利用分子育种技术构建并优化筛选抗恶性疟原虫多表位人工抗原DNA疫苗
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摘要
疟疾是一种在全球范围内严重影响人类健康的传染性疾病。因疟原虫和虫媒对化学药物及杀虫剂的耐药性及抗药性不断增加，全球每年有3~5亿人感染，近250万人死亡。导致目前状况的主要病原体是恶性疟原虫。由于其生活周期复杂，抗原具有阶段特异性、虫株差异性和高度变异性等特点，长期以来形成研制抗疟原虫疫苗的技术瓶颈。因此，针对恶性疟原虫不同生活时期的免疫反应特点，选取诱导产生多种免疫反应类型的不同抗原构建多表位疫苗已经成为研究抗疟疫苗的热点。但是，目前对多抗原表位疫苗的研究仍然是以人工合成多表位肽疫苗或单一固定的串联多表位DNA疫苗为主，前者成本昂贵，后者免疫原性低，难以达到预期的免疫反应多样性和令人满意的保护效果。为了解决多表位DNA疫苗的不足之处，我们首次借鉴了分子育种技术(即DNA改组)的随机重组原理，将其应用到构建多表位DNA疫苗中，建立了一套优化多表位人工抗原DNA疫苗的新方法——表位改组(Epitope shuffling)技术。
在本研究中，针对参与抗疟原虫红内期感染的免疫反应类型，我们选择了14个主要来自恶性疟原虫红细胞内期的B细胞和Th细胞表位作为研究对象。在摸索表位改组方法的过程中，先后提出并试用了聚合酶链式反应组装技术和同尾酶随机重组技术，最终以同尾酶随机重组技术构建了五个不同基因大小的多表位基因抗原库(依小到大命名为L1、L2、L3、L4和L5)。经聚合酶联式反应-单链构象多态性分析，表明了所构建的每个基因抗原库均具有较高的多表位基因随机组装多态性。通过抗原文库免疫方法，表明了不同多表位基因链长度大小的抗原文库产生了不同程度的免疫反应效果。其中以2.0kb分子量的L4和1.2kb分子量的L3多表位抗原库在免疫动物后获得了最好的免疫反应水平，并在随后用鼠疟动物模型进行感染攻击时显示出交叉保护效果。从而证实了不同多表位人工抗原基因链的长度对疫苗免疫原性具有重要的影响。同时，也证明了所构建的多表位抗原库免疫具有较理想的免疫反应效果，适合从中筛选最佳嵌合的多表位基因。
以抗原库免疫抗血清的有限稀释抗体为检测探针，通过高通量免疫化学筛选方案，分别从L3和L4的原核表达文库中筛选到三个高免疫源性基因ES312、ES391和ES452。体内免疫实验结果表明了，在相同基因表达水平的情况下，三个多表位基因的抗体反应水平较基因大小相近的其他多表位基因高出100-200倍；而酶联免疫吸附和免疫共沉淀实验证实了其产生的特异抗体具有较高多样性。在诱发产生CD4细胞水平上，三个多表位基因亦均表现出较高的免疫诱导能力。在鼠疟动物模型实验中，其中多表位基因ES312免疫可获得100％的交叉保护效果；在对恶性疟原虫的体外生长抑制实验中，细胞流式方法检测基因ES312的抑制率可高达95.8％。基因序列分析结果进一步表明了，三个高免疫原性基因在表位间组装方式，及其编码蛋白的二级结构上均具有一定的共有保守结构。这充分说明了多表位基因间的组装方式和全蛋白空间结构决定了多表位基因疫苗的免疫原性。
通过多表位人工抗原基因的体内免疫实验，我们证实其中一种人工抗原—ES312—的多表位基因串联形式能够在机体中诱导产生较强的特异性抗体反应，与此同时，在初次免疫后还诱导出以细胞因子IFN-γ为主的Th1细胞反应，在随后的加强免疫过程中又逐渐诱导出一定水平的Th2细胞反应。最终证实，只有产生这种免疫反应类型的小鼠才能有效地抵抗约氏疟原虫的攻击。通过短暂封闭ES312基因免疫小鼠的CD4或CD8淋巴细胞后再进行攻击实验，发现机体抵抗红内期疟原虫感染的能力显著增强。这些工作进一步证明，特异性CD4细胞免疫反应和体液免疫反应是抵抗红内期疟原虫感染的关键环节，而多表位人工抗原的特定表位基因串联结构对能否诱导此类免疫反应是至关重要的影响因素。
此外，为了更加准确地评价一个红内期抗原疫苗的体内外免疫保护效果，本研究对细胞流式分选方法检测疟原虫虫血率的方案进行了优化，并提出了计算疫苗对疟原虫生长抑制率的修正公式。
本研究的结果表明，我们创建的表位改组方法为构建和优化多表位人工抗原DNA疫苗提供了新的技术方向，通过大量实验数据验证了我们认为人工抗原空间构型决定疫苗免疫原性和免疫保护性的假设。这一新的多表位疫苗构建思路不仅有益于研制抗疟原虫疫苗，对其它病毒、细菌、原生动物等传染性疾病的疫苗设计均能提供有益的思路，在抗肿瘤、抗机体过敏反应和新生儿耐受等基因治疗领域也有广泛的应用潜力。
Malaria is one of the most infectious diseases to human health in the global crisis. It causes approximately 2.5 million deaths, and 300 to 500 million cases of infection per year, since the resistances and tolerances of its parasites and mosquitoes to chemical medicines or insecticides are increased. P. falciparum is the greatest one of pathogen species causes morbidity and mortality, and its complex life cycles, antigenic stage-specificity, diversity and variation, have been the unique obstacle to develop antimalarial vaccines for a long time. Thus, the development of a multiple antigens and epitopes vaccine against P. falciparum to elicit relative immune response at different stage has become a major hotspot in antimalarial vaccine study, according to the characteristic of immune response at each life stage of parasite. However, in the polyepitope vaccine aspect, it is still focused on the artificially synthesized polypeptides or polyepitope gene with single format. For the former is high-cost and the latter is low-immunogenicity, it is too difficult to reach the satisfactory protection results or to obtain immune response diversity after immunization. In order to deal with the shortcoming of polyepitope DNA vaccine, we have developed a method named "epitope shuffling technology" to optimize the polyepitope DNA vaccine by use of the random recombinant principle of molecular breeding technology or DNA shuffling.In this study, we chose 14 B-cell and Th-cell epitopes of antigens mainly from the blood stage of P. falciparum, based on the type of immune response against the blood-stage parasite infection. In the process of epitope shuffling established, we have brought forward and attempted to use the PCR-assemble technology (PAT) and isocaudamer random recombinant technique (IRRT) successively, and finally constructed five sub-libraries (named L1, L2, L3, L4 and L5 according to gene length from small to large) with different polyepitope gene length by the means of IRRT. Each polyepitope library was shown the higher diversity of polyepitope genes based on the PCR-SSCP analysis. With the polyepitope library immunization, we have proved that the length of polyepitope gene affects the immunogenicity of DNA vaccine; the sub-libraries L4 with about 2.0kb gene size and L3 with about 1.2kb size were achieved the best level of immune response, and cross protection in the rodent animal model after library immunization. It is fully demonstrated that the different gene length of polyepitope artificial antigen is significantly influenced on the immunogenicity of DNA vaccine, and that the polyepitope-library immunization can elicit good immune response, and it is feasible to screen the optimal chimeric polyepitope gene from the library.
Three polyepitope genes ES312, ES391 and ES452 with high immunogenicity were screened from the duplicated express library of sub-libraries L3 and L4 in prokaryote, by use of the high throughput immunochemical selection with serial dilution of sera pool from polyepitope library immunization. The experimental results in vivo indicated that the immunogenic levels of three polyepitope gene vaccines were 100-200 times higher than that of other gene vaccine with the appropriate length, and the results detected by ELISA and immunoprecipitation assay showed higher diversity of specific antibodies were induced, under the same express level of each gene. And it is also presented that there are higher ability of the three-polyepitope genes to induce the CD4 cell in vivo. In the rodent animal model, polyepitope gene ES312 immunization has obtained 100％cross protection; and in the experiments of P. falciparum growth inhibition assay in vitro, the efficiency of ES312 against malaria growth detected by flow cytometry is up to 95.8％. The results of gene sequencing further indicated that the epitope assemble formats or the second structure of protein among the three-polyepitope genes was all possessed consensus and conservative structure. All these data is enough to present that the epitope assemble formats and the space structures of full protein determine the immunogenicity of polyepitope gene vaccine.
Through the genetic immunization experiment of polyepitope artificial antigen in vivo, we have demonstrated that one of three polyepitope genes—ES312, with a certain tandem format, could elicit higher specific antibody response. At the same time, we found that mainly cytokine IFN-γderived by Th1 cell was expressed after the gene prime immunization, and higher level of Th2 cell response was induced followed by the second boost. And it is the immune response of host that vaccinated mice can resistant the P. yoelii parasite infection at the blood stage. From the results of ES312-immunized mice challenged after CD4 or CD8 lymphocyte transient blocking, we also found that the ability of host to inhibit the malaria parasite growth was increased. All these seem to further demonstrate that to induce the specific CD4 cell and humoral immune response is critical to prevent the malaria blood-stage infection, and that specific structure of polyepitope gene assembled is vital factor to induce this immune response in host.
In addition, in order to assess the protective effect of a blood-stage vaccine against malaria in vitro with more accurately, here we have optimized the method to detect the parasitemia of parasitized red blood cells by flow cytometry, and brought forward an improved formula to calculate the efficiency of malaria growth inhibition.
The results in this study indicated that the epitope shuffling method developed by us exploits a new way for construction and optimization of DNA vaccine with polyepitope artificial antigen. And these data confirmed our assumption that space conformation of artificial antigen determines the immunogenicity and immune protection of vaccine. The novel strategy of polyepitope vaccine construction is contributed not only to antimalarial vaccine, but also to other vaccine against virus, bacterial, protozoan infectious disease, as well as the gene therapy against tumor, allergy and neonatal tolerance.
在本研究中，针对参与抗疟原虫红内期感染的免疫反应类型，我们选择了14个主要来自恶性疟原虫红细胞内期的B细胞和Th细胞表位作为研究对象。在摸索表位改组方法的过程中，先后提出并试用了聚合酶链式反应组装技术和同尾酶随机重组技术，最终以同尾酶随机重组技术构建了五个不同基因大小的多表位基因抗原库(依小到大命名为L1、L2、L3、L4和L5)。经聚合酶联式反应-单链构象多态性分析，表明了所构建的每个基因抗原库均具有较高的多表位基因随机组装多态性。通过抗原文库免疫方法，表明了不同多表位基因链长度大小的抗原文库产生了不同程度的免疫反应效果。其中以2.0kb分子量的L4和1.2kb分子量的L3多表位抗原库在免疫动物后获得了最好的免疫反应水平，并在随后用鼠疟动物模型进行感染攻击时显示出交叉保护效果。从而证实了不同多表位人工抗原基因链的长度对疫苗免疫原性具有重要的影响。同时，也证明了所构建的多表位抗原库免疫具有较理想的免疫反应效果，适合从中筛选最佳嵌合的多表位基因。
以抗原库免疫抗血清的有限稀释抗体为检测探针，通过高通量免疫化学筛选方案，分别从L3和L4的原核表达文库中筛选到三个高免疫源性基因ES312、ES391和ES452。体内免疫实验结果表明了，在相同基因表达水平的情况下，三个多表位基因的抗体反应水平较基因大小相近的其他多表位基因高出100-200倍；而酶联免疫吸附和免疫共沉淀实验证实了其产生的特异抗体具有较高多样性。在诱发产生CD4细胞水平上，三个多表位基因亦均表现出较高的免疫诱导能力。在鼠疟动物模型实验中，其中多表位基因ES312免疫可获得100％的交叉保护效果；在对恶性疟原虫的体外生长抑制实验中，细胞流式方法检测基因ES312的抑制率可高达95.8％。基因序列分析结果进一步表明了，三个高免疫原性基因在表位间组装方式，及其编码蛋白的二级结构上均具有一定的共有保守结构。这充分说明了多表位基因间的组装方式和全蛋白空间结构决定了多表位基因疫苗的免疫原性。
通过多表位人工抗原基因的体内免疫实验，我们证实其中一种人工抗原—ES312—的多表位基因串联形式能够在机体中诱导产生较强的特异性抗体反应，与此同时，在初次免疫后还诱导出以细胞因子IFN-γ为主的Th1细胞反应，在随后的加强免疫过程中又逐渐诱导出一定水平的Th2细胞反应。最终证实，只有产生这种免疫反应类型的小鼠才能有效地抵抗约氏疟原虫的攻击。通过短暂封闭ES312基因免疫小鼠的CD4或CD8淋巴细胞后再进行攻击实验，发现机体抵抗红内期疟原虫感染的能力显著增强。这些工作进一步证明，特异性CD4细胞免疫反应和体液免疫反应是抵抗红内期疟原虫感染的关键环节，而多表位人工抗原的特定表位基因串联结构对能否诱导此类免疫反应是至关重要的影响因素。
此外，为了更加准确地评价一个红内期抗原疫苗的体内外免疫保护效果，本研究对细胞流式分选方法检测疟原虫虫血率的方案进行了优化，并提出了计算疫苗对疟原虫生长抑制率的修正公式。
本研究的结果表明，我们创建的表位改组方法为构建和优化多表位人工抗原DNA疫苗提供了新的技术方向，通过大量实验数据验证了我们认为人工抗原空间构型决定疫苗免疫原性和免疫保护性的假设。这一新的多表位疫苗构建思路不仅有益于研制抗疟原虫疫苗，对其它病毒、细菌、原生动物等传染性疾病的疫苗设计均能提供有益的思路，在抗肿瘤、抗机体过敏反应和新生儿耐受等基因治疗领域也有广泛的应用潜力。
Malaria is one of the most infectious diseases to human health in the global crisis. It causes approximately 2.5 million deaths, and 300 to 500 million cases of infection per year, since the resistances and tolerances of its parasites and mosquitoes to chemical medicines or insecticides are increased. P. falciparum is the greatest one of pathogen species causes morbidity and mortality, and its complex life cycles, antigenic stage-specificity, diversity and variation, have been the unique obstacle to develop antimalarial vaccines for a long time. Thus, the development of a multiple antigens and epitopes vaccine against P. falciparum to elicit relative immune response at different stage has become a major hotspot in antimalarial vaccine study, according to the characteristic of immune response at each life stage of parasite. However, in the polyepitope vaccine aspect, it is still focused on the artificially synthesized polypeptides or polyepitope gene with single format. For the former is high-cost and the latter is low-immunogenicity, it is too difficult to reach the satisfactory protection results or to obtain immune response diversity after immunization. In order to deal with the shortcoming of polyepitope DNA vaccine, we have developed a method named "epitope shuffling technology" to optimize the polyepitope DNA vaccine by use of the random recombinant principle of molecular breeding technology or DNA shuffling.In this study, we chose 14 B-cell and Th-cell epitopes of antigens mainly from the blood stage of P. falciparum, based on the type of immune response against the blood-stage parasite infection. In the process of epitope shuffling established, we have brought forward and attempted to use the PCR-assemble technology (PAT) and isocaudamer random recombinant technique (IRRT) successively, and finally constructed five sub-libraries (named L1, L2, L3, L4 and L5 according to gene length from small to large) with different polyepitope gene length by the means of IRRT. Each polyepitope library was shown the higher diversity of polyepitope genes based on the PCR-SSCP analysis. With the polyepitope library immunization, we have proved that the length of polyepitope gene affects the immunogenicity of DNA vaccine; the sub-libraries L4 with about 2.0kb gene size and L3 with about 1.2kb size were achieved the best level of immune response, and cross protection in the rodent animal model after library immunization. It is fully demonstrated that the different gene length of polyepitope artificial antigen is significantly influenced on the immunogenicity of DNA vaccine, and that the polyepitope-library immunization can elicit good immune response, and it is feasible to screen the optimal chimeric polyepitope gene from the library.
Three polyepitope genes ES312, ES391 and ES452 with high immunogenicity were screened from the duplicated express library of sub-libraries L3 and L4 in prokaryote, by use of the high throughput immunochemical selection with serial dilution of sera pool from polyepitope library immunization. The experimental results in vivo indicated that the immunogenic levels of three polyepitope gene vaccines were 100-200 times higher than that of other gene vaccine with the appropriate length, and the results detected by ELISA and immunoprecipitation assay showed higher diversity of specific antibodies were induced, under the same express level of each gene. And it is also presented that there are higher ability of the three-polyepitope genes to induce the CD4 cell in vivo. In the rodent animal model, polyepitope gene ES312 immunization has obtained 100％cross protection; and in the experiments of P. falciparum growth inhibition assay in vitro, the efficiency of ES312 against malaria growth detected by flow cytometry is up to 95.8％. The results of gene sequencing further indicated that the epitope assemble formats or the second structure of protein among the three-polyepitope genes was all possessed consensus and conservative structure. All these data is enough to present that the epitope assemble formats and the space structures of full protein determine the immunogenicity of polyepitope gene vaccine.
Through the genetic immunization experiment of polyepitope artificial antigen in vivo, we have demonstrated that one of three polyepitope genes—ES312, with a certain tandem format, could elicit higher specific antibody response. At the same time, we found that mainly cytokine IFN-γderived by Th1 cell was expressed after the gene prime immunization, and higher level of Th2 cell response was induced followed by the second boost. And it is the immune response of host that vaccinated mice can resistant the P. yoelii parasite infection at the blood stage. From the results of ES312-immunized mice challenged after CD4 or CD8 lymphocyte transient blocking, we also found that the ability of host to inhibit the malaria parasite growth was increased. All these seem to further demonstrate that to induce the specific CD4 cell and humoral immune response is critical to prevent the malaria blood-stage infection, and that specific structure of polyepitope gene assembled is vital factor to induce this immune response in host.
In addition, in order to assess the protective effect of a blood-stage vaccine against malaria in vitro with more accurately, here we have optimized the method to detect the parasitemia of parasitized red blood cells by flow cytometry, and brought forward an improved formula to calculate the efficiency of malaria growth inhibition.
The results in this study indicated that the epitope shuffling method developed by us exploits a new way for construction and optimization of DNA vaccine with polyepitope artificial antigen. And these data confirmed our assumption that space conformation of artificial antigen determines the immunogenicity and immune protection of vaccine. The novel strategy of polyepitope vaccine construction is contributed not only to antimalarial vaccine, but also to other vaccine against virus, bacterial, protozoan infectious disease, as well as the gene therapy against tumor, allergy and neonatal tolerance.
引文
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