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季节性流感病毒仍对全球公共卫生安全构成巨大威胁，对老人、儿童以及免疫功能低下人群的危害尤其严重。疫苗接种是目前应对季节性流感疫情重要手段，然而由于抗原转换和抗原漂移，常出现疫苗株与实际病毒流行株的不匹配现象，因此迫切需要开发一种安全高效的广谱流感疫苗来对抗季节性流感病毒和潜在的流感大流行。抗原设计是研发新型疫苗的关键前提，我们利用马赛克（mosaic）遗传算法设计研发了一种具有广谱抗原表位覆盖率的靶向流感病毒神经氨酸酶（Neuraminidase,NA）的新型抗原（Mosaic-NA）。该抗原在最大程度上涵盖了所有已报道甲型流感病毒的NA1蛋白与NA2蛋白序列中的细胞毒性T淋巴细胞（Cytotoxic T lymphocyte,CTL）抗原表位，并保留了天然蛋白空间构象。因此，这种新型抗原预期可有效诱导出靶向保守表位的CTL反应和抗体反应，从而为研发通用流感疫苗提供新思路和理论基础。
Abstract：Seasonal influenza viruses still pose a huge threat to global public health security. They are particularly harmful to the elderly,children and people with immune deficiency. Vaccination is currently an important method to counter seasonal influenza epidemics. However,due to conversion and drift of antigens,there is often a mismatch between vaccine strains and actual circulating virus strains. Therefore,development of a safe,efficient and broad-spectrum influenza vaccine is important. Antigen design is a key prerequisite for development of novel vaccines. We designed a new type of antigen targeting influenza virus neuraminidase(NA)in influenza viruses with broad-spectrum epitope coverage using mosaic genetic algorithms（“Mosaic-NA”）. This antigen contained,to the greatest extent,conserved cytotoxic T lymphocyte(CTL)epitopes in the natural viral sequence. This antigen covered all the CTL epitopes of the NA1 and NA2 proteins of influenza A viruses that had been reported. Mosaic-NA retained the native protein conformation to the greatest extent.This novel antigen is expected to effectively induce CTL responses and antibody responses against conserved epitopes. Our data lay a theoretical foundation and reference for development of universal influenza vaccines.
[1]彭质斌，王大燕，杨娟，杨鹏，张延炀，陈健，陈涛，郑亚明，郑建东，姜世强，徐莉立，康敏，秦颖，赵梦娇，李中杰，冯录召.中国流感疫苗应用现状及促进预防接种的政策探讨[J/OL].中华流行病学杂志，2018,39(8):1045-1050. DOI:10.3760/cma. j. issn. 0254-6450.2018.08.007.
[2] WHO. influenza-（seasonal）,fact-sheets.[EB/OL]2021-2-3;Available from:https：//www. who. int/zh/news-room/fact-sheets/detail/influenza-（seasonal）.
[3] Chen Y Q,Wohlbold T J,Zheng N Y,Huang M,Huang Y,Neu K E,Lee J,Wan H,Rojas K T,Kirkpatrick E,Henry C,Palm A E,Stamper C T,Lan L Y,Topham D J,Treanor J,Wrammert J,Ahmed R, Eichelberger M C, Georgiou G, Krammer F,Wilson P C. Influenza infection in humans induces broadly cross-reactive and protective neuraminidasereactive antibodies[J/OL]. Cell,2018,173(2):417-429 e410. DOI:10.1016/j.cell.2018.03.030.
[4] von Itzstein M. The war against influenza:discovery and development of sialidase inhibitors[J/OL]. Nat Rev Drug Discov,2007,6(12):967-974. DOI:10.1038/nrd2400.
[5] Gao J,Xu K,Sun H,Liu Q,Yang J,Teng Q,Li X,Chen Z,Li Z,Chen H. Generation and characterization of monoclonal antibodies against the NS1 protein of H17N10 bat influenza virus[J/OL]. Acta Biochim Biophys Sin(Shanghai),2017,49(7):649-651. DOI:10.1093/abbs/gmx044.
[6] Wu Y,Wu Y,Tefsen B,Shi Y,Gao G F. Bat-derived influenza-like viruses H17N10 and H18N11[J/OL].Trends Microbiol, 2014, 22(4):183-191. DOI:10.1016/j.tim.2014.01.010.
[7] Wang S F,Lee Y M,Chan Y J,Liu H F,Yen Y F,Liu W T,Huang J C,Chen Y M. Influenza A virus in Taiwan, 1980-2006:Phylogenetic and antigenic characteristics of the hemagglutinin gene[J/OL]. J Med Virol, 2009, 81(8):1457-1470. DOI:10.1002/jmv.21531.
[8] Gerhard W, Yewdell J, Frankel M E, Webster R.Antigenic structure of influenza virus haemagglutinin defined by hybridoma antibodies[J/OL]. Nature,1981,290(5808):713-717. DOI:10.1038/290713a0.
[9] Jackson D C,Murray J M,White D O,Gerhard W U.Enumeration of antigenic sites of influenza virus hemagglutinin[J/OL]. Infect Immun,1982,37(3):912-918. DOI:10.1128/IAI.37.3.912-918.1982.
[10]Zhou Z J,Qiu Y,Pu Y,Huang X,Ge X Y. BioAider:An efficient tool for viral genome analysis and its application in tracing SARS-CoV-2 transmission[J/OL]. Sustain Cities Soc, 2020, 63:102466. DOI:10.1016/j.scs.2020.102466.
[11]Schneider T D,Stephens R M. Sequence logos:a new way to display consensus sequences[J/OL]. Nucleic Acids Res,1990,18(20):6097-6100. DOI:10.1093/nar/18.20.6097.
[12]Jurtz V,Paul S,Andreatta M,Marcatili P,Peters B,Nielsen M. NetMHCpan-4.0:Improved peptide-mhc class i interaction predictions integrating eluted ligand and peptide binding affinity data[J/OL]. J Immunol,2017, 199(9):3360-3368. DOI:10.4049/jimmunol.1700893.
[13]Reynisson B,Alvarez B,Paul S,Peters B,Nielsen M.NetMHCpan-4.1 and NetMHCIIpan-4.0:improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data[J/OL]. Nucleic Acids Res,2020,48(W1):W449-W454. DOI:10.1093/nar/gkaa379.
[14]Grifoni A,Sidney J,Zhang Y,Scheuermann R H,Peters B, Sette A. A sequence homology and bioinformatic approach can predict candidate targets for immune responses to SARS-CoV-2[J/OL]. Cell Host Microbe,2020,27(4):671-680. e2. DOI:10.1016/j.chom.2020.03.002.
[15]Fischer W, Perkins S, Theiler J, Bhattacharya T,Yusim K,Funkhouser R,Kuiken C,Haynes B,Letvin N L,Walker B D,Hahn B H,Korber B T. Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants[J/OL]. Nat Med,2007,13(1):100-106. DOI:10.1038/nm1461.
[16]Barouch D H,Stephenson K E,Borducchi E N,Smith K, Stanley K, McNally A G, Liu J, Abbink P,Maxfield L F,Seaman M S,Dugast A S,Alter G,Ferguson M,Li W,Earl P L,Moss B,Giorgi E E,Szinger J J, Eller L A, Billings E A, Rao M,Tovanabutra S,Sanders-Buell E,Weijtens M,Pau M G,Schuitemaker H,Robb M L,Kim J H,Korber B T,Michael N L. Protective efficacy of a global HIV-1mosaic vaccine against heterologous SHIV challenges in rhesus monkeys[J/OL]. Cell,2013,155(3):531-539.DOI:10.1016/j.cell.2013.09.061.
[17]Kamlangdee A,Kingstad-Bakke B,Anderson T K,Goldberg T L,Osorio J E. Broad protection against avian influenza virus by using a modified vaccinia ankara virus expressing a mosaic hemagglutinin Gene[J/OL]. J Virol,2014,88(22):13300-13309. DOI:10.1128/Jvi.01532-14.
[18]Corder B N,Bullard B L,DeBeauchamp J L,Ilyushina N A,Webby R J,Weaver E A. Influenza H1 mosaic hemagglutinin vaccine induces broad immunity and protection in mice[J/OL]. Vaccines(Basel),2019,7(4). DOI:10.3390/vaccines7040195.
[19]Wedemeyer H,Mizukoshi E,Davis A R,Bennink J R,Rehermann B. Cross-reactivity between hepatitis C virus and Influenza A virus determinant-specific cytotoxic T cells[J/OL]. J Virol,2001,75(23):11392-11400.DOI:10.1128/JVI.75.23.11392-11400.2001.
[20]Gianfrani C,Oseroff C,Sidney J,Chesnut R W,Sette A. Human memory CTL response specific for influenza A virus is broad and multispecific[J/OL]. Hum Immunol,2000,61(5):438-452. DOI:10.1016/s0198-8859(00)00105-1.
[21]Assarsson E,Bui H H,Sidney J,Zhang Q,Glenn J,Oseroff C,Mbawuike I N,Alexander J,Newman M J,Grey H,Sette A. Immunomic analysis of the repertoire of T-cell specificities for influenza A virus in humans[J/OL]. J Virol,2008,82(24):12241-12251. DOI:10.1128/JVI.01563-08.
[22]Babon J A,Cruz J,Orphin L,Pazoles P,Co M D,Ennis F A,Terajima M. Genome-wide screening of human T-cell epitopes in influenza A virus reveals a broad spectrum of CD4(+)T-cell responses to internal proteins,hemagglutinins,and neuraminidases[J/OL].Hum Immunol,2009,70(9):711-721. DOI:10.1016/j.humimm.2009.06.004.
[23]Liu J,Zhang S,Tan S,Yi Y,Wu B,Cao B,Zhu F,Wang C, Wang H, Qi J, Gao G F. Cross-allele cytotoxic T lymphocyte responses against 2009pandemic H1N1 influenza A virus among HLA-A24 and HLA-A3 supertype-positive individuals[J/OL]. J Virol,2012,86(24):13281-13294. DOI:10.1128/JVI.01841-12.
[24]Ge X,Tan V,Bollyky P L,Standifer N E,James E A,Kwok W W. Assessment of seasonal influenza A virus-specific CD4 T-cell responses to 2009 pandemic H1N1 swine-origin influenza A virus[J/OL]. J Virol,2010,84(7):3312-3319. DOI:10.1128/JVI.02226-09.
[25]Ge X,Gebe J A,Bollyky P L,James E A,Yang J,Stern L J, Kwok W W. Peptide-MHC cellular microarray with innovative data analysis system for simultaneously detecting multiple CD4 T-cell responses[J/OL]. PLoS One, 2010, 5(6):e11355. DOI:10.1371/journal.pone.0011355.
[26]Roti M,Yang J,Berger D,Huston L,James E A,Kwok W W. Healthy human subjects have CD4+T cells directed against H5N1 influenza virus[J/OL]. J Immunol,2008,180(3):1758-1768. DOI:10.4049/jimmunol.180.3.1758.
[27]Zhang Z Y,Li M,Zhang X Y,Zheng N,Zhao S G,Wang J Q. A novel urease inhibitor of ruminal microbiota screened through molecular docking[J/OL].Inter J Mol Sci, 2020, 21(17). DOI:10.3390/ijms21176006.
[28]Seffernick J T,Harvey S R,Wysocki V H,Lindert S.Predicting protein complex structure from surfaceinduced dissociation mass spectrometry data[J/OL].Acs Central Science,2019,5(8):1330-1341. DOI:10.1021/acscentsci.8b00912.
[29]张立霞，周剑芳，于在江，舒跃龙.杆状病毒表面展示甲型流感病毒核蛋白的免疫原性及保护效果的初步评价[J/OL].病毒学报，2013,29(3):265-272. DOI:10.13242/j.cnki.bingduxuebao.002385.
[30]Krammer F. The Quest for a Universal Flu Vaccine:Headless HA 2.0[J/OL]. Cell Host Microbe,2015,18(4):395-397. DOI:10.1016/j.chom.2015.10.003.
[31]Krammer F,Pica N,Hai R,Margine I,Palese P.Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies[J/OL]. J Virol,2013,87(12):6542-6550.DOI:10.1128/JVI.00641-13.
[32]Schulman J L,Khakpour M,Kilbourne E D. Protective effects of specific immunity to viral neuraminidase on influenza virus infection of mice[J/OL]. J Virol,1968,2(8):778-786. DOI:10.1128/JVI.2.8.778-786.1968.
[33]Couch R B,Kasel J A,Gerin J L,Schulman J L,Kilbourne E D. Induction of partial immunity to influenza by a neuraminidase-specific vaccine[J/OL]. J Infect Dis,1974,129(4):411-420. DOI:10.1093/infdis/129.4.411.
[34]Johansson B E,Grajower B,Kilbourne E D. Infectionpermissive immunization with influenza virus neuraminidase prevents weight loss in infected mice[J/OL]. Vaccine, 1993, 11(10):1037-1039. DOI:10.1016/0264-410x(93)90130-p.
[35]Kilbourne E D,Couch R B,Kasel J A,Keitel W A,Cate T R,Quarles J H,Grajower B,Pokorny B A,Johansson B E. Purified influenza A virus N2neuraminidase vaccine is immunogenic and non-toxic in humans[J/OL]. Vaccine,1995,13(18):1799-1803.DOI:10.1016/0264-410x(95)00127-m.
[36]Krammer F,Palese P. Influenza virus hemagglutinin stalk-based antibodies and vaccines[J/OL]. Curr Opin Virol, 2013, 3(5):521-530. DOI:10.1016/j.coviro.2013.07.007.
[37]Barouch D H,O'Brien K L,Simmons N L,King S L,Abbink P,Maxfield L F,Sun Y H,La Porte A,Riggs A M,Lynch D M,Clark S L,Backus K,Perry J R,Seaman M S,Carville A,Mansfield K G,Szinger J J,Fischer W,Muldoon M,Korber B. Mosaic HIV-1vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys[J/OL]. Nat Med,2010,16(3):319-323. DOI:10.1038/nm.2089.
[38]Korber B,Gnanakaran S. The implications of patterns in HIV diversity for neutralizing antibody induction and susceptibility[J/OL]. Curr Opin HIV AIDS,2009,4(5):408-417. DOI:10.1097/COH.0b013e32832f129e.
[39]成传刚，慕婷，袁军，谢铎源，李津，吴克.重组病毒载体疫苗研究进展[J/OL].中国病毒病杂志，2018,8:318-328. DOI:10.16505/j.2095-0136.2018.0024.
基本信息:
DOI：10.13242/j.cnki.bingduxuebao.004144
中图分类号:R392
引用信息:
[1]李瑞婷,李敏超,李彦君,等.利用马赛克策略设计靶向神经氨酸酶抗原的广谱流感疫苗[J].病毒学报,2022,38(03):543-553.DOI:10.13242/j.cnki.bingduxuebao.004144.
基金信息:
深圳市科技计划技术攻关重点项目（项目号：JSGG20200225152008136），题目：基于免疫原优化的广谱病毒疫苗研发~~
2022-05-10
2022-05-10
2022-05-10