Abstract
The emergence of new pathogens, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and Ebola virus, poses serious challenges to global public health and highlights the urgent need for novel antiviral approaches. Monoclonal antibodies (mAbs) have been successfully used to treat various diseases, particularly cancer and immunological disorders. Antigen-specific mAbs have been isolated using several different approaches, including hybridoma, transgenic mice, phage display, yeast display, and single B-cell isolation. Consequently, an increasing number of mAbs, which exhibit high potency against emerging viruses in vitro and in animal models of infection, have been developed. In this paper, we summarize historical trends and recent developments in mAb discovery, compare the advantages and disadvantages of various approaches to mAb production, and discuss the potential use of such strategies for the development of antivirals against emerging diseases. We also review the application of recently developed human mAbs against SARS-CoV, MERS-CoV, and Ebola virus and discuss prospects for the development of mAbs as therapeutic agents against emerging viral diseases.
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Drosten C, Günther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, Berger A, Burguière AM, Cinatl J, Eickmann M, Escriou N, Grywna K, Kramme S, Manuguerra JC, Müller S, Rickerts V, Stürmer M, Vieth S, Klenk HD, Osterhaus AD, Schmitz H, Doerr HW. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003; 348(20): 1967–1976
Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Ling AE, Humphrey CD, Shieh WJ, Guarner J, Paddock CD, Rota P, Fields B, De Risi J, Yang JY, Cox N, Hughes JM, Le Duc JW, Bellini WJ, Anderson LJ; SARS Working Group. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003; 348(20): 1953–1966
Peiris JS, Lai ST, Poon LL, Guan Y, Yam LY, Lim W, Nicholls J, Yee WK, Yan WW, Cheung MT, Cheng VC, Chan KH, Tsang DN, Yung RW, Ng TK, Yuen KY; SARS study group. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 2003; 361(9366): 1319–1325
Fouchier RA, Kuiken T, Schutten M, van Amerongen G, van Doornum GJ, van den Hoogen BG, Peiris M, Lim W, Stöhr K, Osterhaus AD. Aetiology: Koch’s postulates fulfilled for SARS virus. Nature 2003; 423(6937): 240
Kuiken T, Fouchier RA, Schutten M, Rimmelzwaan GF, van Amerongen G, van Riel D, Laman JD, de Jong T, van Doornum G, Lim W, Ling AE, Chan PK, Tam JS, Zambon MC, Gopal R, Drosten C, van der Werf S, Escriou N, Manuguerra JC, Stöhr K, Peiris JS, Osterhaus AD. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet 2003; 362(9380): 263–270
World Health Organization. WHO SARS Risk Assessment and Preparedness Framework. See www.who.int/entity/csr/resources/publications/CDS_CSR_ARO_2004_2.pdf. 2014
Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet 2011; 377(9768): 849–862
World Health Organization. Ebola Situation Report — 30 March 2016. See http://apps.who.int/ebola/current-situation/ebola-situation-report-30-march-2016. 2016
Lyon GM, Mehta AK, Varkey JB, Brantly K, Plyler L, McElroy AK, Kraft CS, Towner JS, Spiropoulou C, Ströher U, Uyeki TM, Ribner BS; Emory Serious Communicable Diseases Unit. Clinical care of two patients with Ebola virus disease in the United States. N Engl J Med 2014; 371(25): 2402–2409
Winau F, Winau R. Emil von Behring and serum therapy. Microbes Infect 2002; 4(2): 185–188
Berry JD, Gaudet RG. Antibodies in infectious diseases: polyclonals, monoclonals and niche biotechnology. N Biotechnol 2011; 28(5): 489–501
Casadevall A. Passive antibody therapies: progress and continuing challenges. Clin Immunol 1999; 93(1): 5–15
Dimitrov DS, Marks JD. Therapeutic antibodies: current state and future trends— is a paradigm change coming soon? Methods Mol Biol 2009; 525: 1–27, xiii
Zhu Z, Dimitrov AS, Chakraborti S, Dimitrova D, Xiao X, Broder CC, Dimitrov DS. Development of human monoclonal antibodies against diseases caused by emerging and biodefense-related viruses. Expert Rev Anti Infect Ther 2006; 4(1): 57–66
Shulman M, Wilde CD, Köhler G. A better cell line for making hybridomas secreting specific antibodies. Nature 1978; 276(5685): 269–270
Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 1985; 228(4705): 1315–1317
Smith GP, Petrenko VA. Phage Display. Chem Rev 1997; 97(2): 391–410
Gao C, Mao S, Kaufmann G, Wirsching P, Lerner RA, Janda KD. A method for the generation of combinatorial antibody libraries using pIX phage display. Proc Natl Acad Sci USA 2002; 99(20): 12612–12616
McCafferty J, Fitzgerald KJ, Earnshaw J, Chiswell DJ, Link J, Smith R, Kenten J. Selection and rapid purification of murine antibody fragments that bind a transition-state analog by phage display. Appl Biochem Biotechnol 1994; 47(2-3): 157–173
Davies EL, Smith JS, Birkett CR, Manser JM, Anderson-Dear DV, Young JR. Selection of specific phage-display antibodies using libraries derived from chicken immunoglobulin genes. J Immunol Methods 1995; 186(1): 125–135
Sok D, Briney B, Jardine JG, Kulp DW, Menis S, Pauthner M, Wood A, Lee EC, Le KM, Jones M, Ramos A, Kalyuzhniy O, Adachi Y, Kubitz M, MacPherson S, Bradley A, Friedrich GA, Schief WR, Burton DR. Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice. Science 2016; 353(6307): 1557–1560
Murphy AJ, Macdonald LE, Stevens S, Karow M, Dore AT, Pobursky K, Huang TT, Poueymirou WT, Esau L, Meola M, Mikulka W, Krueger P, Fairhurst J, Valenzuela DM, Papadopoulos N, Yancopoulos GD. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice. Proc Natl Acad Sci USA 2014; 111(14): 5153–5158
Lipke PN, Kurjan J. Sexual agglutination in budding yeasts: structure, function, and regulation of adhesion glycoproteins. Microbiol Rev 1992; 56(1): 180–194
Boder ET, Wittrup KD. Yeast surface display for directed evolution of protein expression, affinity, and stability. Methods Enzymol 2000; 328: 430–444
Boder ET, Wittrup KD. Yeast surface display for screening combinatorial polypeptide libraries. Nat Biotechnol 1997; 15(6): 553–557
Kieke MC, Cho BK, Boder ET, Kranz DM, Wittrup KD. Isolation of anti-T cell receptor scFv mutants by yeast surface display. Protein Eng 1997; 10(11): 1303–1310
Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science 2003; 301(5638): 1374–1377
Walker LM, Phogat SK, Chan-Hui PY, Wagner D, Phung P, Goss JL, Wrin T, Simek MD, Fling S, Mitcham JL, Lehrman JK, Priddy FH, Olsen OA, Frey SM, Hammond PW; Protocol G Principal Investigators, Kaminsky S, Zamb T, Moyle M, Koff WC, Poignard P, Burton DR. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 2009; 326(5950): 285–289
Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien JP, Wang SK, Ramos A, Chan-Hui PY, Moyle M, Mitcham JL, Hammond PW, Olsen OA, Phung P, Fling S, Wong CH, Phogat S, Wrin T, Simek MD; Protocol G Principal Investigators, Koff WC, Wilson IA, Burton DR, Poignard P. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 2011; 477(7365): 466–470
Traggiai E, Becker S, Subbarao K, Kolesnikova L, Uematsu Y, Gismondo MR, Murphy BR, Rappuoli R, Lanzavecchia A. An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nat Med 2004; 10(8): 871–875
Aman P, Ehlin-Henriksson B, Klein G. Epstein-Barr virus susceptibility of normal human B lymphocyte populations. J Exp Med 1984; 159(1): 208–220
Brès P. The epidemic of Ebola haemorrhagic fever in Sudan and Zaire, 1976: introductory note. Bull World Health Organ 1978; 56 (2): 245
Li H, Ying T, Yu F, Lu L, Jiang S. Development of therapeutics for treatment of Ebola virus infection. Microbes Infect 2015; 17(2): 109–117
Ka D, Fall G, Diallo VC, Faye O, Fortes LD, Faye O, Bah EI, Diallo KM, Balique F, Ndour CT, Seydi M, Sall AA. Ebola virus imported from Guinea to Senegal, 2014. Emerg Infect Dis 2017; 23(6): 1026–1028
Li YH, Chen SP. Evolutionary history of Ebola virus. Epidemiol Infect 2014; 142(6): 1138–1145
Huang Y, Xu L, Sun Y, Nabel GJ. The assembly of Ebola virus nucleocapsid requires virion-associated proteins 35 and 24 and posttranslational modification of nucleoprotein. Mol Cell 2002; 10(2): 307–316
Geisbert TW, Jahrling PB. Differentiation of filoviruses by electron microscopy. Virus Res 1995; 39(2-3): 129–150
Lee JE, Fusco ML, Hessell AJ, Oswald WB, Burton DR, Saphire EO. Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor. Nature 2008; 454(7201): 177–182
Hood CL, Abraham J, Boyington JC, Leung K, Kwong PD, Nabel GJ. Biochemical and structural characterization of cathepsin Lprocessed Ebola virus glycoprotein: implications for viral entry and immunogenicity. J Virol 2010; 84(6): 2972–2982
Richardson JS, Yao MK, Tran KN, Croyle MA, Strong JE, Feldmann H, Kobinger GP. Enhanced protection against Ebola virus mediated by an improved adenovirus-based vaccine. PLoS One 2009; 4(4): e5308
Jones SM, Feldmann H, Ströher U, Geisbert JB, Fernando L, Grolla A, Klenk HD, Sullivan NJ, Volchkov VE, Fritz EA, Daddario KM, Hensley LE, Jahrling PB, Geisbert TW. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat Med 2005; 11(7): 786–790
Warfield KL, Swenson DL, Olinger GG, Kalina WV, Aman MJ, Bavari S. Ebola virus-like particle-based vaccine protects nonhuman primates against lethal Ebola virus challenge. J Infect Dis 2007; 196 (Supplement_2): S430–S437
Dowling W, Thompson E, Badger C, Mellquist JL, Garrison AR, Smith JM, Paragas J, Hogan RJ, Schmaljohn C. Influences of glycosylation on antigenicity, immunogenicity, and protective efficacy of Ebola virus GP DNA vaccines. J Virol 2007; 81(4): 1821–1837
Qiu X, Fernando L, Alimonti JB, Melito PL, Feldmann F, Dick D, Ströher U, Feldmann H, Jones SM. Mucosal immunization of cynomolgus macaques with the VSVDeltaG/ZEBOVGP vaccine stimulates strong ebola GP-specific immune responses. PLoS One 2009; 4(5): e5547
Qiu X, Audet J, Wong G, Pillet S, Bello A, Cabral T, Strong JE, Plummer F, Corbett CR, Alimonti JB. Successful treatment of Ebola virus–infected cynomolgus macaques with monoclonal antibodies. Sci Transl Med 2012; 4(138): 138ra81
Olinger GG Jr, Pettitt J, Kim D, Working C, Bohorov O, Bratcher B, Hiatt E, Hume SD, Johnson AK, Morton J, Pauly M, Whaley KJ, Lear CM, Biggins JE, Scully C, Hensley L, Zeitlin L. Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Proc Natl Acad Sci USA 2012; 109(44): 18030–18035
Kugelman JR, Kugelman-Tonos J, Ladner JT, Pettit J, Keeton CM, Nagle ER, Garcia KY, Froude JW, Kuehne AI, Kuhn JH, Bavari S, Zeitlin L, Dye JM, Olinger GG, Sanchez-Lockhart M, Palacios GF. Emergence of Ebola virus escape variants in infected nonhuman primates treated with the MB-003 antibody cocktail. Cell Reports 2015; 12(12): 2111–2120
Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB, Fausther-Bovendo H, Wei H, Aviles J, Hiatt E, Johnson A, Morton J, Swope K, Bohorov O, Bohorova N, Goodman C, Kim D, Pauly MH, Velasco J, Pettitt J, Olinger GG, Whaley K, Xu B, Strong JE, Zeitlin L, Kobinger GP. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 2014; 514(7520): 47–53
Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, Ploquin A, Doria-Rose NA, Staupe RP, Bailey M, Shi W, Choe M, Marcus H, Thompson EA, Cagigi A, Silacci C, Fernandez-Rodriguez B, Perez L, Sallusto F, Vanzetta F, Agatic G, Cameroni E, Kisalu N, Gordon I, Ledgerwood JE, Mascola JR, Graham BS, Muyembe-Tamfun JJ, Trefry JC, Lanzavecchia A, Sullivan NJ. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science 2016; 351(6279): 1339–1342
Misasi J, Gilman MS, Kanekiyo M, Gui M, Cagigi A, Mulangu S, Corti D, Ledgerwood JE, Lanzavecchia A, Cunningham J, Muyembe-Tamfun JJ, Baxa U, Graham BS, Xiang Y, Sullivan NJ, McLellan JS. Structural and molecular basis for Ebola virus neutralization by protective human antibodies. Science 2016; 351(6279): 1343–1346
Dowall SD, Callan J, Zeltina A, Al-Abdulla I, Strecker T, Fehling SK, Krähling V, Bosworth A, Rayner E, Taylor I, Charlton S, Landon J, Cameron I, Hewson R, Nasidi A, Bowden TA, Carroll MW. Development of a cost-effective ovine polyclonal antibodybased product, EBOTAb, to treat Ebola virus infection. J Infect Dis 2016; 213(7): 1124–1133
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426(6965): 450–454
Poutanen SM, Low DE, Henry B, Finkelstein S, Rose D, Green K, Tellier R, Draker R, Adachi D, Ayers M, Chan AK, Skowronski DM, Salit I, Simor AE, Slutsky AS, Doyle PW, Krajden M, Petric M, Brunham RC, McGeer AJ; National Microbiology Laboratory, Canada; Canadian Severe Acute Respiratory Syndrome Study Team. Identification of severe acute respiratory syndrome in Canada. N Engl J Med 2003; 348(20): 1995–2005
Qin E, Zhu Q, Yu M, Fan B, Chang G, Si B, Yang B, Peng W, Jiang T, Liu B, Deng Y, Liu H, Zhang Y, Wang C, Li Y, Gan Y, Li X, Lü F, Tan G, Cao W, Yang R, Wang J, Li W, Xu Z, Li Y, Wu Q, Lin W, Chen W, Tang L, Deng Y, Han Y, Li C, Lei M, Li G, Li W, Lü H, Shi J, Tong Z, Zhang F, Li S, Liu B, Liu S, Dong W, Wang J, Wong GKS, Yu J, Yang H. A complete sequence and comparative analysis of a SARS-associated virus (Isolate BJ01). Chin Sci Bull 2003; 48(10): 941–948
Gallagher TM, Buchmeier MJ. Coronavirus spike proteins in viral entry and pathogenesis. Virology 2001; 279(2): 371–374
Moore KM, Jackwood MW, Hilt DA. Identification of amino acids involved in a serotype and neutralization specific epitope within the s1 subunit of avian infectious bronchitis virus. Arch Virol 1997; 142(11): 2249–2256
Sui J, Li W, Murakami A, Tamin A, Matthews LJ, Wong SK, Moore MJ, Tallarico ASC, Olurinde M, Choe H, Anderson LJ, Bellini WJ, Farzan M, Marasco WA. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc Natl Acad Sci USA 2004; 101(8): 2536–2541
Sui J, Li W, Roberts A, Matthews LJ, Murakami A, Vogel L, Wong SK, Subbarao K, Farzan M, Marasco WA. Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants. J Virol 2005; 79(10): 5900–5906
Yang ZY, Werner HC, Kong WP, Leung K, Traggiai E, Lanzavecchia A, Nabel GJ. Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses. Proc Natl Acad Sci USA 2005; 102(3): 797–801
Zhu Z, Chakraborti S, He Y, Roberts A, Sheahan T, Xiao X, Hensley LE, Prabakaran P, Rockx B, Sidorov IA, Corti D, Vogel L, Feng Y, Kim JO, Wang LF, Baric R, Lanzavecchia A, Curtis KM, Nabel GJ, Subbarao K, Jiang S, Dimitrov DS. Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodies. Proc Natl Acad Sci USA 2007; 104(29): 12123–12128
van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM, Osterhaus AD, Haagmans BL, Gorbalenya AE, Snijder EJ, Fouchier RA. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 2012; 3(6): e00473–e12
Al-Tawfiq JA, Memish ZA. Middle East respiratory syndrome coronavirus: epidemiology and disease control measures. Infect Drug Resist 2014; 7: 281–287
Butler D. Receptor for new coronavirus found. Nature 2013; 495(7440): 149–150
Peiris JS, Guan Y, Yuen KY. Severe acute respiratory syndrome. Nat Med 2004; 10(12 Suppl): S88–S97
Al-Tawfiq JA, Memish ZA. An update on Middle East respiratory syndrome: 2 years later. Expert Rev Respir Med 2015; 9(3): 327–335
Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y, Bao J, Zhang B, Shi Y, Yan J, Gao GF. Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature 2013; 500(7461): 227–231
Gorrell MD, Gysbers V, McCaughan GW. CD26: a multifunctional integral membrane and secreted protein of activated lymphocytes. Scand J Immunol 2001; 54(3): 249–264
Yang Y, Du L, Liu C, Wang L, Ma C, Tang J, Baric RS, Jiang S, Li F. Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. Proc Natl Acad Sci USA 2014; 111(34): 12516–12521
Ying T, Du L, Ju TW, Prabakaran P, Lau CC, Lu L, Liu Q, Wang L, Feng Y, Wang Y, Zheng BJ, Yuen KY, Jiang S, Dimitrov DS. Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. J Virol 2014; 88(14): 7796–7805
Jiang L, Wang N, Zuo T, Shi X, Poon KM, Wu Y, Gao F, Li D, Wang R, Guo J, Fu L, Yuen KY, Zheng BJ, Wang X, Zhang L. Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. Sci Transl Med 2014; 6(234): 234ra59
Tang XC, Agnihothram SS, Jiao Y, Stanhope J, Graham RL, Peterson EC, Avnir Y, Tallarico AS, Sheehan J, Zhu Q, Baric RS, Marasco WA. Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution. Proc Natl Acad Sci USA 2014; 111(19): E2018–E2026
Ying T, Prabakaran P, Du L, Shi W, Feng Y, Wang Y, Wang L, Li W, Jiang S, Dimitrov DS, Zhou T. Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody. Nat Commun 2015; 6: 8223
Corti D, Passini N, Lanzavecchia A, Zambon M. Rapid generation of a human monoclonal antibody to combat Middle East respiratory syndrome. J Infect Public Health 2016; 9(3): 231–235
Pascal KE, Coleman CM, Mujica AO, Kamat V, Badithe A, Fairhurst J, Hunt C, Strein J, Berrebi A, Sisk JM, Matthews KL, Babb R, Chen G, Lai KM, Huang TT, Olson W, Yancopoulos GD, Stahl N, Frieman MB, Kyratsous CA. Pre-and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. Proc Natl Acad Sci USA 2015; 112(28): 8738–8743
Bossart KN, Geisbert TW, Feldmann H, Zhu Z, Feldmann F, Geisbert JB, Yan L, Feng YR, Brining D, Scott D, Wang Y, Dimitrov AS, Callison J, Chan YP, Hickey AC, Dimitrov DS, Broder CC, Rockx B. A neutralizing human monoclonal antibody protects african green monkeys from hendra virus challenge. Sci Transl Med 2011; 3(105): 105ra103
Geisbert TW, Mire CE, Geisbert JB, Chan YP, Agans KN, Feldmann F, Fenton KA, Zhu Z, Dimitrov DS, Scott DP, Bossart KN, Feldmann H, Broder CC. Therapeutic treatment of Nipah virus infection in nonhuman primates with a neutralizing human monoclonal antibody. Sci Transl Med 2014; 6(242): 242ra82
Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7(9): 715–725
Wang L, Ying T. New directions for half-life extension of protein therapeutics: the rise of antibody Fc domains and fragments. Curr Pharm Biotechnol 2016; 17(15): 1348–1352
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Nos. 31570936, 81501735, and 81561128006), the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Technology Service Platform for detecting high-level biological safety pathogenic microorganisms supported by the Shanghai Science and Technology Commission (No. 15DZ2290200).
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Jin, Y., Lei, C., Hu, D. et al. Human monoclonal antibodies as candidate therapeutics against emerging viruses. Front. Med. 11, 462–470 (2017). https://doi.org/10.1007/s11684-017-0596-6
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DOI: https://doi.org/10.1007/s11684-017-0596-6