流感功能表位筛选与复合多表位核酸疫苗设计及免疫研究
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摘要
流感是由流感病毒引起的急性呼吸道传染病。几十年来,人流感的流行一直以A型H3/H1亚型以及B型流感为主,禽流感的流行以A型H5/H7/H9亚型为主,其流行已造成了巨大的损失。近年来,禽流感病毒的多个亚型(H5/H7/H9/H10)开始不断突破种间屏障感染人类,并可能造成大流行。当前,传统的流感疫苗已无法有效应对这一趋势,各国学者纷纷进行新型流感疫苗的开发以应对流感跨种传播及多亚型并存的现状。
本论文即拟对多亚型流感病毒复合多表位核酸疫苗进行研究。在搜集已发表流感功能表位的基础上,应用生物信息学理论对H1/H3/H5/H7/H9亚型的保护性抗原血凝素及神经氨酸酶进行了CTL、Th、B细胞表位的预测和筛选分析。设计组建了多表位功能基因盒,并进行了人工模拟优化,应用体外实验方式分析了预测的Th和B细胞功能表位抗原性。根据针对所属动物及预防目的的不同,我们构建了三种主导型H3/H1(针对人),H5/H3(针对人和猪),H5/H7(针对人和禽)的复合多表位核酸疫苗,通过RT-PCR及间接免疫荧光方法证实疫苗中各抗原组分可有效表达。最后,我们将所构建的复合多表位核酸疫苗进行了小鼠、猪、鸡的实验免疫研究,通过对ELISA及HI抗体水平、淋巴细胞刺激指数、IFNγ-ELISPOT和T淋巴细胞亚类数量、血清细胞因子含量等指标的综合分析,对不同复合多表位疫苗进行了免疫原性评价。结果显示,复合多表位疫苗组在针对主要抗原的抗体水平与不含表位组相当的情况下,表位相关抗原的抗体水平显示了一定的优势。表位相关抗原的淋巴细胞刺激指数显著升高,IFNγ-ELISPOT斑点数不同程度增加。复合多表位疫苗免疫组CD4~+T淋巴细胞数量和血清Th2类细胞因子含量显著增加。以上结果证实,复合多表位疫苗在诱导细胞及体液免疫方面均显示了优势,与各免疫对照组相比复合多表位DNA疫苗诱导的机体整体免疫水平最优。本研究对可同时预防多种亚型流感病毒,可对多种动物免疫保护,可提供机体长久免疫保护的跨种通用流感疫苗进行了有益尝试。
Influenza is an acute respiratory infectious disease caused by type A influenza virus. To date influenza virus infection continues to be a major public health threat to human society and animals.For years,H3 and H1 subtypes of influenza A virus and influenza B virus are the major prevalent pathogens for humans,and H5,H7,H9 subtypes of influenza A virus are dominant subtypes in avians.So far,influenza infections have caused huge losses of human resources and material resources.Moreover,multi-subtypes (H5/H7/H9/H10) of avian influenza have overcome the species barrier and infected humans,which may cause new pandemics.
Due to lack of effective influenza drugs,vaccine is still an effective way to prevent influenza infection and transmission.At present,the prevention of human and avian influenza mainly depends on inactivated and live attenuated vaccines.For years,they had been proved safe and effective,and also played an important role in preventing influenza. However,inactivated and attenuated vaccines themselves have some deficiencies,which can not be avoided.The deficiencies of inactivated vaccines are as follows:weak in stimulating celluar immunity;can only provide protection to the strain of the virus matched to vaccine antigen;the use of adjuvant may induce stress response;high production costs;affect the immune monitoring.Live attenuated vaccines may take mutation into highly pathogenic influenza.Moreover,these two vaccines are unable to effectively cope with the rapid mutation of influenza virus,the coexistence of multiple subtypes of influenza,and the disappearing of species boundaries.
DNA vaccine is a technology beginning in the 20th century 90's.Because of stimulating the humoral and cellular immunity simultaneously,DNA vaccine had been favored.DNA vaccine has advantages of easy to use,stability,security,fast to build, which make it more facilitate in response to the variation of influenza virus.The emergence of epitope provided a new idea for the development of influenza vaccine. Developing influenza epitope vaccine,can not only be effective in using protective antigens of influenza and enhancing the specific immune response,but also have the advantages of selecting cross-protective epitopes to achieve the prevention of a number of subtypes.Especially,by monitoring the epidemic,epitopes can be synthesized in time to response to the rapid spread of influenza.A large number of studies have confirmed that the epitope vaccine had a potential future in the development of influenza vaccine.In this study,combined with the advantages of DNA vaccine and epitope vaccine,combined multi-epitope vaccines were designed and constructed.The more informations as follows:
Based on collecting published influenza epitopes,we predicted and analyzed CTL, Th,and B-cell epitopes of HA and NA of H1/H3/H5/H7/H9 subtype of influenza by bioinformatics methods.Screening of HA and NA,17 CTL epitopes and 12 Th/B epitopes were acquired.Based the above epitopes,CTL and ThB boxes were designed. Then the boxes were optimized by software simulation.Ultimately,two CTL and two ThB boxes were synthesized,which laid the foundation for the further study of epitope functional research and immunization experiments.
The antigenicity of predicted ThB epitopes were assessed by positive serum binding analysis,which explained the ability of predicted epitopes to be functional ones.The result showed H1 HA_(188～205)、H1 HA_(125～139)、H1 HA_(73～87)、H5 HA_(302～316)、H9 HA_(73～90)、H9 HA_(37～54)、H9 HA_(123～140),were potential functional epitopes on BALB/c mice.The result also showed H5 HA_(206～223)、H5 HA_(141～155)、H5 HA_(302～316)、H9 HA_(73～90)、H9 HA_(37～54)、H9 HA_(123～140) were potential functional epitopes on SPF chickens.This study laid the foundation for revealing the further study of influenza infection and immune mechanisms, identifying of functional epitopes,and developing of influenza epitope vaccine.
Then,we cloned H5HA,H1HA1,NP gene of influenza virus,and synthesize H7HA and H3HA gene.Primers were designed for PCR transformation,all the relative fragments were accessed with the restriction sites and linker sequences of the research needs.After molecular design and optimization,three series of combined multi-epitope vaccines were constructed for different purposes.One for human H1/H3 subtypes,was expected to prevent the major subtypes of human and also other subtypes(H5、H7、H9) at the same time.One for human and pig H5/H3 subtypes,was expected to prevent the potential pandemic of H3/H5 subtypes and also other subtypes(H1、H7、H9) at the same time.One for human and avian H5/H7 subtypes,was expected to prevent the HPAI of H5/H7 subtypes and also other subtypes(H1、H3、H9) at the same time.Combined multi-epitope vaccines were transfected into BHK cells and identified by RT-PCR and IFA.The result showed all the antigenic components were expressed effectively in eukaryotic cells.This study laid the foundation for the animal immunization experiments.
As a mammalian model,mice were employed to evaluate the immunogenicity of the H3/H1 combined multi-epitope vaccine by humoral and cellular immune detection.The result showed the main antigen(H3/H1) related ELISA serum antibody level,which was stimulated by the H3/H1 combined multi-epitope vaccine,was equal to the single-antigen expressing group.And the H3/H1 combined multi-epitope vaccine also showed the advantages of enhancing H5 specific ELISA antibody level.Comprehensive analysis of indicators of cellular immunity,the combined multi-epitope vaccine group got the best cellular immunity response.The addition of epitopes and co-immunization with NP enhanced the cellular immunity level effectively,and more inclined to enhance the function of CD4~+ T lymphocytes.Analyzed from the influenza subtype specific cellular immunity level,the SI and IFN-γsecretion of main antigen(H3/H1) were mainly depended on HA alone or/and co-immunization with NP.The addition of epitopes enhanced specific cellular immunity response of the epitope-related subtypes(H5/H7/H9) and more inclined to induce the function of Th2 cells,especially seen from the T lymphocyte proliferation stimulated by H5 or H9 antigen.
Mice were employed to evaluate the immunogenicity of the H5/H7 combined multi-epitope vaccine.The result showed the main antigen(H5/H7) related ELISA serum antibody level,which was stimulated by the H5/H7 combined multi-epitope vaccine group,was equal to the single-antigen expressing group.But there was no significant advantages on ELISA serum antibody level of epitope-related subtypes.Comprehensive analysis of indicators of cellular immunity,the combined multi-epitope vaccine group got the best cellular immunity response.The addition of epitopes and co-immunization with NP enhanced the cellular immunity level effectively,and more inclined to enhance the function of CD4~+ T lymphocytes.Analyzed from the influenza subtype specific cellular immunity level,the SI and IFN-γsecretion of main antigen(H5/H7) was mainly depended on HA or/and co-immunization with NP.The addition of epitopes enhanced H1/H9 specific SI of the epitope-related subtypes significantly.However,not always significantly with other groups,the indicators of the combined multi-epitope vaccine group were highest in most detections.Our study inferred that if we could enhance the expression efficiency of DNA vaccine in mice effectively,such as combined with the adjuvant or used a different immunization way,the combined multi-epitope vaccine would display more significant advantages.
Pigs were employed to evaluate the immunogenicity of the H5/H3 combined multi-epitope vaccine.The result showed the main antigen(H5/H3) related ELISA serum antibody level,which was stimulated by the H5/H3 combined multi-epitope vaccine group,was equal to the single-antigen expressing group.But there was no significant advantages on ELISA serum antibody level of epitope-related subtypes(H1/H7/H9).The result of HI detection was similar as the result of ELISA detection.From the serum levels of cytokines induced by combined multi-epitope vaccine,comparing to the co-immunization double-subtype group,there were no significant differences in IFN-γ, but significant higher in IL-4.The result showed that when helped with the NP co-immunization,the vaccines effectively stimulated IFN-γ,secretion by the Th1 lymphocytes.The addition of epitopes enhanced the Th2 immune response,which would promote the humoral immune response.Comprehensive analysis of indicators of cellular immunity,the combined multi-epitope vaccine group got the best cellular immunity response.The addition of epitopes and co-immunization with NP enhanced the cellular immunity effectively,and more inclined to enhance the function of CD4~+ T lymphocytes. Analyzed from the influenza subtype specific cellular immunity,the SI and IFN-γ, secretion of main antigen(H3/H1) was mainly depended on HA or/and co-immunization with NP.The addition of epitopes enhanced H1/H7 specific SI of the epitope-related subtypes significantly,and more inclined to induce the function of Th2 cells.
After the mice immunization,chickens were employed to evaluate the immunogenicity of the H5/H7 combined multi-epitope vaccine.The result showed the main antigen(H5/H7) related ELISA serum antibody level,which was stimulated by the H5/H7 combined multi-epitope vaccine group,was equal to the single-antigen expressing group.And the H5/H7 combined multi-epitope vaccine also showed the advantages of enhancing H9 specific ELISA antibody level.The result of HI detection was similar as the result of ELISA detection.From the serum levels of cytokines,there were no significant differences in the IFN-γ,but the IL-2 induced by combined multi-epitope vaccine was lower than that of the co-immunization double-subtype group.However, IL-4 and IL-6 levels were significantly higher than that of the co-immunization double-subtype group.The result suggested that combined multi-epitope vaccine was good at inducing a balanced Th1/Th2 response pattern,and this group acquired the best overall immunity response.Seen from SI,co-immunization with NP enhanced the cellular immunity effectively.Analyzed from the influenza subtype specific cellular immunity level by H5 or H7 antigen,there were no significant differences between the combined multi-epitope vaccine group and other immunization groups.The result was depended on the factors as follows:HA played a decisive role in the induction of subtype specific cellular immunity;chickens might have individual differences that influenced SI level;different components of combined multi-epitope vaccine might induce the immune synergy response.But when stimulated by epitope-related antigens(H1/H3/H9),H9 subtype specific SI increased significantly.
The results of all the animal experiments confirmed that combined multi-epitope vaccine had significant advantages on induction of both humoral immunity and cellular immunity.Epitope-components can make their functions under the model of combined multi-epitope vaccine.The addition of epitopes enhanced immunity response of the epitope-related subtypes significantly,especially in celluar immunity response.However, we knew DNA vaccine has relatively weak immunogenicity,and this may weaken the function of epitopes.In our research,we assessed the vaccines on the view of subtype. Though we realized there were immune synergy between different antigen components, we did not conduct a detailed evaluation.In addition,the assessment of functional epitope did not meet the function of a single epitope level.And all these will be our next step of further research.Our study had made some benefical exploration in universal influenza vaccine,which was aim at providing protection for multiple subtypes of influenza A virus on many kinds of animals for years.
本论文即拟对多亚型流感病毒复合多表位核酸疫苗进行研究。在搜集已发表流感功能表位的基础上,应用生物信息学理论对H1/H3/H5/H7/H9亚型的保护性抗原血凝素及神经氨酸酶进行了CTL、Th、B细胞表位的预测和筛选分析。设计组建了多表位功能基因盒,并进行了人工模拟优化,应用体外实验方式分析了预测的Th和B细胞功能表位抗原性。根据针对所属动物及预防目的的不同,我们构建了三种主导型H3/H1(针对人),H5/H3(针对人和猪),H5/H7(针对人和禽)的复合多表位核酸疫苗,通过RT-PCR及间接免疫荧光方法证实疫苗中各抗原组分可有效表达。最后,我们将所构建的复合多表位核酸疫苗进行了小鼠、猪、鸡的实验免疫研究,通过对ELISA及HI抗体水平、淋巴细胞刺激指数、IFNγ-ELISPOT和T淋巴细胞亚类数量、血清细胞因子含量等指标的综合分析,对不同复合多表位疫苗进行了免疫原性评价。结果显示,复合多表位疫苗组在针对主要抗原的抗体水平与不含表位组相当的情况下,表位相关抗原的抗体水平显示了一定的优势。表位相关抗原的淋巴细胞刺激指数显著升高,IFNγ-ELISPOT斑点数不同程度增加。复合多表位疫苗免疫组CD4~+T淋巴细胞数量和血清Th2类细胞因子含量显著增加。以上结果证实,复合多表位疫苗在诱导细胞及体液免疫方面均显示了优势,与各免疫对照组相比复合多表位DNA疫苗诱导的机体整体免疫水平最优。本研究对可同时预防多种亚型流感病毒,可对多种动物免疫保护,可提供机体长久免疫保护的跨种通用流感疫苗进行了有益尝试。
Influenza is an acute respiratory infectious disease caused by type A influenza virus. To date influenza virus infection continues to be a major public health threat to human society and animals.For years,H3 and H1 subtypes of influenza A virus and influenza B virus are the major prevalent pathogens for humans,and H5,H7,H9 subtypes of influenza A virus are dominant subtypes in avians.So far,influenza infections have caused huge losses of human resources and material resources.Moreover,multi-subtypes (H5/H7/H9/H10) of avian influenza have overcome the species barrier and infected humans,which may cause new pandemics.
Due to lack of effective influenza drugs,vaccine is still an effective way to prevent influenza infection and transmission.At present,the prevention of human and avian influenza mainly depends on inactivated and live attenuated vaccines.For years,they had been proved safe and effective,and also played an important role in preventing influenza. However,inactivated and attenuated vaccines themselves have some deficiencies,which can not be avoided.The deficiencies of inactivated vaccines are as follows:weak in stimulating celluar immunity;can only provide protection to the strain of the virus matched to vaccine antigen;the use of adjuvant may induce stress response;high production costs;affect the immune monitoring.Live attenuated vaccines may take mutation into highly pathogenic influenza.Moreover,these two vaccines are unable to effectively cope with the rapid mutation of influenza virus,the coexistence of multiple subtypes of influenza,and the disappearing of species boundaries.
DNA vaccine is a technology beginning in the 20th century 90's.Because of stimulating the humoral and cellular immunity simultaneously,DNA vaccine had been favored.DNA vaccine has advantages of easy to use,stability,security,fast to build, which make it more facilitate in response to the variation of influenza virus.The emergence of epitope provided a new idea for the development of influenza vaccine. Developing influenza epitope vaccine,can not only be effective in using protective antigens of influenza and enhancing the specific immune response,but also have the advantages of selecting cross-protective epitopes to achieve the prevention of a number of subtypes.Especially,by monitoring the epidemic,epitopes can be synthesized in time to response to the rapid spread of influenza.A large number of studies have confirmed that the epitope vaccine had a potential future in the development of influenza vaccine.In this study,combined with the advantages of DNA vaccine and epitope vaccine,combined multi-epitope vaccines were designed and constructed.The more informations as follows:
Based on collecting published influenza epitopes,we predicted and analyzed CTL, Th,and B-cell epitopes of HA and NA of H1/H3/H5/H7/H9 subtype of influenza by bioinformatics methods.Screening of HA and NA,17 CTL epitopes and 12 Th/B epitopes were acquired.Based the above epitopes,CTL and ThB boxes were designed. Then the boxes were optimized by software simulation.Ultimately,two CTL and two ThB boxes were synthesized,which laid the foundation for the further study of epitope functional research and immunization experiments.
The antigenicity of predicted ThB epitopes were assessed by positive serum binding analysis,which explained the ability of predicted epitopes to be functional ones.The result showed H1 HA_(188～205)、H1 HA_(125～139)、H1 HA_(73～87)、H5 HA_(302～316)、H9 HA_(73～90)、H9 HA_(37～54)、H9 HA_(123～140),were potential functional epitopes on BALB/c mice.The result also showed H5 HA_(206～223)、H5 HA_(141～155)、H5 HA_(302～316)、H9 HA_(73～90)、H9 HA_(37～54)、H9 HA_(123～140) were potential functional epitopes on SPF chickens.This study laid the foundation for revealing the further study of influenza infection and immune mechanisms, identifying of functional epitopes,and developing of influenza epitope vaccine.
Then,we cloned H5HA,H1HA1,NP gene of influenza virus,and synthesize H7HA and H3HA gene.Primers were designed for PCR transformation,all the relative fragments were accessed with the restriction sites and linker sequences of the research needs.After molecular design and optimization,three series of combined multi-epitope vaccines were constructed for different purposes.One for human H1/H3 subtypes,was expected to prevent the major subtypes of human and also other subtypes(H5、H7、H9) at the same time.One for human and pig H5/H3 subtypes,was expected to prevent the potential pandemic of H3/H5 subtypes and also other subtypes(H1、H7、H9) at the same time.One for human and avian H5/H7 subtypes,was expected to prevent the HPAI of H5/H7 subtypes and also other subtypes(H1、H3、H9) at the same time.Combined multi-epitope vaccines were transfected into BHK cells and identified by RT-PCR and IFA.The result showed all the antigenic components were expressed effectively in eukaryotic cells.This study laid the foundation for the animal immunization experiments.
As a mammalian model,mice were employed to evaluate the immunogenicity of the H3/H1 combined multi-epitope vaccine by humoral and cellular immune detection.The result showed the main antigen(H3/H1) related ELISA serum antibody level,which was stimulated by the H3/H1 combined multi-epitope vaccine,was equal to the single-antigen expressing group.And the H3/H1 combined multi-epitope vaccine also showed the advantages of enhancing H5 specific ELISA antibody level.Comprehensive analysis of indicators of cellular immunity,the combined multi-epitope vaccine group got the best cellular immunity response.The addition of epitopes and co-immunization with NP enhanced the cellular immunity level effectively,and more inclined to enhance the function of CD4~+ T lymphocytes.Analyzed from the influenza subtype specific cellular immunity level,the SI and IFN-γsecretion of main antigen(H3/H1) were mainly depended on HA alone or/and co-immunization with NP.The addition of epitopes enhanced specific cellular immunity response of the epitope-related subtypes(H5/H7/H9) and more inclined to induce the function of Th2 cells,especially seen from the T lymphocyte proliferation stimulated by H5 or H9 antigen.
Mice were employed to evaluate the immunogenicity of the H5/H7 combined multi-epitope vaccine.The result showed the main antigen(H5/H7) related ELISA serum antibody level,which was stimulated by the H5/H7 combined multi-epitope vaccine group,was equal to the single-antigen expressing group.But there was no significant advantages on ELISA serum antibody level of epitope-related subtypes.Comprehensive analysis of indicators of cellular immunity,the combined multi-epitope vaccine group got the best cellular immunity response.The addition of epitopes and co-immunization with NP enhanced the cellular immunity level effectively,and more inclined to enhance the function of CD4~+ T lymphocytes.Analyzed from the influenza subtype specific cellular immunity level,the SI and IFN-γsecretion of main antigen(H5/H7) was mainly depended on HA or/and co-immunization with NP.The addition of epitopes enhanced H1/H9 specific SI of the epitope-related subtypes significantly.However,not always significantly with other groups,the indicators of the combined multi-epitope vaccine group were highest in most detections.Our study inferred that if we could enhance the expression efficiency of DNA vaccine in mice effectively,such as combined with the adjuvant or used a different immunization way,the combined multi-epitope vaccine would display more significant advantages.
Pigs were employed to evaluate the immunogenicity of the H5/H3 combined multi-epitope vaccine.The result showed the main antigen(H5/H3) related ELISA serum antibody level,which was stimulated by the H5/H3 combined multi-epitope vaccine group,was equal to the single-antigen expressing group.But there was no significant advantages on ELISA serum antibody level of epitope-related subtypes(H1/H7/H9).The result of HI detection was similar as the result of ELISA detection.From the serum levels of cytokines induced by combined multi-epitope vaccine,comparing to the co-immunization double-subtype group,there were no significant differences in IFN-γ, but significant higher in IL-4.The result showed that when helped with the NP co-immunization,the vaccines effectively stimulated IFN-γ,secretion by the Th1 lymphocytes.The addition of epitopes enhanced the Th2 immune response,which would promote the humoral immune response.Comprehensive analysis of indicators of cellular immunity,the combined multi-epitope vaccine group got the best cellular immunity response.The addition of epitopes and co-immunization with NP enhanced the cellular immunity effectively,and more inclined to enhance the function of CD4~+ T lymphocytes. Analyzed from the influenza subtype specific cellular immunity,the SI and IFN-γ, secretion of main antigen(H3/H1) was mainly depended on HA or/and co-immunization with NP.The addition of epitopes enhanced H1/H7 specific SI of the epitope-related subtypes significantly,and more inclined to induce the function of Th2 cells.
After the mice immunization,chickens were employed to evaluate the immunogenicity of the H5/H7 combined multi-epitope vaccine.The result showed the main antigen(H5/H7) related ELISA serum antibody level,which was stimulated by the H5/H7 combined multi-epitope vaccine group,was equal to the single-antigen expressing group.And the H5/H7 combined multi-epitope vaccine also showed the advantages of enhancing H9 specific ELISA antibody level.The result of HI detection was similar as the result of ELISA detection.From the serum levels of cytokines,there were no significant differences in the IFN-γ,but the IL-2 induced by combined multi-epitope vaccine was lower than that of the co-immunization double-subtype group.However, IL-4 and IL-6 levels were significantly higher than that of the co-immunization double-subtype group.The result suggested that combined multi-epitope vaccine was good at inducing a balanced Th1/Th2 response pattern,and this group acquired the best overall immunity response.Seen from SI,co-immunization with NP enhanced the cellular immunity effectively.Analyzed from the influenza subtype specific cellular immunity level by H5 or H7 antigen,there were no significant differences between the combined multi-epitope vaccine group and other immunization groups.The result was depended on the factors as follows:HA played a decisive role in the induction of subtype specific cellular immunity;chickens might have individual differences that influenced SI level;different components of combined multi-epitope vaccine might induce the immune synergy response.But when stimulated by epitope-related antigens(H1/H3/H9),H9 subtype specific SI increased significantly.
The results of all the animal experiments confirmed that combined multi-epitope vaccine had significant advantages on induction of both humoral immunity and cellular immunity.Epitope-components can make their functions under the model of combined multi-epitope vaccine.The addition of epitopes enhanced immunity response of the epitope-related subtypes significantly,especially in celluar immunity response.However, we knew DNA vaccine has relatively weak immunogenicity,and this may weaken the function of epitopes.In our research,we assessed the vaccines on the view of subtype. Though we realized there were immune synergy between different antigen components, we did not conduct a detailed evaluation.In addition,the assessment of functional epitope did not meet the function of a single epitope level.And all these will be our next step of further research.Our study had made some benefical exploration in universal influenza vaccine,which was aim at providing protection for multiple subtypes of influenza A virus on many kinds of animals for years.
引文
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