 840 845
Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln
850 855 860
Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala
865 870 875 880
Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala
885 890 895
Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser
900 905 910
Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu
915 920 925
Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr
930 935 940
Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala
945 950 955 960
Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
965 970 975
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln
980 985 990
Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala
995 1000 1005
Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys
1010 1015 1020
Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp
1025 1030 1035 1040
Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp
1045 1050 1055
Asn Thr Phe Val Ser Gly Ser Cys Asp Val Val Ile Gly Ile Val Asn
1060 1065 1070
Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu
1075 1080 1085
Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu
1090 1095 1100
Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu
1105 1110 1115 1120
Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile
1125 1130 1135
Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Gly Val Lys Leu His Tyr
1140 1145 1150
Thr
<210> 2
<211> 329
<212> PRT
<213> 人源CD86 (Homo sapiens)
<400> 2
Met Asp Pro Gln Cys Thr Met Gly Leu Ser Asn Ile Leu Phe Val Met
1 5 10 15
Ala Phe Leu Leu Ser Gly Ala Ala Pro Leu Lys Ile Gln Ala Tyr Phe
20 25 30
Asn Glu Thr Ala Asp Leu Pro Cys Gln Phe Ala Asn Ser Gln Asn Gln
35 40 45
Ser Leu Ser Glu Leu Val Val Phe Trp Gln Asp Gln Glu Asn Leu Val
50 55 60
Leu Asn Glu Val Tyr Leu Gly Lys Glu Lys Phe Asp Ser Val His Ser
65 70 75 80
Lys Tyr Met Gly Arg Thr Ser Phe Asp Ser Asp Ser Trp Thr Leu Arg
85 90 95
Leu His Asn Leu Gln Ile Lys Asp Lys Gly Leu Tyr Gln Cys Ile Ile
100 105 110
His His Lys Lys Pro Thr Gly Met Ile Arg Ile His Gln Met Asn Ser
115 120 125
Glu Leu Ser Val Leu Ala Asn Phe Ser Gln Pro Glu Ile Val Pro Ile
130 135 140
Ser Asn Ile Thr Glu Asn Val Tyr Ile Asn Leu Thr Cys Ser Ser Ile
145 150 155 160
His Gly Tyr Pro Glu Pro Lys Lys Met Ser Val Leu Leu Arg Thr Lys
165 170 175
Asn Ser Thr Ile Glu Tyr Asp Gly Val Met Gln Lys Ser Gln Asp Asn
180 185 190
Val Thr Glu Leu Tyr Asp Val Ser Ile Ser Leu Ser Val Ser Phe Pro
195 200 205
Asp Val Thr Ser Asn Met Thr Ile Phe Cys Ile Leu Glu Thr Asp Lys
210 215 220
Thr Arg Leu Leu Ser Ser Pro Phe Ser Ile Glu Leu Glu Asp Pro Gln
225 230 235 240
Pro Pro Pro Asp His Ile Pro Trp Ile Thr Ala Val Leu Pro Thr Val
245 250 255
Ile Ile Cys Val Met Val Phe Cys Leu Ile Leu Trp Lys Trp Lys Lys
260 265 270
Lys Lys Arg Pro Arg Asn Ser Tyr Lys Cys Gly Thr Asn Thr Met Glu
275 280 285
Arg Glu Glu Ser Glu Gln Thr Lys Lys Arg Glu Lys Ile His Ile Pro
290 295 300
Glu Arg Ser Asp Glu Ala Gln Arg Val Phe Lys Ser Ser Lys Thr Ser
305 310 315 320
Ser Cys Asp Lys Ser Asp Thr Cys Phe
325
<210> 3
<211> 302
<212> PRT
<213> 人源CD80 (Homo sapiens)
<400> 3
Met Arg Leu Gly Ser Pro Gly Leu Leu Phe Leu Leu Phe Ser Ser Leu
1 5 10 15
Arg Ala Asp Thr Gln Glu Lys Glu Val Arg Ala Met Val Gly Ser Asp
20 25 30
Val Glu Leu Ser Cys Ala Cys Pro Glu Gly Ser Arg Phe Asp Leu Asn
35 40 45
Asp Val Tyr Val Tyr Trp Gln Thr Ser Glu Ser Lys Thr Val Val Thr
50 55 60
Tyr His Ile Pro Gln Asn Ser Ser Leu Glu Asn Val Asp Ser Arg Tyr
65 70 75 80
Arg Asn Arg Ala Leu Met Ser Pro Ala Gly Met Leu Arg Gly Asp Phe
85 90 95
Ser Leu Arg Leu Phe Asn Val Thr Pro Gln Asp Glu Gln Lys Phe His
100 105 110
Cys Leu Val Leu Ser Gln Ser Leu Gly Phe Gln Glu Val Leu Ser Val
115 120 125
Glu Val Thr Leu His Val Ala Ala Asn Phe Ser Val Pro Val Val Ser
130 135 140
Ala Pro His Ser Pro Ser Gln Asp Glu Leu Thr Phe Thr Cys Thr Ser
145 150 155 160
Ile Asn Gly Tyr Pro Arg Pro Asn Val Tyr Trp Ile Asn Lys Thr Asp
165 170 175
Asn Ser Leu Leu Asp Gln Ala Leu Gln Asn Asp Thr Val Phe Leu Asn
180 185 190
Met Arg Gly Leu Tyr Asp Val Val Ser Val Leu Arg Ile Ala Arg Thr
195 200 205
Pro Ser Val Asn Ile Gly Cys Cys Ile Glu Asn Val Leu Leu Gln Gln
210 215 220
Asn Leu Thr Val Gly Ser Gln Thr Gly Asn Asp Ile Gly Glu Arg Asp
225 230 235 240
Lys Ile Thr Glu Asn Pro Val Ser Thr Gly Glu Lys Asn Ala Ala Thr
245 250 255
Trp Ser Ile Leu Ala Val Leu Cys Leu Leu Val Val Val Ala Val Ala
260 265 270
Ile Gly Trp Val Cys Arg Asp Arg Cys Leu Gln His Ser Tyr Ala Gly
275 280 285
Ala Trp Ala Val Ser Pro Glu Thr Glu Leu Thr Gly His Val
290 295 300
<210> 4
<211> 199
<212> PRT
<213> 人源OX40L(Homo sapiens)
<400> 4
Met Glu Gly Glu Gly Val Gln Pro Pro Asp Glu Asn Leu Glu Asn Gly
1 5 10 15
Ser Arg Pro Arg Phe Lys Trp Lys Lys Val Leu Arg Leu Val Val Ser
20 25 30
Gly Ile Lys Ala Ala Gly Leu Leu Leu Cys Val Val Tyr Val Cys Leu
35 40 45
Gln Phe Ser Ser Ser Pro Ala Lys Asp Ser Pro Ile Gln Arg Leu Arg
50 55 60
Ala Pro Val Thr Gly Cys Glu Gly Gly Arg Leu Phe Ile Gly Thr Ser
65 70 75 80
Lys Asn Glu Tyr Glu Thr Met Glu Val Gln Asn Asn Ser Val Ile Ile
85 90 95
Asn Cys Asp Gly Leu Tyr Leu Ile His Leu Lys Gly Ser Phe Phe Gln
100 105 110
Glu Val Lys Ile Asn Leu His Phe Arg Lys Asp Arg Ser Pro Ile Phe
115 120 125
Val Pro Met Leu Asn Asn Gly Gln Arg Val Val Phe Thr Val Val Thr
130 135 140
Ser Leu Ala Phe Lys Asp Glu Val Tyr Leu Thr Val Asn Ala Ser Asp
145 150 155 160
Thr Leu Cys Glu His Leu Gln Ile Asn Asp Gly Glu Leu Ile Ile Val
165 170 175
Gln Leu Thr Pro Asn Gly Tyr Cys Ala Pro Glu Arg Pro Tyr Ser Ser
180 185 190
Thr Val Asn Gln Val Pro Leu
195
<210> 5
<211> 277
<212> PRT
<213> 人源CD40 (Homo sapiens)
<400> 5
Met Val Arg Leu Pro Leu Gln Cys Val Leu Trp Gly Cys Leu Leu Thr
1 5 10 15
Ala Val His Pro Glu Pro Pro Thr Ala Cys Arg Glu Lys Gln Tyr Leu
20 25 30
Ile Asn Ser Gln Cys Cys Ser Leu Cys Gln Pro Gly Gln Lys Leu Val
35 40 45
Ser Asp Cys Thr Glu Phe Thr Glu Thr Glu Cys Leu Pro Cys Gly Glu
50 55 60
Ser Glu Phe Leu Asp Thr Trp Asn Arg Glu Thr His Cys His Gln His
65 70 75 80
Lys Tyr Cys Asp Pro Asn Leu Gly Leu Arg Val Gln Gln Lys Gly Thr
85 90 95
Ser Glu Thr Asp Thr Ile Cys Thr Cys Glu Glu Gly Trp His Cys Thr
100 105 110
Ser Glu Ala Cys Glu Ser Cys Val Leu His Arg Ser Cys Ser Pro Gly
115 120 125
Phe Gly Val Lys Gln Ile Ala Thr Gly Val Ser Asp Thr Ile Cys Glu
130 135 140
Pro Cys Pro Val Gly Phe Phe Ser Asn Val Ser Ser Ala Phe Glu Lys
145 150 155 160
Cys His Pro Trp Thr Ser Cys Glu Thr Lys Asp Leu Val Val Gln Gln
165 170 175
Ala Gly Thr Asn Lys Thr Asp Val Val Cys Gly Pro Gln Asp Arg Leu
180 185 190
Arg Ala Leu Val Val Ile Pro Ile Ile Phe Gly Ile Leu Phe Ala Ile
195 200 205
Leu Leu Val Leu Val Phe Ile Lys Lys Val Ala Lys Lys Pro Thr Asn
210 215 220
Lys Ala Pro His Pro Lys Gln Glu Pro Gln Glu Ile Asn Phe Pro Asp
225 230 235 240
Asp Leu Pro Gly Ser Asn Thr Ala Ala Pro Val Gln Glu Thr Leu His
245 250 255
Gly Cys Gln Pro Val Thr Gln Glu Asp Gly Lys Glu Ser Arg Ile Ser
260 265 270
Val Gln Glu Arg Gln
275
<210> 6
<211> 254
<212> PRT
<213> 人源4-1BBL (Homo sapiens)
<400> 6
Met Glu Tyr Ala Ser Asp Ala Ser Leu Asp Pro Glu Ala Pro Trp Pro
1 5 10 15
Pro Ala Pro Arg Ala Arg Ala Cys Arg Val Leu Pro Trp Ala Leu Val
20 25 30
Ala Gly Leu Leu Leu Leu Leu Leu Leu Ala Ala Ala Cys Ala Val Phe
35 40 45
Leu Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly Ser
50 55 60
Ala Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp Asp
65 70 75 80
Pro Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu Val
85 90 95
Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser Asp
100 105 110
Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys Glu
115 120 125
Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val Phe
130 135 140
Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly Ser
145 150 155 160
Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala
165 170 175
Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala
180 185 190
Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala
195 200 205
Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His
210 215 220
Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val
225 230 235 240
Thr Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu
245 250
<210> 7
<211> 193
<212> PRT
<213> 人源CD70 (Homo sapiens)
<400> 7
Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly
1 5 10 15
Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile
20 25 30
Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu
35 40 45
Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His
50 55 60
Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala
65 70 75 80
Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu
85 90 95
Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu
100 105 110
Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu
115 120 125
Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg
130 135 140
Leu Ser Phe His Gln Gly Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro
145 150 155 160
Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu
165 170 175
Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg
180 185 190
Pro
<210> 8
<211> 234
<212> PRT
<213> 人源CD30L (Homo sapiens)
<400> 8
Met Asp Pro Gly Leu Gln Gln Ala Leu Asn Gly Met Ala Pro Pro Gly
1 5 10 15
Asp Thr Ala Met His Val Pro Ala Gly Ser Val Ala Ser His Leu Gly
20 25 30
Thr Thr Ser Arg Ser Tyr Phe Tyr Leu Thr Thr Ala Thr Leu Ala Leu
35 40 45
Cys Leu Val Phe Thr Val Ala Thr Ile Met Val Leu Val Val Gln Arg
50 55 60
Thr Asp Ser Ile Pro Asn Ser Pro Asp Asn Val Pro Leu Lys Gly Gly
65 70 75 80
Asn Cys Ser Glu Asp Leu Leu Cys Ile Leu Lys Arg Ala Pro Phe Lys
85 90 95
Lys Ser Trp Ala Tyr Leu Gln Val Ala Lys His Leu Asn Lys Thr Lys
100 105 110
Leu Ser Trp Asn Lys Asp Gly Ile Leu His Gly Val Arg Tyr Gln Asp
115 120 125
Gly Asn Leu Val Ile Gln Phe Pro Gly Leu Tyr Phe Ile Ile Cys Gln
130 135 140
Leu Gln Phe Leu Val Gln Cys Pro Asn Asn Ser Val Asp Leu Lys Leu
145 150 155 160
Glu Leu Leu Ile Asn Lys His Ile Lys Lys Gln Ala Leu Val Thr Val
165 170 175
Cys Glu Ser Gly Met Gln Thr Lys His Val Tyr Gln Asn Leu Ser Gln
180 185 190
Phe Leu Leu Asp Tyr Leu Gln Val Asn Thr Thr Ile Ser Val Asn Val
195 200 205
Asp Thr Phe Gln Tyr Ile Asp Thr Ser Thr Phe Pro Leu Glu Asn Val
210 215 220
Leu Ser Ile Phe Leu Tyr Ser Asn Ser Asp
225 230
<210> 9
<211> 243
<212> PRT
<213> 人源CD48 (Homo sapiens)
<400> 9
Met Cys Ser Arg Gly Trp Asp Ser Cys Leu Ala Leu Glu Leu Leu Leu
1 5 10 15
Leu Pro Leu Ser Leu Leu Val Thr Ser Ile Gln Gly His Leu Val His
20 25 30
Met Thr Val Val Ser Gly Ser Asn Val Thr Leu Asn Ile Ser Glu Ser
35 40 45
Leu Pro Glu Asn Tyr Lys Gln Leu Thr Trp Phe Tyr Thr Phe Asp Gln
50 55 60
Lys Ile Val Glu Trp Asp Ser Arg Lys Ser Lys Tyr Phe Glu Ser Lys
65 70 75 80
Phe Lys Gly Arg Val Arg Leu Asp Pro Gln Ser Gly Ala Leu Tyr Ile
85 90 95
Ser Lys Val Gln Lys Glu Asp Asn Ser Thr Tyr Ile Met Arg Val Leu
100 105 110
Lys Lys Thr Gly Asn Glu Gln Glu Trp Lys Ile Lys Leu Gln Val Leu
115 120 125
Asp Pro Val Pro Lys Pro Val Ile Lys Ile Glu Lys Ile Glu Asp Met
130 135 140
Asp Asp Asn Cys Tyr Leu Lys Leu Ser Cys Val Ile Pro Gly Glu Ser
145 150 155 160
Val Asn Tyr Thr Trp Tyr Gly Asp Lys Arg Pro Phe Pro Lys Glu Leu
165 170 175
Gln Asn Ser Val Leu Glu Thr Thr Leu Met Pro His Asn Tyr Ser Arg
180 185 190
Cys Tyr Thr Cys Gln Val Ser Asn Ser Val Ser Ser Lys Asn Gly Thr
195 200 205
Val Cys Leu Ser Pro Pro Cys Thr Leu Ala Arg Ser Phe Gly Val Glu
210 215 220
Trp Ile Ala Ser Trp Leu Val Val Thr Val Pro Thr Ile Leu Gly Leu
225 230 235 240
Leu Leu Thr

Claims (10)

1.一种病毒抗原-免疫共激活因子的双分子DNA疫苗，其特征在于：包括表达载体和装载在同一表达载体上的病毒抗原分子基因片段、人源免疫活性因子基因片段，所述表达载体为DNA质粒；所述病毒抗原分子基因片段为任一病毒特异性抗原基因片段；所述人源免疫活性因子是人源T细胞共激活分子。
2.根据权利要求1所述的病毒抗原-免疫共激活因子的双分子DNA疫苗，其特征在于：所述人源T细胞共激活分子均在B细胞或抗原呈递细胞内表达为T细胞激活必须的第二信号。
3.根据权利要求1所述的病毒抗原-免疫共激活因子的双分子DNA疫苗，其特征在于：所述人源T细胞共激活因子包括CD80、CD86、ICOSL、OX40L、CD40、4-1BBL、CD70、CD30L、CD48中的任一种。
4.根据权利要求3所述的病毒抗原-免疫共激活因子的双分子DNA疫苗，其特征在于：所述人源T细胞共激活因子可特异激活不同类型的T细胞亚群，所述T细胞亚群包括CD4细胞、CD8细胞、NK细胞、细胞毒性T细胞、淋巴因子T细胞、诱导性T细胞、辅助性T细胞中的任一种。
5.根据权利要求2或3所述的病毒抗原-免疫共激活因子的双分子DNA疫苗，其特征在于：所述人源T细胞共激活因子在细胞内表达为一个或多个活化T细胞因子的同源或异源融合分子。
6.根据权利要求5所述的病毒抗原-免疫共激活因子的双分子DNA疫苗，其特征在于：所述人源免疫活性因子基因片段在细胞内表达为有功能活性的蛋白质或蛋白多肽。
7.根据权利要求6所述的病毒抗原-免疫共激活因子的双分子DNA疫苗，其特征在于：所述蛋白多肽包括经过剪接修饰或突变的活性蛋白多肽。
8.根据权利要求1所述的病毒抗原-免疫共激活因子的双分子DNA疫苗，其特征在于：所述病毒抗原分子基因片段和人源免疫活性因子基因片段共同装载在一个DNA质粒内并且同时表达非融合的两个蛋白分子。
9.根据权利要求1所述的病毒抗原-免疫共激活因子的双分子DNA疫苗，其特征在于：任一病毒抗原分子基因片段表达的具有抗原性的病毒蛋白分子均能作为双分子中的一分子与人源免疫活性因子基因片段表达的人源免疫共激活因子构建组成双分子DNA疫苗。
10.根据权利要求1、3、8、9任一项所述的病毒抗原-免疫共激活因子的双分子DNA疫苗，其特征在于：所述病毒抗原分子为SARS-CoV-2病毒的S抗原。
CN202010369825.6A 2020-04-30 2020-04-30 一种病毒抗原-免疫共激活因子的双分子dna疫苗 Pending CN111588843A (zh)

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WO2022171904A1 (en) 2021-02-15 2022-08-18 Livingmed Biotech S.R.L. Genetically modified clostridium strains expressing recombinant antigens and uses thereof

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CN110859968A (zh) * 2019-11-21 2020-03-06 四川安可康生物医药有限公司 激活对肿瘤的系统免疫反应的基因生物药物

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CN110859968A (zh) * 2019-11-21 2020-03-06 四川安可康生物医药有限公司 激活对肿瘤的系统免疫反应的基因生物药物

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