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Newly Emerging Human Coronaviruses: Animal Models and Vaccine Research for SARS, MERS, and COVID-19

  • Pureum Lee (Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Doo-Jin Kim (Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology)
  • Received : 2020.05.28
  • Accepted : 2020.06.29
  • Published : 2020.08.31

Abstract

The recent emergence of the novel coronavirus (CoV) or severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a global threat to human health and economy. As of June 26, 2020, over 9.4 million cases of infection, including 482,730 deaths, had been confirmed across 216 countries. To combat a devastating virus pandemic, numerous studies on vaccine development are urgently being accelerated. In this review article, we take a brief look at the characteristics of SARS-CoV-2 in comparison to SARS and Middle East respiratory syndrome (MERS)-CoVs and discuss recent approaches to coronavirus disease-2019 (COVID-19) vaccine development.

Keywords

Acknowledgement

This work was supported by grants of the Bio & Medical Technology Development Program (2016M3A9B6918675 and 2018M3A9H4077992) of the National Research Foundation of Korea (NRF) and the KRIBB Initiative program (KGM9942011), funded by the Korean government (Ministry of Science & ICT). We would like to thank Editage (www.editage.co.kr) for English language editing.

References

  1. Amanat F, Krammer F. SARS-CoV-2 vaccines: status report. Immunity 2020;52:583-589.
  2. Drosten C, Gunther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003;348:1967-1976.
  3. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012;367:1814-1820.
  4. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727-733.
  5. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020;5:536-544.
  6. Masters PS. The molecular biology of coronaviruses. Adv Virus Res 2006;66:193-292.
  7. Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 2019;17:181-192.
  8. Hofer U. Viral evolution: fooling the coronavirus proofreading machinery. Nat Rev Microbiol 2013;11:662-663.
  9. DeDiego ML, Nieto-Torres JL, Jimenez-Guardeno JM, Regla-Nava JA, Alvarez E, Oliveros JC, Zhao J, Fett C, Perlman S, Enjuanes L. Severe acute respiratory syndrome coronavirus envelope protein regulates cell stress response and apoptosis. PLoS Pathog 2011;7:e1002315.
  10. World Health Organization. Summary of probable SARS cases with onset of illness from 1 November 2002 to 1 July 2003 [Internet]. Available at https://www.who.int/csr/sars/country/table2004_04_21/en/ [accessed on 25 June 2020].
  11. Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, Law KI, Tang BS, Hon TY, Chan CS, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 2003;361:1767-1772.
  12. Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, Lit LC, Hui DS, Chan MH, Chung SS, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004;136:95-103.
  13. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-454.
  14. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004;203:631-637.
  15. Law HK, Cheung CY, Ng HY, Sia SF, Chan YO, Luk W, Nicholls JM, Peiris JS, Lau YL. Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood 2005;106:2366-2374.
  16. Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, Chu CM, Hui PK, Mak KL, Lim W, et al. Lung pathology of fatal severe acute respiratory syndrome. Lancet 2003;361:1773-1778.
  17. World Health Organization. MERS situation update, January 2020 [Internet]. Available at http://www.emro.who.int/health-topics/mers-cov/mers-outbreaks.html [accessed on 25 June 2020].
  18. Ki M. 2015 MERS outbreak in Korea: hospital-to-hospital transmission. Epidemiol Health 2015;37:e2015033.
  19. Arabi YM, Arifi AA, Balkhy HH, Najm H, Aldawood AS, Ghabashi A, Hawa H, Alothman A, Khaldi A, Al Raiy B. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. Ann Intern Med 2014;160:389-397.
  20. Zhou J, Li C, Zhao G, Chu H, Wang D, Yan HH, Poon VK, Wen L, Wong BH, Zhao X, et al. Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus. Sci Adv 2017;3:eaao4966.
  21. Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. Lancet 2015;386:995-1007.
  22. Ng DL, Al Hosani F, Keating MK, Gerber SI, Jones TL, Metcalfe MG, Tong S, Tao Y, Alami NN, Haynes LM, et al. Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the united Arab Emirates, April 2014. Am J Pathol 2016;186:652-658. 
  23. Alagaili AN, Briese T, Mishra N, Kapoor V, Sameroff SC, Burbelo PD, de Wit E, Munster VJ, Hensley LE, Zalmout IS, et al. Middle East respiratory syndrome coronavirus infection in dromedary camels in Saudi Arabia. MBio 2014;5:e00884-14.
  24. De Benedictis P, Marciano S, Scaravelli D, Priori P, Zecchin B, Capua I, Monne I, Cattoli G. Alpha and lineage C betaCoV infections in Italian bats. Virus Genes 2014;48:366-371.
  25. Wacharapluesadee S, Sintunawa C, Kaewpom T, Khongnomnan K, Olival KJ, Epstein JH, Rodpan A, Sangsri P, Intarut N, Chindamporn A, et al. Group C betacoronavirus in bat guano fertilizer, Thailand. Emerg Infect Dis 2013;19:1349-1351.
  26. Chowell G, Abdirizak F, Lee S, Lee J, Jung E, Nishiura H, Viboud C. Transmission characteristics of MERS and SARS in the healthcare setting: a comparative study. BMC Med 2015;13:210.
  27. Raj VS, Mou H, Smits SL, Dekkers DH, Muller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013;495:251-254.
  28. Meyerholz DK, Lambertz AM, McCray PB Jr. Dipeptidyl peptidase 4 distribution in the human respiratory tract: implications for the Middle East respiratory syndrome. Am J Pathol 2016;186:78-86.
  29. Lau SK, Lau CC, Chan KH, Li CP, Chen H, Jin DY, Chan JF, Woo PC, Yuen KY. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. J Gen Virol 2013;94:2679-2690.
  30. Tynell J, Westenius V, Ronkko E, Munster VJ, Melen K, Osterlund P, Julkunen I. Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells. J Gen Virol 2016;97:344-355.
  31. Zhou J, Chu H, Li C, Wong BH, Cheng ZS, Poon VK, Sun T, Lau CC, Wong KK, Chan JY, et al. Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis. J Infect Dis 2014;209:1331-1342.
  32. Min CK, Cheon S, Ha NY, Sohn KM, Kim Y, Aigerim A, Shin HM, Choi JY, Inn KS, Kim JH, et al. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci Rep 2016;6:25359.
  33. Wu JT, Leung K, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet 2020;395:689-697.
  34. World Health Organization. coronavirus disease (covid-19) pandemic [internet]. Available at https://www.who.int/emergencies/diseases/novel-coronavirus-2019 [accessed on 26 June 2020].
  35. Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, Zhong W, Hao P. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci 2020;63:457-460.
  36. Ji W, Wang W, Zhao X, Zai J, Li X. Cross-species transmission of the newly identified coronavirus 2019- nCoV. J Med Virol 2020;92:433-440.
  37. Lam TT, Jia N, Zhang YW, Shum MH, Jiang JF, Zhu HC, Tong YG, Shi YX, Ni XB, Liao YS, et al. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Nature 2020. doi: 10.1038/s41586-020-2169-0.
  38. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020;181:281-292.e6.
  39. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by fulllength human ACE2. Science 2020;367:1444-1448. 
  40. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 2020;5:562-569.
  41. Leung JM, Yang CX, Tam A, Shaipanich T, Hackett TL, Singhera GK, Dorscheid DR, Sin DD. ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. Eur Respir J 2020;55:2000688.
  42. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res 2020;116:1097-1100.
  43. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
  44. Lin L, Jiang X, Zhang Z, Huang S, Zhang Z, Fang Z, Gu Z, Gao L, Shi H, Mai L, et al. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut 2020;69:997-1001.
  45. Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C, Boscolo-Rizzo P. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA 2020;323:2089.
  46. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R, Jordan TX, Oishi K, Panis M, Sachs D, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020;181:1036-1045.e9.
  47. Vanderheiden A, Ralfs P, Chirkova T, Upadhyay AA, Zimmerman MG, Bedoya S, Aoued H, Tharpb GM, Pellegrini KL, Lowen AC, et al. Type I and type III IFN restrict SARS-CoV-2 infection of human airway epithelial cultures. bioRxiv 2020. doi: 10.1101/2020.05.19.105437.
  48. Konno Y, Kimura I, Uriu K, Fukushi M, Irie T, Koyanagi Y, Nakagawa S, Sato K. SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant. bioRxiv 2020. doi: 10.1101/2020.05.11.088179.
  49. Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, Cheng L, Li J, Wang X, Wang F, et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med 2020;26:842-844.
  50. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K, Shang K, Wang W, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis 2020. doi: 10.1093/cid/ciaa248.
  51. Zhang X, Tan Y, Ling Y, Lu G, Liu F, Yi Z, Jia X, Wu M, Shi B, Xu S, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature 2020. doi: 10.1038/s41586-020-2355-0.
  52. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, Chen L, Li M, Liu Y, Wang G, et al. Reduction and functional exhaustion of t cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol 2020;11:827.
  53. Li T, Qiu Z, Zhang L, Han Y, He W, Liu Z, Ma X, Fan H, Lu W, Xie J, et al. Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome. J Infect Dis 2004;189:648-651.
  54. Chu H, Zhou J, Wong BH, Li C, Chan JF, Cheng ZS, Yang D, Wang D, Lee AC, Li C, et al. Middle East respiratory syndrome coronavirus efficiently infects human primary t lymphocytes and activates the extrinsic and intrinsic apoptosis pathways. J Infect Dis 2016;213:904-914.
  55. Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, Xu Y, Tian Z. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol 2020;17:533-535.
  56. Wang LF, Shi Z, Zhang S, Field H, Daszak P, Eaton BT. Review of bats and SARS. Emerg Infect Dis 2006;12:1834-1840.
  57. Glass WG, Subbarao K, Murphy B, Murphy PM. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol 2004;173:4030-4039. 
  58. Hogan RJ, Gao G, Rowe T, Bell P, Flieder D, Paragas J, Kobinger GP, Wivel NA, Crystal RG, Boyer J, et al. Resolution of primary severe acute respiratory syndrome-associated coronavirus infection requires Stat1. J Virol 2004;78:11416-11421.
  59. Frieman M, Yount B, Agnihothram S, Page C, Donaldson E, Roberts A, Vogel L, Woodruff B, Scorpio D, Subbarao K, et al. Molecular determinants of severe acute respiratory syndrome coronavirus pathogenesis and virulence in young and aged mouse models of human disease. J Virol 2012;86:884-897.
  60. Roberts A, Paddock C, Vogel L, Butler E, Zaki S, Subbarao K. Aged BALB/c mice as a model for increased severity of severe acute respiratory syndrome in elderly humans. J Virol 2005;79:5833-5838.
  61. Zhao J, Zhao J, Legge K, Perlman S. Age-related increases in PGD2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J Clin Invest 2011;121:4921-4930.
  62. Yang XH, Deng W, Tong Z, Liu YX, Zhang LF, Zhu H, Gao H, Huang L, Liu YL, Ma CM, et al. Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection. Comp Med 2007;57:450-459.
  63. McCray PB Jr, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L, Shi L, Netland J, Jia HP, Halabi C, Sigmund CD, et al. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol 2007;81:813-821.
  64. Frieman MB, Chen J, Morrison TE, Whitmore A, Funkhouser W, Ward JM, Lamirande EW, Roberts A, Heise M, Subbarao K, et al. SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog 2010;6:e1000849.
  65. Sheahan T, Morrison TE, Funkhouser W, Uematsu S, Akira S, Baric RS, Heise MT. MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV. PLoS Pathog 2008;4:e1000240.
  66. Roberts A, Vogel L, Guarner J, Hayes N, Murphy B, Zaki S, Subbarao K. Severe acute respiratory syndrome coronavirus infection of golden Syrian hamsters. J Virol 2005;79:503-511.
  67. Chu YK, Ali GD, Jia F, Li Q, Kelvin D, Couch RC, Harrod KS, Hutt JA, Cameron C, Weiss SR, et al. The SARS-CoV ferret model in an infection-challenge study. Virology 2008;374:151-163.
  68. Martina BE, Haagmans BL, Kuiken T, Fouchier RA, Rimmelzwaan GF, Van Amerongen G, Peiris JS, Lim W, Osterhaus AD. Virology: SARS virus infection of cats and ferrets. Nature 2003;425:915.
  69. Rowe T, Gao G, Hogan RJ, Crystal RG, Voss TG, Grant RL, Bell P, Kobinger GP, Wivel NA, Wilson JM. Macaque model for severe acute respiratory syndrome. J Virol 2004;78:11401-11404.
  70. McAuliffe J, Vogel L, Roberts A, Fahle G, Fischer S, Shieh WJ, Butler E, Zaki S, St Claire M, Murphy B, et al. Replication of SARS coronavirus administered into the respiratory tract of African Green, rhesus and cynomolgus monkeys. Virology 2004;330:8-15.
  71. Lawler JV, Endy TP, Hensley LE, Garrison A, Fritz EA, Lesar M, Baric RS, Kulesh DA, Norwood DA, Wasieloski LP, et al. Cynomolgus macaque as an animal model for severe acute respiratory syndrome. PLoS Med 2006;3:e149.
  72. Greenough TC, Carville A, Coderre J, Somasundaran M, Sullivan JL, Luzuriaga K, Mansfield K. Pneumonitis and multi-organ system disease in common marmosets (Callithrix jacchus) infected with the severe acute respiratory syndrome-associated coronavirus. Am J Pathol 2005;167:455-463.
  73. Zhao J, Li K, Wohlford-Lenane C, Agnihothram SS, Fett C, Zhao J, Gale MJ Jr, Baric RS, Enjuanes L, Gallagher T, et al. Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci U S A 2014;111:4970-4975. 
  74. Agrawal AS, Garron T, Tao X, Peng BH, Wakamiya M, Chan TS, Couch RB, Tseng CT. Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease. J Virol 2015;89:3659-3670.
  75. Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, Gibson-Corley KN, Meyerholz DK, McCray PB Jr. Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis 2016;213:712-722.
  76. van Doremalen N, Munster VJ. Animal models of Middle East respiratory syndrome coronavirus infection. Antiviral Res 2015;122:28-38.
  77. Li K, Wohlford-Lenane CL, Channappanavar R, Park JE, Earnest JT, Bair TB, Bates AM, Brogden KA, Flaherty HA, Gallagher T, et al. Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice. Proc Natl Acad Sci U S A 2017;114:E3119-E3128.
  78. Cockrell AS, Yount BL, Scobey T, Jensen K, Douglas M, Beall A, Tang XC, Marasco WA, Heise MT, Baric RS. A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nat Microbiol 2016;2:16226.
  79. Adney DR, Bielefeldt-Ohmann H, Hartwig AE, Bowen RA. Infection, replication, and transmission of Middle East respiratory syndrome coronavirus in alpacas. Emerg Infect Dis 2016;22:1031-1037.
  80. Adney DR, van Doremalen N, Brown VR, Bushmaker T, Scott D, de Wit E, Bowen RA, Munster VJ. Replication and shedding of MERS-CoV in upper respiratory tract of inoculated dromedary camels. Emerg Infect Dis 2014;20:1999-2005.
  81. Munster VJ, de Wit E, Feldmann H. Pneumonia from human coronavirus in a macaque model. N Engl J Med 2013;368:1560-1562.
  82. Falzarano D, de Wit E, Feldmann F, Rasmussen AL, Okumura A, Peng X, Thomas MJ, van Doremalen N, Haddock E, Nagy L, et al. Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS Pathog 2014;10:e1004250.
  83. Yao Y, Bao L, Deng W, Xu L, Li F, Lv Q, Yu P, Chen T, Xu Y, Zhu H, et al. An animal model of MERS produced by infection of rhesus macaques with MERS coronavirus. J Infect Dis 2014;209:236-242.
  84. Bao L, Deng W, Huang B, Gao H, Liu J, Ren L, Wei Q, Yu P, Xu Y, Qi F, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature 2020. doi: 10.1038/s41586-020-2312-y
  85. Chan JF, Zhang AJ, Yuan S, Poon VK, Chan CC, Lee AC, Chan WM, Fan Z, Tsoi HW, Wen L, et al. Simulation of the clinical and pathological manifestations of coronavirus disease 2019 (COVID-19) in golden Syrian hamster model: implications for disease pathogenesis and transmissibility. Clin Infect Dis 2020. doi: 10.1093/cid/ciaa325.
  86. Kim YI, Kim SG, Kim SM, Kim EH, Park SJ, Yu KM, Chang JH, Kim EJ, Lee S, Casel MA, et al. Infection and rapid transmission of SARS-CoV-2 in ferrets. Cell Host Microbe 2020;27:704-709.e2.
  87. Shi J, Wen Z, Zhong G, Yang H, Wang C, Huang B, Liu R, He X, Shuai L, Sun Z, et al. Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science 2020;368:1016-1020.
  88. Rockx B, Kuiken T, Herfst S, Bestebroer T, Lamers MM, Oude Munnink BB, de Meulder D, van Amerongen G, van den Brand J, Okba NM, et al. Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model. Science 2020;368:1012-1015.
  89. Yu P, Qi F, Xu Y, Li F, Liu P, Liu J, Bao L, Deng W, Gao H, Xiang Z, et al. Age-related rhesus macaque models of COVID-19. Animal Model Exp Med 2020;3:93-97.
  90. Sun J, Zhuang Z, Zheng J, Li K, Wong RL, Liu D, Huang J, He J, Zhu A, Zhao J, et al. Generation of a broadly useful model for covid-19 pathogenesis, vaccination, and treatment. Cell 2020. doi: 10.1016/j.cell.2020.06.010. 
  91. Netland J, DeDiego ML, Zhao J, Fett C, Alvarez E, Nieto-Torres JL, Enjuanes L, Perlman S. Immunization with an attenuated severe acute respiratory syndrome coronavirus deleted in E protein protects against lethal respiratory disease. Virology 2010;399:120-128.
  92. Lamirande EW, DeDiego ML, Roberts A, Jackson JP, Alvarez E, Sheahan T, Shieh WJ, Zaki SR, Baric R, Enjuanes L, et al. A live attenuated severe acute respiratory syndrome coronavirus is immunogenic and efficacious in golden Syrian hamsters. J Virol 2008;82:7721-7724.
  93. Menachery VD, Yount BL Jr, Josset L, Gralinski LE, Scobey T, Agnihothram S, Katze MG, Baric RS. Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-O-methyltransferase activity. J Virol 2014;88:4251-4264.
  94. Almazan F, DeDiego ML, Sola I, Zuniga S, Nieto-Torres JL, Marquez-Jurado S, Andres G, Enjuanes L. Engineering a replication-competent, propagation-defective Middle East respiratory syndrome coronavirus as a vaccine candidate. MBio 2013;4:e00650-13.
  95. Menachery VD, Gralinski LE, Mitchell HD, Dinnon KH 3rd, Leist SR, Yount BL Jr, Graham RL, McAnarney ET, Stratton KG, Cockrell AS, et al. Middle East respiratory syndrome coronavirus nonstructural protein 16 is necessary for interferon resistance and viral pathogenesis. MSphere 2017;2:e00346-17.
  96. Takasuka N, Fujii H, Takahashi Y, Kasai M, Morikawa S, Itamura S, Ishii K, Sakaguchi M, Ohnishi K, Ohshima M, et al. A subcutaneously injected UV-inactivated SARS coronavirus vaccine elicits systemic humoral immunity in mice. Int Immunol 2004;16:1423-1430.
  97. Spruth M, Kistner O, Savidis-Dacho H, Hitter E, Crowe B, Gerencer M, Bruhl P, Grillberger L, Reiter M, Tauer C, et al. A double-inactivated whole virus candidate SARS coronavirus vaccine stimulates neutralising and protective antibody responses. Vaccine 2006;24:652-661.
  98. Kong WP, Xu L, Stadler K, Ulmer JB, Abrignani S, Rappuoli R, Nabel GJ. Modulation of the immune response to the severe acute respiratory syndrome spike glycoprotein by gene-based and inactivated virus immunization. J Virol 2005;79:13915-13923.
  99. Agrawal AS, Tao X, Algaissi A, Garron T, Narayanan K, Peng BH, Couch RB, Tseng CT. Immunization with inactivated Middle East respiratory syndrome coronavirus vaccine leads to lung immunopathology on challenge with live virus. Hum Vaccin Immunother 2016;12:2351-2356.
  100. Deng Y, Lan J, Bao L, Huang B, Ye F, Chen Y, Yao Y, Wang W, Qin C, Tan W. Enhanced protection in mice induced by immunization with inactivated whole viruses compare to spike protein of Middle East respiratory syndrome coronavirus. Emerg Microbes Infect 2018;7:60.
  101. Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M, Li Y, Zhu L, Wang N, Lv Z, et al. Development of an inactivated vaccine candidate for SARS-CoV-2. Science 2020.doi: 10.1126/science.abc1932.
  102. He Y, Lu H, Siddiqui P, Zhou Y, Jiang S. Receptor-binding domain of severe acute respiratory syndrome coronavirus spike protein contains multiple conformation-dependent epitopes that induce highly potent neutralizing antibodies. J Immunol 2005;174:4908-4915.
  103. He Y, Zhou Y, Liu S, Kou Z, Li W, Farzan M, Jiang S. Receptor-binding domain of SARS-CoV spike protein induces highly potent neutralizing antibodies: implication for developing subunit vaccine. Biochem Biophys Res Commun 2004;324:773-781.
  104. Bisht H, Roberts A, Vogel L, Subbarao K, Moss B. Neutralizing antibody and protective immunity to SARS coronavirus infection of mice induced by a soluble recombinant polypeptide containing an N-terminal segment of the spike glycoprotein. Virology 2005;334:160-165.
  105. He Y, Li J, Heck S, Lustigman S, Jiang S. Antigenic and immunogenic characterization of recombinant baculovirus-expressed severe acute respiratory syndrome coronavirus spike protein: implication for vaccine design. J Virol 2006;80:5757-5767. 
  106. Kam YW, Kien F, Roberts A, Cheung YC, Lamirande EW, Vogel L, Chu SL, Tse J, Guarner J, Zaki SR, et al. Antibodies against trimeric S glycoprotein protect hamsters against SARS-CoV challenge despite their capacity to mediate FcγRII-dependent entry into B cells in vitro. Vaccine 2007;25:729-740.
  107. Mou H, Raj VS, van Kuppeveld FJ, Rottier PJ, Haagmans BL, Bosch BJ. The receptor binding domain of the new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies. J Virol 2013;87:9379-9383.
  108. Lan J, Yao Y, Deng Y, Chen H, Lu G, Wang W, Bao L, Deng W, Wei Q, Gao GF, et al. Recombinant receptor binding domain protein induces partial protective immunity in rhesus macaques against Middle East respiratory syndrome coronavirus challenge. EBioMedicine 2015;2:1438-1446.
  109. Zhang N, Channappanavar R, Ma C, Wang L, Tang J, Garron T, Tao X, Tasneem S, Lu L, Tseng CT, et al. Identification of an ideal adjuvant for receptor-binding domain-based subunit vaccines against Middle East respiratory syndrome coronavirus. Cell Mol Immunol 2016;13:180-190.
  110. Tang J, Zhang N, Tao X, Zhao G, Guo Y, Tseng CT, Jiang S, Du L, Zhou Y. Optimization of antigen dose for a receptor-binding domain-based subunit vaccine against MERS coronavirus. Hum Vaccin Immunother 2015;11:1244-1250.
  111. Du L, Kou Z, Ma C, Tao X, Wang L, Zhao G, Chen Y, Yu F, Tseng CT, Zhou Y, et al. A truncated receptor-binding domain of MERS-CoV spike protein potently inhibits MERS-CoV infection and induces strong neutralizing antibody responses: implication for developing therapeutics and vaccines. PLoS One 2013;8:e81587.
  112. Tai W, Zhao G, Sun S, Guo Y, Wang Y, Tao X, Tseng CK, Li F, Jiang S, Du L, et al. A recombinant receptorbinding domain of MERS-CoV in trimeric form protects human dipeptidyl peptidase 4 (hDPP4) transgenic mice from MERS-CoV infection. Virology 2016;499:375-382.
  113. Ma C, Li Y, Wang L, Zhao G, Tao X, Tseng CT, Zhou Y, Du L, Jiang S. Intranasal vaccination with recombinant receptor-binding domain of MERS-CoV spike protein induces much stronger local mucosal immune responses than subcutaneous immunization: Implication for designing novel mucosal MERS vaccines. Vaccine 2014;32:2100-2108.
  114. Wang L, Shi W, Joyce MG, Modjarrad K, Zhang Y, Leung K, Lees CR, Zhou T, Yassine HM, Kanekiyo M, et al. Evaluation of candidate vaccine approaches for MERS-CoV. Nat Commun 2015;6:7712.
  115. Jiaming L, Yanfeng Y, Yao D, Yawei H, Linlin B, Baoying H, Jinghua Y, Gao GF, Chuan Q, Wenjie T. The recombinant N-terminal domain of spike proteins is a potential vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Vaccine 2017;35:10-18.
  116. Coleman CM, Liu YV, Mu H, Taylor JK, Massare M, Flyer DC, Smith GE, Frieman MB. Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice. Vaccine 2014;32:3169-3174.
  117. Coleman CM, Venkataraman T, Liu YV, Glenn GM, Smith GE, Flyer DC, Frieman MB. MERS-CoV spike nanoparticles protect mice from MERS-CoV infection. Vaccine 2017;35:1586-1589.
  118. Jung SY, Kang KW, Lee EY, Seo DW, Kim HL, Kim H, Kwon T, Park HL, Kim H, Lee SM, et al. Heterologous prime-boost vaccination with adenoviral vector and protein nanoparticles induces both Th1 and Th2 responses against Middle East respiratory syndrome coronavirus. Vaccine 2018;36:3468-3476.
  119. Mortola E, Roy P. Efficient assembly and release of SARS coronavirus-like particles by a heterologous expression system. FEBS Lett 2004;576:174-178.
  120. Lu B, Huang Y, Huang L, Li B, Zheng Z, Chen Z, Chen J, Hu Q, Wang H. Effect of mucosal and systemic immunization with virus-like particles of severe acute respiratory syndrome coronavirus in mice. Immunology 2010;130:254-261. 
  121. Lu X, Chen Y, Bai B, Hu H, Tao L, Yang J, Chen J, Chen Z, Hu Z, Wang H. Immune responses against severe acute respiratory syndrome coronavirus induced by virus-like particles in mice. Immunology 2007;122:496-502.
  122. Liu YV, Massare MJ, Barnard DL, Kort T, Nathan M, Wang L, Smith G. Chimeric severe acute respiratory syndrome coronavirus (SARS-CoV) S glycoprotein and influenza matrix 1 efficiently form virus-like particles (VLPs) that protect mice against challenge with SARS-CoV. Vaccine 2011;29:6606-6613.
  123. Wang C, Zheng X, Gai W, Zhao Y, Wang H, Wang H, Feng N, Chi H, Qiu B, Li N, et al. MERS-CoV viruslike particles produced in insect cells induce specific humoural and cellular imminity in rhesus macaques. Oncotarget 2017;8:12686-12694.
  124. Yang ZY, Kong WP, Huang Y, Roberts A, Murphy BR, Subbarao K, Nabel GJ. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature 2004;428:561-564.
  125. Hu H, Lu X, Tao L, Bai B, Zhang Z, Chen Y, Zheng F, Chen J, Chen Z, Wang H. Induction of specific immune responses by severe acute respiratory syndrome coronavirus spike DNA vaccine with or without interleukin-2 immunization using different vaccination routes in mice. Clin Vaccine Immunol 2007;14:894-901.
  126. Zakhartchouk AN, Liu Q, Petric M, Babiuk LA. Augmentation of immune responses to SARS coronavirus by a combination of DNA and whole killed virus vaccines. Vaccine 2005;23:4385-4391.
  127. Chunling M, Kun Y, Jian X, Jian Q, Hua S, Minsheng Z. Enhanced induction of SARS-CoV nucleocapsid protein-specific immune response using DNA vaccination followed by adenovirus boosting in BALB/c mice. Intervirology 2006;49:307-318.
  128. Hu H, Tao L, Wang Y, Chen L, Yang J, Wang H. Enhancing immune responses against SARS-CoV nucleocapsid DNA vaccine by co-inoculating interleukin-2 expressing vector in mice. Biotechnol Lett 2009;31:1685-1693.
  129. Muthumani K, Falzarano D, Reuschel EL, Tingey C, Flingai S, Villarreal DO, Wise M, Patel A, Izmirly A, Aljuaid A, et al. A synthetic consensus anti-spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates. Sci Transl Med 2015;7:301ra132.
  130. Al-Amri SS, Abbas AT, Siddiq LA, Alghamdi A, Sanki MA, Al-Muhanna MK, Alhabbab RY, Azhar EI, Li X, Hashem AM. Immunogenicity of candidate MERS-CoV DNA vaccines based on the spike protein. Sci Rep 2017;7:44875.
  131. Smith TR, Patel A, Ramos S, Elwood D, Zhu X, Yan J, Gary EN, Walker SN, Schultheis K, Purwar M, et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun 2020;11:2601.
  132. Yu J, Tostanoski LH, Peter L, Mercado NB, McMahan K, Mahrokhian SH, Nkolola JP, Liu J, Li Z, Chandrashekar A, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 2020. doi: 10.1126/science.abc6284.
  133. Czub M, Weingartl H, Czub S, He R, Cao J. Evaluation of modified vaccinia virus Ankara based recombinant SARS vaccine in ferrets. Vaccine 2005;23:2273-2279.
  134. Chen Z, Zhang L, Qin C, Ba L, Yi CE, Zhang F, Wei Q, He T, Yu W, Yu J, et al. Recombinant modified vaccinia virus Ankara expressing the spike glycoprotein of severe acute respiratory syndrome coronavirus induces protective neutralizing antibodies primarily targeting the receptor binding region. J Virol 2005;79:2678-2688.
  135. Bisht H, Roberts A, Vogel L, Bukreyev A, Collins PL, Murphy BR, Subbarao K, Moss B. Severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice. Proc Natl Acad Sci U S A 2004;101:6641-6646.
  136. Guo X, Deng Y, Chen H, Lan J, Wang W, Zou X, Hung T, Lu Z, Tan W. Systemic and mucosal immunity in mice elicited by a single immunization with human adenovirus type 5 or 41 vector-based vaccines carrying the spike protein of Middle East respiratory syndrome coronavirus. Immunology 2015;145:476-484. 
  137. Kim E, Okada K, Kenniston T, Raj VS, AlHajri MM, Farag EA, AlHajri F, Osterhaus AD, Haagmans BL, Gambotto A. Immunogenicity of an adenoviral-based Middle East respiratory syndrome coronavirus vaccine in BALB/c mice. Vaccine 2014;32:5975-5982.
  138. Dicks MD, Spencer AJ, Edwards NJ, Wadell G, Bojang K, Gilbert SC, Hill AV, Cottingham MG. A novel chimpanzee adenovirus vector with low human seroprevalence: improved systems for vector derivation and comparative immunogenicity. PLoS One 2012;7:e40385.
  139. Alharbi NK, Padron-Regalado E, Thompson CP, Kupke A, Wells D, Sloan MA, Grehan K, Temperton N, Lambe T, Warimwe G, et al. ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice. Vaccine 2017;35:3780-3788.
  140. Munster VJ, Wells D, Lambe T, Wright D, Fischer RJ, Bushmaker T, Saturday G, van Doremalen N, Gilbert SC, de Wit E, et al. Protective efficacy of a novel simian adenovirus vaccine against lethal MERS-CoV challenge in a transgenic human DPP4 mouse model. NPJ Vaccines 2017;2:28.
  141. Alharbi NK, Qasim I, Almasoud A, Aljami HA, Alenazi MW, Alhafufi A, Aldibasi OS, Hashem AM, Kasem S, Albrahim R, et al. Humoral immunogenicity and efficacy of a single dose of ChAdOx1 MERS vaccine candidate in dromedary camels. Sci Rep 2019;9:16292.
  142. Volz A, Kupke A, Song F, Jany S, Fux R, Shams-Eldin H, Schmidt J, Becker C, Eickmann M, Becker S, et al. Protective efficacy of recombinant modified vaccinia virus Ankara delivering Middle East respiratory syndrome coronavirus spike glycoprotein. J Virol 2015;89:8651-8656.
  143. Haagmans BL, van den Brand JM, Raj VS, Volz A, Wohlsein P, Smits SL, Schipper D, Bestebroer TM, Okba N, Fux R, et al. An orthopoxvirus-based vaccine reduces virus excretion after MERS-CoV infection in dromedary camels. Science 2016;351:77-81.
  144. Veit S, Jany S, Fux R, Sutter G, Volz A. CD8+  T cells responding to the Middle East respiratory syndrome coronavirus nucleocapsid protein delivered by vaccinia virus MVA in mice. Viruses 2018;10:718.
  145. Bodmer BS, Fiedler AH, Hanauer JR, Prufer S, Muhlebach MD. Live-attenuated bivalent measles virus-derived vaccines targeting Middle East respiratory syndrome coronavirus induce robust and multifunctional T cell responses against both viruses in an appropriate mouse model. Virology 2018;521:99-107.
  146. Malczyk AH, Kupke A, Prufer S, Scheuplein VA, Hutzler S, Kreuz D, Beissert T, Bauer S, Hubich-Rau S, Tondera C, et al. A highly immunogenic and protective Middle East respiratory syndrome coronavirus vaccine based on a recombinant measles virus vaccine platform. J Virol 2015;89:11654-11667.
  147. Wirblich C, Coleman CM, Kurup D, Abraham TS, Bernbaum JG, Jahrling PB, Hensley LE, Johnson RF, Frieman MB, Schnell MJ. One-health: a safe, efficient, dual-use vaccine for humans and animals against Middle East respiratory syndrome coronavirus and rabies virus. J Virol 2017;91:e02040-16.
  148. World Health Organization. Draft landscape of COVID-19 candidate vaccines [Internet]. Available at https://www.who.int/who-documents-detail/draft-landscape-of-covid-19-candidate-vaccines [accessed on 22 June 2020].
  149. Roberts A, Deming D, Paddock CD, Cheng A, Yount B, Vogel L, Herman BD, Sheahan T, Heise M, Genrich GL, et al. A mouse-adapted SARS-coronavirus causes disease and mortality in BALB/c mice. PLoS Pathog 2007;3:e5.
  150. Day CW, Baric R, Cai SX, Frieman M, Kumaki Y, Morrey JD, Smee DF, Barnard DL. A new mouseadapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo. Virology 2009;395:210-222.
  151. van Doremalen N, Miazgowicz KL, Milne-Price S, Bushmaker T, Robertson S, Scott D, Kinne J, McLellan JS, Zhu J, Munster VJ. Host species restriction of Middle East respiratory syndrome coronavirus through its receptor, dipeptidyl peptidase 4. J Virol 2014;88:9220-9232. 
  152. de Wit E, Prescott J, Baseler L, Bushmaker T, Thomas T, Lackemeyer MG, Martellaro C, Milne-Price S, Haddock E, Haagmans BL, et al. The Middle East respiratory syndrome coronavirus (MERS-CoV) does not replicate in Syrian hamsters. PLoS One 2013;8:e69127.
  153. Cockrell AS, Peck KM, Yount BL, Agnihothram SS, Scobey T, Curnes NR, Baric RS, Heise MT. Mouse dipeptidyl peptidase 4 is not a functional receptor for Middle East respiratory syndrome coronavirus infection. J Virol 2014;88:5195-5199.
  154. Lauring AS, Jones JO, Andino R. Rationalizing the development of live attenuated virus vaccines. Nat Biotechnol 2010;28:573-579.
  155. See RH, Zakhartchouk AN, Petric M, Lawrence DJ, Mok CP, Hogan RJ, Rowe T, Zitzow LA, Karunakaran KP, Hitt MM, et al. Comparative evaluation of two severe acute respiratory syndrome (SARS) vaccine candidates in mice challenged with SARS coronavirus. J Gen Virol 2006;87:641-650.
  156. Stadler K, Roberts A, Becker S, Vogel L, Eickmann M, Kolesnikova L, Klenk HD, Murphy B, Rappuoli R, Abrignani S, et al. SARS vaccine protective in mice. Emerg Infect Dis 2005;11:1312-1314.
  157. Qin E, Shi H, Tang L, Wang C, Chang G, Ding Z, Zhao K, Wang J, Chen Z, Yu M, et al. Immunogenicity and protective efficacy in monkeys of purified inactivated Vero-cell SARS vaccine. Vaccine 2006;24:1028-1034.
  158. Zhou J, Wang W, Zhong Q, Hou W, Yang Z, Xiao SY, Zhu R, Tang Z, Wang Y, Xian Q, et al. Immunogenicity, safety, and protective efficacy of an inactivated SARS-associated coronavirus vaccine in rhesus monkeys. Vaccine 2005;23:3202-3209.
  159. Crank MC, Ruckwardt TJ, Chen M, Morabito KM, Phung E, Costner PJ, Holman LA, Hickman SP, Berkowitz NM, Gordon IJ, et al. A proof of concept for structure-based vaccine design targeting RSV in humans. Science 2019;365:505-509.
  160. Valkenburg SA, Mallajosyula VV, Li OT, Chin AW, Carnell G, Temperton N, Varadarajan R, Poon LL. Stalking influenza by vaccination with pre-fusion headless HA mini-stem. Sci Rep 2016;6:22666.
  161. McLellan JS, Chen M, Joyce MG, Sastry M, Stewart-Jones GB, Yang Y, Zhang B, Chen L, Srivatsan S, Zheng A, et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 2013;342:592-598.
  162. Cheng C, Pancera M, Bossert A, Schmidt SD, Chen RE, Chen X, Druz A, Narpala S, Doria-Rose NA, McDermott AB, et al. Immunogenicity of a prefusion HIV-1 envelope trimer in complex with a quaternarystructure-specific antibody. J Virol 2015;90:2740-2755.
  163. Kushnir N, Streatfield SJ, Yusibov V. Virus-like particles as a highly efficient vaccine platform: diversity of targets and production systems and advances in clinical development. Vaccine 2012;31:58-83.
  164. Tang DC, DeVit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature 1992;356:152-154.
  165. Choi YJ, Hur SY, Kim TJ, Hong SR, Lee JK, Cho CH, Park KS, Woo JW, Sung YC, Suh YS, et al. A phase II, prospective, randomized, multicenter, open-label study of GX-188E, an HPV DNA vaccine, in patients with cervical intraepithelial neoplasia 3. Clin Cancer Res 2020;26:1616-1623.
  166. Gary EN, Weiner DB. DNA vaccines: prime time is now. Curr Opin Immunol 2020;65:21-27.
  167. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov 2018;17:261-279.
  168. Food and Drug Administration. Approval letter - Ervebo (Ebloa Zaire Vaccine, Live) [Internet]. Available at https://www.fda.gov/media/133757/download [accessed on 19 December 2019].
  169. Ura T, Okuda K, Shimada M. Developments in viral vector-based vaccines. Vaccines (Basel) 2014;2:624-641. 
  170. Du L, Zhao G, Lin Y, Sui H, Chan C, Ma S, He Y, Jiang S, Wu C, Yuen KY, et al. Intranasal vaccination of recombinant adeno-associated virus encoding receptor-binding domain of severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein induces strong mucosal immune responses and provides long-term protection against SARS-CoV infection. J Immunol 2008;180:948-956.
  171. Choi JH, Woo HM, Lee TY, Lee SY, Shim SM, Park WJ, Yang JS, Kim JA, Yun MR, Kim DW, et al. Characterization of a human monoclonal antibody generated from a B-cell specific for a prefusionstabilized spike protein of Middle East respiratory syndrome coronavirus. PLoS One 2020;15:e0232757.
  172. Widjaja I, Wang C, van Haperen R, Gutierrez-Alvarez J, van Dieren B, Okba NM, Raj VS, Li W, FernandezDelgado R, Grosveld F, et al. Towards a solution to MERS: protective human monoclonal antibodies targeting different domains and functions of the MERS-coronavirus spike glycoprotein. Emerg Microbes Infect 2019;8:516-530.
  173. Coughlin MM, Babcook J, Prabhakar BS. Human monoclonal antibodies to SARS-coronavirus inhibit infection by different mechanisms. Virology 2009;394:39-46.
  174. Channappanavar R, Fett C, Zhao J, Meyerholz DK, Perlman S. Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection. J Virol 2014;88:11034-11044.
  175. Zhao J, Zhao J, Perlman S. T cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice. J Virol 2010;84:9318-9325.
  176. Zhao J, Zhao J, Mangalam AK, Channappanavar R, Fett C, Meyerholz DK, Agnihothram S, Baric RS, David CS, Perlman S. Airway memory CD4+  T cells mediate protective immunity against emerging respiratory coronaviruses. Immunity 2016;44:1379-1391.
  177. Tirado SM, Yoon KJ. Antibody-dependent enhancement of virus infection and disease. Viral Immunol 2003;16:69-86.
  178. Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, He L, Chen Y, Wu J, Shi Z, et al. Molecular mechanism for antibody-dependent enhancement of coronavirus entry. J Virol 2020;94:e02015-19.
  179. Polack FP, Hoffman SJ, Crujeiras G, Griffin DE. A role for nonprotective complement-fixing antibodies with low avidity for measles virus in atypical measles. Nat Med 2003;9:1209-1213.
  180. Polack FP, Teng MN, Collins PL, Prince GA, Exner M, Regele H, Lirman DD, Rabold R, Hoffman SJ, Karp CL, et al. A role for immune complexes in enhanced respiratory syncytial virus disease. J Exp Med 2002;196:859-865.
  181. Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, Parrott RH. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 1969;89:422-434.
  182. Luo F, Liao FL, Wang H, Tang HB, Yang ZQ, Hou W. Evaluation of antibody-dependent enhancement of SARS-CoV infection in rhesus macaques immunized with an inactivated SARS-CoV vaccine. Virol Sin 2018;33:201-204.
  183. Houser KV, Broadbent AJ, Gretebeck L, Vogel L, Lamirande EW, Sutton T, Bock KW, Minai M, Orandle M, Moore IN, et al. Enhanced inflammation in New Zealand white rabbits when MERS-CoV reinfection occurs in the absence of neutralizing antibody. PLoS Pathog 2017;13:e1006565.
  184. Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, Cuomo-Dannenburg G, Thompson H, Walker PG, Fu H, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis 2020;20:669-677.
  185. Cruz-Valdez A, Valdez-Zapata G, Patel SS, Castelli FV, Garcia MG, Jansen WT, Arora AK, Heijnen E. MF59-adjuvanted influenza vaccine (FLUAD®) elicits higher immune responses than a non-adjuvanted influenza vaccine (Fluzone®): a randomized, multicenter, Phase III pediatric trial in Mexico. Hum Vaccin Immunother 2018;14:386-395. 
  186. Robertson CA, DiazGranados CA, Decker MD, Chit A, Mercer M, Greenberg DP. Fluzone® high-dose influenza vaccine. Expert Rev Vaccines 2016;15:1495-1505.
  187. Camilloni B, Basileo M, Valente S, Nunzi E, Iorio AM. Immunogenicity of intramuscular MF59-adjuvanted and intradermal administered influenza enhanced vaccines in subjects aged over 60: a literature review. Hum Vaccin Immunother 2015;11:553-563.
  188. Rogers TF, Zhao F, Huang D, Beutler N, Burns A, He WT, Limbo O, Smith C, Song G, Woehl J, et al. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science 2020. doi: 10.1126/science.abc7520.
  189. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A 2020;117:9490-9496.
  190. Chandrashekar A, Liu J, Martinot AJ, McMahan K, Mercado NB, Peter L, Tostanoski LH, Yu J, Maliga Z, Nekorchuk M, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science 2020. doi: 10.1126/science.abc4776.