EB病毒疫苗研究进展
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摘要
EB病毒(EBV)是一种感染人的γ-疱疹病毒,与人类很多疾病有关,如单核细胞增多症、鼻咽癌、霍奇金淋巴瘤、伯基特淋巴瘤、移植后淋巴细胞增生症等。EBV相关疫苗作为预防EBV感染和治疗EBV相关肿瘤的手段一直以来是疫苗领域研究的热点。预防性疫苗是以病毒的包膜糖蛋白为靶蛋白,刺激机体产生中和抗体阻止病毒感染;治疗性疫苗主要用于治疗EBV潜伏感染相关的恶性肿瘤,是以肿瘤细胞中表达的EBV蛋白为靶位,刺激机体产生细胞免疫反应,增强毒性T淋巴细胞对肿瘤细胞的杀伤作用。本文从预防性疫苗和治疗性疫苗两方面对EBV疫苗的研究进展进行阐述。
Epstein-Barr virus( EBV) is a human gamma herpes virus,which is associated with many human diseases,such as infectious mononucleosis,nasopharyngeal carcinoma,Hodgkin lymphomas,Burkitt lymphoma,and post-transplant lymphoproliferative disorder. EBV vaccine has long been an important research topic to develop a means to prevent EBV infection and to treat EBV malignancies. Prophylactic EBV vaccine uses the viral envelope glycoprotein as a target protein to induce neutralizing antibodies to prevent virus infection. Therapeutic EBV vaccine is used to treat malignancies related to the latent infection of EBV; it targets EBV protein expressed in malignant cells to generate a specific cellular immune response and to enhance specific cytotoxic T lymphocyte responses. This article reviews research progress on prophylactic and therapeutic EBV vaccines.
Epstein-Barr virus( EBV) is a human gamma herpes virus,which is associated with many human diseases,such as infectious mononucleosis,nasopharyngeal carcinoma,Hodgkin lymphomas,Burkitt lymphoma,and post-transplant lymphoproliferative disorder. EBV vaccine has long been an important research topic to develop a means to prevent EBV infection and to treat EBV malignancies. Prophylactic EBV vaccine uses the viral envelope glycoprotein as a target protein to induce neutralizing antibodies to prevent virus infection. Therapeutic EBV vaccine is used to treat malignancies related to the latent infection of EBV; it targets EBV protein expressed in malignant cells to generate a specific cellular immune response and to enhance specific cytotoxic T lymphocyte responses. This article reviews research progress on prophylactic and therapeutic EBV vaccines.
引文
[1]COHEN JI,FAUCI AS,VARMUS H,et al.Epstein-Barr virus:an important vaccine target for cancer prevention[J].Science Translational Medicine,2011,3(107):107fs7.
[2]张美惠.病毒感染与人类肿瘤—从基础科学到临床预防[M].北京:科学出版社,2016:74-109.ZHANG Meihui.Viruses and human cancer from basic science to clinical prevention[M].Beijing:Science Press,2016:74-109.
[3]SITOMPUL LS,WIDODO N,DJATI MS,et al.Epitope mapping of gp350/220 conserved domain of Epstein Barr virus to develop nasopharyngeal carcinoma(NPC)vaccine[J].Bioinformation,2012,8(10):479-482.
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[6]SOKAL EM,HOPPENBROUWERS K,VANDERMEULEN C,et al.Recombinant gp350 vaccine for infectious mononucleosis:a phase 2,randomized,double-blind,placebo-controlled trial to evaluate the safety,immunogenicity,and efficacy of an EpsteinBarr virus vaccine in healthy young adults[J].The Journal of Infectious Diseases,2008,196(12):1749-1753.
[7]OGEMBO JG,MURASWKI MR,MCGINNES LW,et al.A chimeric EBV gp350/220-based VLP replicates the virion B-cell attachment mechanism and elicits long-lasting neutralizing antibodies in mice[J].J Transl Med,2015,13(1):50.
[8]KANEKIYO M,BU W,JOYCE MG,et al.Rational design of an Epstein-Barr virus vaccine targeting the receptor-binding site[J].Cell,2015,162(5):1090-1100.
[9]LI Q,TURK SM,HUTT-FLETCHER LM.The Epstein-Barr virus(EBV)BZLF2 gene product associates with the g H and g L homologs of EBV and carries an epitope critical to infection of B cells but not of epithelial cells[J].Journal of Virology,1995,69(7):3987-3994.
[10]CUI XL,CAO ZH,CHEN QY,et al.Rabbits immunized with Epstein-Barr virus g H/g L or g B recombinant proteins elicit higher serum virus neutralizing activity than gp350[J].Vaccine,2016,34(34):4050-4055.
[11]KANG MS,KIEFF E.Epstein-Barr virus latent genes[J].Exp Mol Med,2015,47:e131.
[12]TAYLOR GS,JIA H,HARRINGTON K,et al.A recombinant modified vaccinia Ankara vaccine encoding Epstein-Barr virus(EBV)target antigens:a phase I trial in UK patients with EBVpositive cancer[J].Clin Cancer Res,2014,20(19):5009-5022.
[13]HUI EP,TAYLOR GS,JIA H,et al.Phase I trial of recombinant modified vaccinia Ankara encoding Epstein-Barr viral tumor antigens in nasopharyngeal carcinoma patients[J].Cancer Research,2013,73(6):1676-1688.
[14]SI YF,DENG ZX,LAN GP,et al.The safety and immunological effects of r Ad5-EBV-LMP2 vaccine in nasopharyngeal carcinoma patients:a phase I clinical trial and two-year follow-up[J].Chemical&Pharmaceutical Bulletin,2016,64(8):1118-1123.
[15]杨松梅,王湛,周玲,等.携带EBV-LMP2基因的DNA疫苗、腺相关病毒疫苗和腺病毒疫苗免疫小鼠的特异性细胞免疫应答[J].中国科学(C辑:生命科学),2009,39(4):342-345.YANG SM,WANG Z,ZHOU L,et al.Specific cellular immune responses in mice immunized with DNA,adeno-associated virus and adenoviral vaccines of Epstein-Barr virus-LMP2 alone or in combination[J].Science in China(Series C:Life Sciences),2009,39(4):342-345.
[16]LI W,CHEN Q,CHEN H,et al.Immune response of mice to a latency membrane protein 2 multiepitope antigen of Epstein-Barr virus applied as DNA vaccine and/or peptide vaccine[J].Acta Virol,2013,57(1):51-58.
[17]DOMINICI M,LE BLANC K,MUELLER I,et al.Minimal criteria for defining multipotent mesenchymal stromal cells,the International Society for Cellular Therapy position statement[J].Cytotherapy,2006,8(4):315-317.
[18]LIN CL,LO WF,LEE TH,et al.Immunization with EpsteinBarr virus(EBV)peptide-pulsed dendritic cells induces functional CD8+T-cell immunity and may lead to tumor regression in patients with EBV-positive nasopharyngeal carcinoma[J].Cancer Res,2002,62(23):6952-6958.
[19]杜海军.树突状细胞-EBV-LMP2疫苗治疗鼻咽癌的初步研究[D].北京:中国疾病预防控制中心,2010.DU HJ.The preliminary study of DC-EBV-LMP2 vaccine on nasopharyngeal carcinoma[D].Beijing:Chinese Center for Disease Control and Prevention,2010.
[20]CHIA WK,WANG WW,TEO M,et al.A phase II study evaluating the safety and efficacy of an adenovirus-DLMP1-LMP2transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma[J].Ann Oncol,2012,23(4):997-1005.
[21]朱伟,黎桂仙,陈洪浪,等.CSF2A融合基因真核表达载体的构建及其对EBV+肿瘤细胞增殖和凋亡的影响[J].吉林大学学报(医学版),2016,42(3):424-429,637.ZHU W,LI GX,CHEN HL,et al.Construction of CSF2A fusion gene recombinant eukaryotic expression vector and its effect on proliferation and apoptosis of EBV+tumor cells[J].Journal of Jilin University(Medicine Edition),2016,42(3):424-429,637.
[22]孙立莹,杜海军,李红霞,等.表达EBV LMP2的小鼠骨髓间充质干细胞免疫原性初讨[J].中国病毒病杂志,2015,5(3):201-207.SUN LY,DU HJ,LI HX,et al.A preliminary study on the immunological effect of mouse mesenchymal stem cells expressing EBV LMP2[J].Chinese Journal of Viral Diseases,2015,5(3):201-207.
[23]SMITH C,TSANG J,BEAGLEY L,et al.Effective treatment of metastatic forms of Epstein-Barr virus-associated nasopharyngeal carcinoma with a novel adenovirus-based adoptive immunotherapy[J].Cancer Res,2012,72(5):1116-1125.
[24]CHIA WK,TEO M,WANG WW,et al.Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma[J].Mol Ther,2014,22(1):132-139.
[25]BOLLARD CM,GOTTSCHALK S,TORRANO VA,et al.Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins[J].J Clin Oncol,2014,32(8):798-808.
[26]唐小军.LMP1靶向嵌合抗原受体T细胞对EBV相关恶性肿瘤杀伤作用的实验研究[D].南京:南京医科大学,2014.TANG XJ.T cells expressing a LMP1-specific chimeric antigen receptor mediate antitumor effects against EBV-associated malignancies in vitro and in vivo[D].Nanjing:Nanjing Medical University,2014.
[27]NOH KW,PARK J,KANG MS.Targeted disruption of EBNA1in EBV-infected cells attenuated cell growth[J].BMB Rep,2016,49(4):226-231.
[2]张美惠.病毒感染与人类肿瘤—从基础科学到临床预防[M].北京:科学出版社,2016:74-109.ZHANG Meihui.Viruses and human cancer from basic science to clinical prevention[M].Beijing:Science Press,2016:74-109.
[3]SITOMPUL LS,WIDODO N,DJATI MS,et al.Epitope mapping of gp350/220 conserved domain of Epstein Barr virus to develop nasopharyngeal carcinoma(NPC)vaccine[J].Bioinformation,2012,8(10):479-482.
[4]COHEN JI.Epstein-Barr virus vaccines[J].Clinical&Translational Immunology,2015,4(1):e32.
[5]SAIRENJI T,BERTONI G,MEDVECZKY MM,et al.Inhibition of Epstein-Barr virus(EBV)release from P3HR-1 and B95-8 cell lines by monoclonal antibodies to EBV membrane antigen gp350/220[J].Journal of Virology,1988,62(8):2614-2621.
[6]SOKAL EM,HOPPENBROUWERS K,VANDERMEULEN C,et al.Recombinant gp350 vaccine for infectious mononucleosis:a phase 2,randomized,double-blind,placebo-controlled trial to evaluate the safety,immunogenicity,and efficacy of an EpsteinBarr virus vaccine in healthy young adults[J].The Journal of Infectious Diseases,2008,196(12):1749-1753.
[7]OGEMBO JG,MURASWKI MR,MCGINNES LW,et al.A chimeric EBV gp350/220-based VLP replicates the virion B-cell attachment mechanism and elicits long-lasting neutralizing antibodies in mice[J].J Transl Med,2015,13(1):50.
[8]KANEKIYO M,BU W,JOYCE MG,et al.Rational design of an Epstein-Barr virus vaccine targeting the receptor-binding site[J].Cell,2015,162(5):1090-1100.
[9]LI Q,TURK SM,HUTT-FLETCHER LM.The Epstein-Barr virus(EBV)BZLF2 gene product associates with the g H and g L homologs of EBV and carries an epitope critical to infection of B cells but not of epithelial cells[J].Journal of Virology,1995,69(7):3987-3994.
[10]CUI XL,CAO ZH,CHEN QY,et al.Rabbits immunized with Epstein-Barr virus g H/g L or g B recombinant proteins elicit higher serum virus neutralizing activity than gp350[J].Vaccine,2016,34(34):4050-4055.
[11]KANG MS,KIEFF E.Epstein-Barr virus latent genes[J].Exp Mol Med,2015,47:e131.
[12]TAYLOR GS,JIA H,HARRINGTON K,et al.A recombinant modified vaccinia Ankara vaccine encoding Epstein-Barr virus(EBV)target antigens:a phase I trial in UK patients with EBVpositive cancer[J].Clin Cancer Res,2014,20(19):5009-5022.
[13]HUI EP,TAYLOR GS,JIA H,et al.Phase I trial of recombinant modified vaccinia Ankara encoding Epstein-Barr viral tumor antigens in nasopharyngeal carcinoma patients[J].Cancer Research,2013,73(6):1676-1688.
[14]SI YF,DENG ZX,LAN GP,et al.The safety and immunological effects of r Ad5-EBV-LMP2 vaccine in nasopharyngeal carcinoma patients:a phase I clinical trial and two-year follow-up[J].Chemical&Pharmaceutical Bulletin,2016,64(8):1118-1123.
[15]杨松梅,王湛,周玲,等.携带EBV-LMP2基因的DNA疫苗、腺相关病毒疫苗和腺病毒疫苗免疫小鼠的特异性细胞免疫应答[J].中国科学(C辑:生命科学),2009,39(4):342-345.YANG SM,WANG Z,ZHOU L,et al.Specific cellular immune responses in mice immunized with DNA,adeno-associated virus and adenoviral vaccines of Epstein-Barr virus-LMP2 alone or in combination[J].Science in China(Series C:Life Sciences),2009,39(4):342-345.
[16]LI W,CHEN Q,CHEN H,et al.Immune response of mice to a latency membrane protein 2 multiepitope antigen of Epstein-Barr virus applied as DNA vaccine and/or peptide vaccine[J].Acta Virol,2013,57(1):51-58.
[17]DOMINICI M,LE BLANC K,MUELLER I,et al.Minimal criteria for defining multipotent mesenchymal stromal cells,the International Society for Cellular Therapy position statement[J].Cytotherapy,2006,8(4):315-317.
[18]LIN CL,LO WF,LEE TH,et al.Immunization with EpsteinBarr virus(EBV)peptide-pulsed dendritic cells induces functional CD8+T-cell immunity and may lead to tumor regression in patients with EBV-positive nasopharyngeal carcinoma[J].Cancer Res,2002,62(23):6952-6958.
[19]杜海军.树突状细胞-EBV-LMP2疫苗治疗鼻咽癌的初步研究[D].北京:中国疾病预防控制中心,2010.DU HJ.The preliminary study of DC-EBV-LMP2 vaccine on nasopharyngeal carcinoma[D].Beijing:Chinese Center for Disease Control and Prevention,2010.
[20]CHIA WK,WANG WW,TEO M,et al.A phase II study evaluating the safety and efficacy of an adenovirus-DLMP1-LMP2transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma[J].Ann Oncol,2012,23(4):997-1005.
[21]朱伟,黎桂仙,陈洪浪,等.CSF2A融合基因真核表达载体的构建及其对EBV+肿瘤细胞增殖和凋亡的影响[J].吉林大学学报(医学版),2016,42(3):424-429,637.ZHU W,LI GX,CHEN HL,et al.Construction of CSF2A fusion gene recombinant eukaryotic expression vector and its effect on proliferation and apoptosis of EBV+tumor cells[J].Journal of Jilin University(Medicine Edition),2016,42(3):424-429,637.
[22]孙立莹,杜海军,李红霞,等.表达EBV LMP2的小鼠骨髓间充质干细胞免疫原性初讨[J].中国病毒病杂志,2015,5(3):201-207.SUN LY,DU HJ,LI HX,et al.A preliminary study on the immunological effect of mouse mesenchymal stem cells expressing EBV LMP2[J].Chinese Journal of Viral Diseases,2015,5(3):201-207.
[23]SMITH C,TSANG J,BEAGLEY L,et al.Effective treatment of metastatic forms of Epstein-Barr virus-associated nasopharyngeal carcinoma with a novel adenovirus-based adoptive immunotherapy[J].Cancer Res,2012,72(5):1116-1125.
[24]CHIA WK,TEO M,WANG WW,et al.Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma[J].Mol Ther,2014,22(1):132-139.
[25]BOLLARD CM,GOTTSCHALK S,TORRANO VA,et al.Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins[J].J Clin Oncol,2014,32(8):798-808.
[26]唐小军.LMP1靶向嵌合抗原受体T细胞对EBV相关恶性肿瘤杀伤作用的实验研究[D].南京:南京医科大学,2014.TANG XJ.T cells expressing a LMP1-specific chimeric antigen receptor mediate antitumor effects against EBV-associated malignancies in vitro and in vivo[D].Nanjing:Nanjing Medical University,2014.
[27]NOH KW,PARK J,KANG MS.Targeted disruption of EBNA1in EBV-infected cells attenuated cell growth[J].BMB Rep,2016,49(4):226-231.