Middle East respiratory syndrome coronavirus: a comprehensive review

Abstract

The Middle East respiratory syndrome coronavirus was first identified in 2012 and has since then remained uncontrolled. Cases have been mostly reported in the Middle East, however travel-associated cases and outbreaks have also occurred. Nosocomial and zoonotic transmission of the virus appear to be the most important routes. The infection is severe and highly fatal thus necessitating rapid and efficacious interventions. Here, we performed a comprehensive review of published literature and summarized the epidemiology of the virus. In addition, we summarized the virological aspects of the infection and reviewed the animal models used as well as vaccination and antiviral tested against it.

Keywords

MERS / coronavirus / review

References

[1] Hamre D, Procknow JJ. A new virus isolated from the human respiratory tract. Proc Soc Exp Biol Med 1966; 121(1): 190–193

[2] McIntosh K, Dees JH, Becker WB, Kapikian AZ, Chanock RM. Recovery in tracheal organ cultures of novel viruses from patients with respiratory disease. Proc Natl Acad Sci USA 1967; 57(4): 933–940

[3] 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

[4] Woo PC, Lau SK, Lam CS, Lau CC, Tsang AK, Lau JH, Bai R, Teng JL, Tsang CC, Wang M, Zheng BJ, Chan KH, Yuen KY. Discovery of seven novel Mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J Virol 2012; 86(7): 3995–4008

[5] 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(19): 1814–1820

[6] de Groot RJ, Baker SC, Baric RS, Brown CS, Drosten C, Enjuanes L, Fouchier RA, Galiano M, Gorbalenya AE, Memish ZA, Perlman S, Poon LL, Snijder EJ, Stephens GM, Woo PC, Zaki AM, Zambon M, Ziebuhr J. Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol 2013; 87(14): 7790–7792

[7] 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): e00473-12

[8] Cotten M, Watson SJ, Kellam P, Al-Rabeeah AA, Makhdoom HQ, Assiri A, Al-Tawfiq JA, Alhakeem RF, Madani H, AlRabiah FA, Al Hajjar S, Al-nassir WN, Albarrak A, Flemban H, Balkhy HH, Alsubaie S, Palser AL, Gall A, Bashford-Rogers R, Rambaut A, Zumla AI, Memish ZA. Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study. Lancet 2013; 382(9909): 1993–2002

[9] Bialek SR, Allen D, Alvarado-Ramy F, Arthur R, Balajee A, Bell D, Best S, Blackmore C, Breakwell L, Cannons A, Brown C, Cetron M, Chea N, Chommanard C, Cohen N, Conover C, Crespo A, Creviston J, Curns AT, Dahl R, Dearth S, DeMaria A, Echols F, Erdman DD, Feikin D, Frias M, Gerber SI, Gulati R, Hale C, Haynes LM, Heberlein-Larson L, Holton K, Ijaz K, Kapoor M, Kohl K, Kuhar DT, Kumar AM, Kundich M, Lippold S, Liu L, Lovchik JC, Madoff L, Martell S, Matthews S, Moore J, Murray LR, Onofrey S, Pallansch MA, Pesik N, Pham H, Pillai S, Pontones P, Pringle K, Pritchard S, Rasmussen S, Richards S, Sandoval M, Schneider E, Schuchat A, Sheedy K, Sherin K, Swerdlow DL, Tappero JW, Vernon MO, Watkins S, Watson J; Centers for Disease Control and Prevention (CDC). First confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in the United States, updated information on the epidemiology of MERS-CoV infection, and guidance for the public, clinicians, and public health authorities—May 2014. MMWR Morb Mortal Wkly Rep 2014; 63(19): 431–436

[10] Gorbalenya AE, Enjuanes L, Ziebuhr J, Snijder EJ. Nidovirales: evolving the largest RNA virus genome. Virus Res 2006; 117(1): 17–37

[11] Ziebuhr J, Snijder EJ, Gorbalenya AE. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol 2000; 81(Pt 4): 853–879

[12] Raj VS, Smits SL, Provacia LB, van den Brand JM, Wiersma L, Ouwendijk WJ, Bestebroer TM, Spronken MI, van Amerongen G, Rottier PJ, Fouchier RA, Bosch BJ, Osterhaus AD, Haagmans BL. Adenosine deaminase acts as a natural antagonist for dipeptidyl peptidase 4-mediated entry of the Middle East respiratory syndrome coronavirus. J Virol 2014; 88(3): 1834–1838

[13] Chan JF, Chan KH, Choi GK, To KK, Tse H, Cai JP, Yeung ML, Cheng VC, Chen H, Che XY, Lau SK, Woo PC, Yuen KY. Differential cell line susceptibility to the emerging novel human betacoronavirus 2c EMC/2012: implications for disease pathogenesis and clinical manifestation. J Infect Dis 2013; 207(11): 1743–1752

[14] Müller MA, Raj VS, Muth D, Meyer B, Kallies S, Smits SL, Wollny R, Bestebroer TM, Specht S, Suliman T, Zimmermann K, Binger T, Eckerle I, Tschapka M, Zaki AM, Osterhaus AD, Fouchier RA, Haagmans BL, Drosten C. Human coronavirus EMC does not require the SARS-coronavirus receptor and maintains broad replicative capability in mammalian cell lines. MBio 2012; 3(6): e00515-12

[15] Meyer B, García-Bocanegra I, Wernery U, Wernery R, Sieberg A, Müller MA, Drexler JF, Drosten C, Eckerle I. Serologic assessment of possibility for MERS-CoV infection in equids. Emerg Infect Dis 2015; 21(1): 181–182

[16] Du L, Zhao G, Kou Z, Ma C, Sun S, Poon VK, Lu L, Wang L, Debnath AK, Zheng BJ, Zhou Y, Jiang S. Identification of a receptor-binding domain in the S protein of the novel human coronavirus Middle East respiratory syndrome coronavirus as an essential target for vaccine development. J Virol 2013; 87(17): 9939–9942

[17] 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(16): 9379–9383

[18] Ma C, Wang L, Tao X, Zhang N, Yang Y, Tseng CT, Li F, Zhou Y, Jiang S, Du L. Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments—the importance of immunofocusing in subunit vaccine design. Vaccine 2014; 32(46): 6170–6176

[19] Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013; 495(7440): 251–254

[20] Chan JF, To KK, Tse H, Jin DY, Yuen KY. Interspecies transmission and emergence of novel viruses: lessons from bats and birds. Trends Microbiol 2013; 21(10): 544–555

[21] Lambeir AM, Durinx C, Scharpé S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci 2003; 40(3): 209–294

[22] Lu L, Liu Q, Zhu Y, Chan KH, Qin L, Li Y, Wang Q, Chan JF, Du L, Yu F, Ma C, Ye S, Yuen KY, Zhang R, Jiang S. Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. Nat Commun 2014; 5: 3067

[23] Gao J, Lu G, Qi J, Li Y, Wu Y, Deng Y, Geng H, Li H, Wang Q, Xiao H, Tan W, Yan J, Gao GF. Structure of the fusion core and inhibition of fusion by a heptad repeat peptide derived from the S protein of Middle East respiratory syndrome coronavirus. J Virol 2013; 87(24): 13134–13140

[24] Gierer S, Bertram S, Kaup F, Wrensch F, Heurich A, Krämer-Kühl A, Welsch K, Winkler M, Meyer B, Drosten C, Dittmer U, von Hahn T, Simmons G, Hofmann H, Pöhlmann S. The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies. J Virol 2013; 87(10): 5502–5511

[25] Gierer S, Müller MA, Heurich A, Ritz D, Springstein BL, Karsten CB, Schendzielorz A, Gnirß K, Drosten C, Pöhlmann S. Inhibition of proprotein convertases abrogates processing of the middle eastern respiratory syndrome coronavirus spike protein in infected cells but does not reduce viral infectivity. J Infect Dis 2015; 211(6): 889–897

[26] Qian Z, Dominguez SR, Holmes KV. Role of the spike glycoprotein of human Middle East respiratory syndrome coronavirus (MERS-CoV) in virus entry and syncytia formation. PLoS ONE 2013; 8(10): e76469

[27] Millet JK, Whittaker GR. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proc Natl Acad Sci USA 2014; 111(42): 15214–15219

[28] Thomas G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 2002; 3(10): 753–766

[29] de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW, Posthuma CC, van der Meer Y, Bárcena M, Haagmans BL, Snijder EJ, van den Hoogen BG. MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment. J Gen Virol 2013; 94(Pt 8): 1749–1760

[30] Lu L, Liu Q, Du L, Jiang S. Middle East respiratory syndrome coronavirus (MERS-CoV): challenges in identifying its source and controlling its spread. Microbes Infect 2013; 15(8-9): 625–629

[31] Lei J, Mesters JR, Drosten C, Anemüller S, Ma Q, Hilgenfeld R. Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features. Antiviral Res 2014; 109: 72–82

[32] Narayanan K, Maeda A, Maeda J, Makino S. Characterization of the coronavirus M protein and nucleocapsid interaction in infected cells. J Virol 2000; 74(17): 8127–8134

[33] Stadler K, Masignani V, Eickmann M, Becker S, Abrignani S, Klenk HD, Rappuoli R. SARS—beginning to understand a new virus. Nat Rev Microbiol 2003; 1(3): 209–218

[34] Coleman CM, Matthews KL, Goicochea L, Frieman MB. Wild-type and innate immune-deficient mice are not susceptible to the Middle East respiratory syndrome coronavirus. J Gen Virol 2014; 95(Pt 2): 408–412

[35] Zhao J, Li K, Wohlford-Lenane C, Agnihothram SS, Fett C, Zhao J, Gale MJ Jr, Baric RS, Enjuanes L, Gallagher T, McCray PB Jr, Perlman S. Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci USA 2014; 111(13): 4970–4975

[36] 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(7): 3659–3670

[37] 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

[38] Munster VJ, de Wit E, Feldmann H. Pneumonia from human coronavirus in a macaque model. N Engl J Med 2013; 368(16): 1560–1562

[39] 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(16): 9220–9232

[40] de Wit E, Rasmussen AL, Falzarano D, Bushmaker T, Feldmann F, Brining DL, Fischer ER, Martellaro C, Okumura A, Chang J, Scott D, Benecke AG, Katze MG, Feldmann H, Munster VJ. Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc Natl Acad Sci USA 2013; 110(41): 16598–16603

[41] Yao Y, Bao L, Deng W, Xu L, Li F, Lv Q, Yu P, Chen T, Xu Y, Zhu H, Yuan J, Gu S, Wei Q, Chen H, Yuen KY, Qin C. An animal model of MERS produced by infection of rhesus macaques with MERS coronavirus. J Infect Dis 2014; 209(2): 236–242

[42] Falzarano D, de Wit E, Feldmann F, Rasmussen AL, Okumura A, Peng X, Thomas MJ, van Doremalen N, Haddock E, Nagy L, LaCasse R, Liu T, Zhu J, McLellan JS, Scott DP, Katze MG, Feldmann H, Munster VJ. Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS Pathog 2014; 10(8): e1004250

[43] de Wit E, Prescott J, Baseler L, Bushmaker T, Thomas T, Lackemeyer MG, Martellaro C, Milne-Price S, Haddock E, Haagmans BL, Feldmann H, Munster VJ. The Middle East respiratory syndrome coronavirus (MERS-CoV) does not replicate in Syrian hamsters. PLoS ONE 2013; 8(7): e69127

[44] Haagmans BL, van den Brand JM, Provacia LB, Raj VS, Stittelaar KJ, Getu S, de Waal L, Bestebroer TM, van Amerongen G, Verjans GM, Fouchier RA, Smits SL, Kuiken T, Osterhaus AD. Asymptomatic Middle East respiratory syndrome coronavirus infection in rabbits. J Virol 2015; 89(11): 6131–6135

[45] ProMed-Mail: Novel coronavirus—Saudi Arabia: human isolate. Archive Number: 20120920.1302733. <Date>Published Date: 2012-09-20</Date>

[46] Wise J. Patient with new strain of coronavirus is treated in intensive care at London hospital. BMJ 2012; 345: e6455

[47] WHO. Novel coronavirus infection in the United Kingdom. 2012

[48] WHO. Middle East respiratory syndrome coronavirus (MERS-CoV)—Saudi Arabia. <Date>August 21</Date> 2015. Available from: www.who.int/csr/don/21-august-2015-mers-saudi-arabia/en/

[49] Cauchemez S, Fraser C, Van Kerkhove MD, Donnelly CA, Riley S, Rambaut A, Enouf V, van der Werf S, Ferguson NM. Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility. Lancet Infect Dis 2014; 14(1): 50–56

[50] WHO. MERS-CoV in the Republic of Korea at a glance. 2015

[51] WHO. Laboratory testing for Middle East respiratory syndrome coronavirus — Interim recommendations (revised). 2014

[52] WHO. Revised case definition for reporting to WHO—Middle East respiratory syndrome coronavirus—Interim case definition as of 14 July 2014. 2014

[53] CDC. Middle east respiratory syndrome (MERS), case definition. 2015

[54] WHO. Middle East respiratory syndrome coronavirus, case definition for reporting to WHO, interim case definition as of 14 July 2015. 2015

[55] WHO. Middle East respiratory syndrome coronavirus (MERS-CoV): summary of current situation, literature update and risk assessment. 2015

[56] CDC. Interim guidelines for collecting, handling, and testing clinical specimens from patients under investigation (PUIs) for Middle East respiratory syndrome coronavirus (MERS-CoV). 2014; Version 2.1

[57] Corman VM, Müller MA, Costabel U, Timm J, Binger T, Meyer B, Kreher P, Lattwein E, Eschbach-Bludau M, Nitsche A, Bleicker T, Landt O, Schweiger B, Drexler JF, Osterhaus AD, Haagmans BL, Dittmer U, Bonin F, Wolff T, Drosten C. Assays for laboratory confirmation of novel human coronavirus (hCoV-EMC) infections. Euro Surveill 2012; 17(49): 20334

[58] WHO. Laboratory testing for Middle East respiratory syndrome coronavirus. 2014

[59] Chan KH, Chan JF, Tse H, Chen H, Lau CC, Cai JP, Tsang AK, Xiao X, To KK, Lau SK, Woo PC, Zheng BJ, Wang M, Yuen KY. Cross-reactive antibodies in convalescent SARS patients’ sera against the emerging novel human coronavirus EMC (2012) by both immunofluorescent and neutralizing antibody tests. J Infect 2013; 67(2): 130–140

[60] Buchholz U, Müller MA, Nitsche A, Sanewski A, Wevering N, Bauer-Balci T, Bonin F, Drosten C, Schweiger B, Wolff T, Muth D, Meyer B, Buda S, Krause G, Schaade L, Haas W. Contact investigation of a case of human novel coronavirus infection treated in a German hospital, October-November 2012. Euro Surveill 2013; 18(8): 20406

[61] Reusken C, Mou H, Godeke GJ, van der Hoek L, Meyer B, Müller MA, Haagmans B, de Sousa R, Schuurman N, Dittmer U, Rottier P, Osterhaus A, Drosten C, Bosch BJ, Koopmans M. Specific serology for emerging human coronaviruses by protein microarray. Euro Surveill 2013; 18(14): 20441

[62] Drosten C, Meyer B, Müller MA, Corman VM, Al-Masri M, Hossain R, Madani H, Sieberg A, Bosch BJ, Lattwein E, Alhakeem RF, Assiri AM, Hajomar W, Albarrak AM, Al-Tawfiq JA, Zumla AI, Memish ZA. Transmission of MERS-coronavirus in household contacts. N Engl J Med 2014; 371(9): 828–835

[63] Perera RA, Wang P, Gomaa MR, El-Shesheny R, Kandeil A, Bagato O, Siu LY, Shehata MM, Kayed AS, Moatasim Y, Li M, Poon LL, Guan Y, Webby RJ, Ali MA, Peiris JS, Kayali G. Seroepidemiology for MERS coronavirus using microneutralisation and pseudoparticle virus neutralisation assays reveal a high prevalence of antibody in dromedary camels in Egypt, June 2013. Euro Surveill 2013; 18(36): 20574

[64] WHO. Laboratory testing for Middle East respiratory syndrome coronavirus. 2013

[65] Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, Al-Rabiah FA, Al-Hajjar S, Al-Barrak A, Flemban H, Al-Nassir WN, Balkhy HH, Al-Hakeem RF, Makhdoom HQ, Zumla AI, Memish ZA. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis 2013; 13(9): 752–761

[66] Mailles A, Blanckaert K, Chaud P, van der Werf S, Lina B, Caro V, Campese C, Guéry B, Prouvost H, Lemaire X, Paty MC, Haeghebaert S, Antoine D, Ettahar N, Noel H, Behillil S, Hendricx S, Manuguerra JC, Enouf V, La Ruche G, Semaille C, Coignard B, Lévy-Bruhl D, Weber F, Saura C, Che D; Investigation Team. First cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infections in France, investigations and implications for the prevention of human-to-human transmission, France, May 2013. Euro Surveill 2013; 18(24): 20502

[67] Cowling BJ, Park M, Fang VJ, Wu P, Leung GM, Wu JT. Preliminary epidemiological assessment of MERS-CoV outbreak in South Korea, May to June 2015. Euro Surveill 2015; 20(25): 21163

[68] CDC. Update: severe respiratory illness associated with Middle East respiratory syndrome coronavirus (MERS-CoV)—worldwide, 2012–2013. 2013

[69] Memish ZA, Zumla AI, Al-Hakeem RF, Al-Rabeeah AA, Stephens GM. Family cluster of Middle East respiratory syndrome coronavirus infections. N Engl J Med 2013; 368(26): 2487–2494

[70] Guery B, Poissy J, el Mansouf L, Séjourné C, Ettahar N, Lemaire X, Vuotto F, Goffard A, Behillil S, Enouf V, Caro V, Mailles A, Che D, Manuguerra JC, Mathieu D, Fontanet A, van der Werf S; MERS-CoV Study Group. Clinical features and viral diagnosis of two cases of infection with Middle East respiratory syndrome coronavirus: a report of nosocomial transmission. Lancet 2013; 381(9885): 2265–2272

[71] Drosten C. Is MERS another SARS? Lancet Infect Dis 2013; 13(9): 727–728

[72] Shalhoub S, Farahat F, Al-Jiffri A, Simhairi R, Shamma O, Siddiqi N, Mushtaq A. IFN-α2a or IFN-β1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother 2015; 70(7): 2129–2132

[73] Memish ZA, Al-Tawfiq JA, Assiri A, AlRabiah FA, Al Hajjar S, Albarrak A, Flemban H, Alhakeem RF, Makhdoom HQ, Alsubaie S, Al-Rabeeah AA. Middle East respiratory syndrome coronavirus disease in children. Pediatr Infect Dis J 2014; 33(9): 904–906

[74] Payne DC, Iblan I, Alqasrawi S, Al Nsour M, Rha B, Tohme RA, Abedi GR, Farag NH, Haddadin A, Al Sanhouri T, Jarour N, Swerdlow DL, Jamieson DJ, Pallansch MA, Haynes LM, Gerber SI, Al Abdallat MM; Jordan MERS-CoV Investigation Team. Sabri N, Al Azhari M, Khazali H, Al Maayah M, Bilbeisi A, Dawood N, Al Zubi B, Meflih J, Mounts T, Fitzner J, Eltom A, Mafi A, Miao C, Caidi H, Trivedi S, Kamili S, Hall AJ, Curns A, Moore J, Pham H, Zimmerman C, Farnon E, Giorgi G, Gerber R, Kuhar D. Stillbirth during infection with Middle East respiratory syndrome coronavirus. J Infect Dis 2014; 209(12): 1870–1872

[75] Memish ZA, Zumla AI, Assiri A. Middle East respiratory syndrome coronavirus infections in health care workers. N Engl J Med 2013; 369(9): 884–886

[76] Oboho IK, Tomczyk SM, Al-Asmari AM, Banjar AA, Al-Mugti H, Aloraini MS, Alkhaldi KZ, Almohammadi EL, Alraddadi BM, Gerber SI, Swerdlow DL, Watson JT, Madani TA. 2014 MERS-CoV outbreak in Jeddah—a link to health care facilities. N Engl J Med 2015; 372(9): 846–854

[77] Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA, Cummings DA, Alabdullatif ZN, Assad M, Almulhim A, Makhdoom H, Madani H, Alhakeem R, Al-Tawfiq JA, Cotten M, Watson SJ, Kellam P, Zumla AI, Memish ZA; KSA MERS-CoV Investigation Team. Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med 2013; 369(5): 407–416

[78] Müller MA, Meyer B, Corman VM, Al-Masri M, Turkestani A, Ritz D, Sieberg A, Aldabbagh S, Bosch BJ, Lattwein E, Alhakeem RF, Assiri AM, Albarrak AM, Al-Shangiti AM, Al-Tawfiq JA, Wikramaratna P, Alrabeeah AA, Drosten C, Memish ZA. Presence of Middle East respiratory syndrome coronavirus antibodies in Saudi Arabia: a nationwide, cross-sectional, serological study. Lancet Infect Dis 2015; 15(6): 629

[79] Abroug F, Slim A, Ouanes-Besbes L, Hadj Kacem MA, Dachraoui F, Ouanes I, Lu X, Tao Y, Paden C, Caidi H, Miao C, Al-Hajri MM, Zorraga M, Ghaouar W, BenSalah A, Gerber SI; World Health Organization Global Outbreak Alert and Response Network Middle East Respiratory Syndrome Coronavirus International Investigation Team. Family cluster of Middle East respiratory syndrome coronavirus infections, Tunisia, 2013. Emerg Infect Dis 2014; 20(9): 1527–1530

[80] Hui DS, Perlman S, Zumla A. Spread of MERS to South Korea and China. Lancet Respir Med 2015; 3(7): 509–510

[81] WHO. Summary and risk assessment of current situation in Republic of Korea and China. 2015

[82] CDC. Health Alert Network. Notice to health care providers: updated Guidelines for Evaluation of Severe Respiratory Illness Associated with Middle East respiratory syndrome coronavirus (MERS-CoV). 2013

[83] Park HY, Lee EJ, Ryu YW, Kim Y, Kim H, Lee H, Yi SJ. Epidemiological investigation of MERS-CoV spread in a single hospital in South Korea, May to June 2015. Euro Surveill 2015; 20(25): 21169

[84] Breban R, Riou J, Fontanet A. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk. Lancet 2013; 382(9893): 694–699

[85] Bauch CT, Oraby T. Assessing the pandemic potential of MERS-CoV. Lancet 2013; 382(9893): 662–664

[86] Azhar EI, El-Kafrawy SA, Farraj SA, Hassan AM, Al-Saeed MS, Hashem AM, Madani TA. Evidence for camel-to-human transmission of MERS coronavirus. N Engl J Med 2014; 370(26): 2499–2505

[87] Al-Gethamy M, Corman VM, Hussain R, Al-Tawfiq JA, Drosten C, Memish ZA. A case of long-term excretion and subclinical infection with Middle East respiratory syndrome coronavirus in a healthcare worker. Clin Infect Dis 2015; 60(6): 973–974

[88] Rha B, Rudd J, Feikin D, Watson J, Curns AT, Swerdlow DL, Pallansch MA, Gerber SI; Centers for Disease Control and Prevention (CDC). Update on the epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, and guidance for the public, clinicians, and public health authorities—January 2015. MMWR Morb Mortal Wkly Rep 2015; 64(3): 61–62

[89] Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. Lancet 2015; 386(9997): 995–1007

[90] WHO. Middle East respiratory syndrome coronavirus (MERS-CoV): summary of current situation, literature update and risk assessment—as of 5 February 2015. 2015

[91] Al-Abdallat MM, Payne DC, Alqasrawi S, Rha B, Tohme RA, Abedi GR, Al Nsour M, Iblan I, Jarour N, Farag NH, Haddadin A, Al-Sanouri T, Tamin A, Harcourt JL, Kuhar DT, Swerdlow DL, Erdman DD, Pallansch MA, Haynes LM, Gerber SI; Jordan MERS-CoV Investigation Team.Sabri N, Al Azhari M, Khazali H, Al Maayah M, Bilbeisi A, Dawood N, Al Zubi B, Meflih J, Mounds T, Fitzner J, Eltom A, Mafi A, Miao C, Caidi H, Trivedi S, Kamili S, Hall AJ, Curns A, Moore J, Pham H, Zimmerman C, Farnon E, Giorgi G, Gerber R. Hospital-associated outbreak of Middle East respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description. Clin Infect Dis 2014; 59(9): 1225–1233

[92] Bermingham A, Chand MA, Brown CS, Aarons E, Tong C, Langrish C, Hoschler K, Brown K, Galiano M, Myers R, Pebody RG, Green HK, Boddington NL, Gopal R, Price N, Newsholme W, Drosten C, Fouchier RA, Zambon M. Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012. Euro Surveill 2012; 17(40): 20290

[93] WHO. WHO risk assessment. Middle East respiratory syndrome coronavirus (MERS-CoV). 2014

[94] Hemida MG, Chu DK, Poon LL, Perera RA, Alhammadi MA, Ng HY, Siu LY, Guan Y, Alnaeem A, Peiris M. MERS coronavirus in dromedary camel herd, Saudi Arabia. Emerg Infect Dis 2014; 20(7): 1231–1234

[95] Hemida MG, Perera RA, Al Jassim RA, Kayali G, Siu LY, Wang P, Chu KW, Perlman S, Ali MA, Alnaeem A, Guan Y, Poon LL, Saif L, Peiris M. Seroepidemiology of Middle East respiratory syndrome (MERS) coronavirus in Saudi Arabia (1993) and Australia (2014) and characterisation of assay specificity. Euro Surveill 2014; 19(23): 20828

[96] Corman VM, Ithete NL, Richards LR, Schoeman MC, Preiser W, Drosten C, Drexler JF. Rooting the phylogenetic tree of middle East respiratory syndrome coronavirus by characterization of a conspecific virus from an African bat. J Virol 2014; 88(19): 11297–11303

[97] Memish ZA, Mishra N, Olival KJ, Fagbo SF, Kapoor V, Epstein JH, Alhakeem R, Durosinloun A, Al Asmari M, Islam A, Kapoor A, Briese T, Daszak P, Al Rabeeah AA, Lipkin WI. Middle East respiratory syndrome coronavirus in bats, Saudi Arabia. Emerg Infect Dis 2013; 19(11): 1819–1823

[98] Annan A, Baldwin HJ, Corman VM, Klose SM, Owusu M, Nkrumah EE, Badu EK, Anti P, Agbenyega O, Meyer B, Oppong S, Sarkodie YA, Kalko EK, Lina PH, Godlevska EV, Reusken C, Seebens A, Gloza-Rausch F, Vallo P, Tschapka M, Drosten C, Drexler JF. Human betacoronavirus 2c EMC/2012-related viruses in bats, Ghana and Europe. Emerg Infect Dis 2013; 19(3): 456–459

[99] Ithete NL, Stoffberg S, Corman VM, Cottontail VM, Richards LR, Schoeman MC, Drosten C, Drexler JF, Preiser W. Close relative of human Middle East respiratory syndrome coronavirus in bat, South Africa. Emerg Infect Dis 2013; 19(10): 1697–1699

[100] The Lancet Infectious Diseases. Need for global cooperation in control of MERS-CoV. Lancet Infect Dis 2013; 13(8): 639

[101] Reusken CB, Ababneh M, Raj VS, Meyer B, Eljarah A, Abutarbush S, Godeke GJ, Bestebroer TM, Zutt I, Muller MA, Bosch BJ, Rottier PJ, Osterhaus AD, Drosten C, Haagmans BL, Koopmans MP. Middle East respiratory syndrome coronavirus (MERS-CoV) serology in major livestock species in an affected region in Jordan, June to September 2013. Euro Surveill 2013; 18(50): 20662

[102] Reusken CB, Haagmans BL, Müller MA, Gutierrez C, Godeke GJ, Meyer B, Muth D, Raj VS, Smits-De Vries L, Corman VM, Drexler JF, Smits SL, El Tahir YE, De Sousa R, van Beek J, Nowotny N, van Maanen K, Hidalgo-Hermoso E, Bosch BJ, Rottier P, Osterhaus A, Gortázar-Schmidt C, Drosten C, Koopmans MP. Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. Lancet Infect Dis 2013; 13(10): 859–866

[103] Aburizaiza AS, Mattes FM, Azhar EI, Hassan AM, Memish ZA, Muth D, Meyer B, Lattwein E, Müller MA, Drosten C. Investigation of anti-middle East respiratory syndrome antibodies in blood donors and slaughterhouse workers in Jeddah and Makkah, Saudi Arabia, fall 2012. J Infect Dis 2014; 209(2): 243–246

[104] Meyer B, Müller MA, Corman VM, Reusken CB, Ritz D, Godeke GJ, Lattwein E, Kallies S, Siemens A, van Beek J, Drexler JF, Muth D, Bosch BJ, Wernery U, Koopmans MP, Wernery R, Drosten C. Antibodies against MERS coronavirus in dromedary camels, United Arab Emirates, 2003 and 2013. Emerg Infect Dis 2014; 20(4): 552–559

[105] Chan SM, Damdinjav B, Perera RA, Chu DK, Khishgee B, Enkhbold B, Poon LL, Peiris M. Absence of MERS-Coronavirus in Bactrian Camels, Southern Mongolia, November 2014. Emerg Infect Dis 2015; 21(7): 1269–1271

[106] M�ller MA, Corman VM, Jores J, Meyer B, Younan M, Liljander A, Bosch BJ, Lattwein E, Hilali M, Musa BE, Bornstein S, Drosten C. MERS coronavirus neutralizing antibodies in camels, Eastern Africa, 1983–1997. Emerg Infect Dis 2014; 20(12): 2093–2095

[107] Chu DK, Poon LL, Gomaa MM, Shehata MM, Perera RA, Abu Zeid D, El Rifay AS, Siu LY, Guan Y, Webby RJ, Ali MA, Peiris M, Kayali G. MERS coronaviruses in dromedary camels, Egypt. Emerg Infect Dis 2014; 20(6): 1049–1053

[108] Haagmans BL, Al Dhahiry SH, Reusken CB, Raj VS, Galiano M, Myers R, Godeke GJ, Jonges M, Farag E, Diab A, Ghobashy H, Alhajri F, Al-Thani M, Al-Marri SA, Al Romaihi HE, Al Khal A, Bermingham A, Osterhaus AD, AlHajri MM, Koopmans MP. Middle East respiratory syndrome coronavirus in dromedary camels: an outbreak investigation. Lancet Infect Dis 2014; 14(2): 140–145

[109] Hemida MG, Perera RA, Wang P, Alhammadi MA, Siu LY, Li M, Poon LL, Saif L, Alnaeem A, Peiris M. Middle East Respiratory Syndrome (MERS) coronavirus seroprevalence in domestic livestock in Saudi Arabia, 2010 to 2013. Euro Surveill 2013; 18(50): 20659

[110] Alexandersen S, Kobinger GP, Soule G, Wernery U. Middle East respiratory syndrome coronavirus antibody reactors among camels in Dubai, United Arab Emirates, in 2005. Transbound Emerg Dis 2014; 61(2): 105–108

[111] Reusken CB, Messadi L, Feyisa A, Ularamu H, Godeke GJ, Danmarwa A, Dawo F, Jemli M, Melaku S, Shamaki D, Woma Y, Wungak Y, Gebremedhin EZ, Zutt I, Bosch BJ, Haagmans BL, Koopmans MP. Geographic distribution of MERS coronavirus among dromedary camels, Africa. Emerg Infect Dis 2014; 20(8): 1370–1374

[112] Corman VM, Jores J, Meyer B, Younan M, Liljander A, Said MY, Gluecks I, Lattwein E, Bosch BJ, Drexler JF, Bornstein S, Drosten C, Müller MA. Antibodies against MERS coronavirus in dromedary camels, Kenya, 1992–2013. Emerg Infect Dis 2014; 20(8): 1319–1322

[113] 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(12): 1999–2005

[114] Alagaili AN, Briese T, Mishra N, Kapoor V, Sameroff SC, Burbelo PD, de Wit E, Munster VJ, Hensley LE, Zalmout IS, Kapoor A, Epstein JH, Karesh WB, Daszak P, Mohammed OB, Lipkin WI. Middle East respiratory syndrome coronavirus infection in dromedary camels in Saudi Arabia. MBio 2014; 5(2): e00884–e14

[115] Gierer S, Hofmann-Winkler H, Albuali WH, Bertram S, Al-Rubaish AM, Yousef AA, Al-Nafaie AN, Al-Ali AK, Obeid OE, Alkharsah KR, Pöhlmann S. Lack of MERS coronavirus neutralizing antibodies in humans, eastern province, Saudi Arabia. Emerg Infect Dis 2013; 19(12): 2034–2036

[116] 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(18): 2100–2108

[117] 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

[118] Du L, Kou Z, Ma C, Tao X, Wang L, Zhao G, Chen Y, Yu F, Tseng CT, Zhou Y, Jiang S. 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(12): e81587

[119] Zhao G, Du L, Ma C, Li Y, Li L, Poon VK, Wang L, Yu F, Zheng BJ, Jiang S, Zhou Y. A safe and convenient pseudovirus-based inhibition assay to detect neutralizing antibodies and screen for viral entry inhibitors against the novel human coronavirus MERS-CoV. Virol J 2013; 10(1): 266

[120] Lan J, Deng Y, Chen H, Lu G, Wang W, Guo X, Lu Z, Gao GF, Tan W. Tailoring subunit vaccine immunity with adjuvant combinations and delivery routes using the Middle East respiratory coronavirus (MERS-CoV) receptor-binding domain as an antigen. PLoS ONE 2014; 9(11): e112602

[121] Coleman CM, Liu YV, Mu H, Taylor JK, Massare M, Flyer DC, Glenn GM, Smith GE, Frieman MB. Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice. Vaccine 2014; 32(26): 3169–3174

[122] 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(45): 5975–5982

[123] 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(4): 476–484

[124] Song F, Fux R, Provacia LB, Volz A, Eickmann M, Becker S, Osterhaus AD, Haagmans BL, Sutter G. Middle East respiratory syndrome coronavirus spike protein delivered by modified vaccinia virus Ankara efficiently induces virus-neutralizing antibodies. J Virol 2013; 87(21): 11950–11954

[125] Volz A, Kupke A, Song F, Jany S, Fux R, Shams-Eldin H, Schmidt J, Becker C, Eickmann M, Becker S, Sutter G. Protective efficacy of recombinant Modified Vaccinia virus Ankara (MVA) delivering Middle East Respiratory Syndrome coronavirus spike glycoprotein. J Virol 2015; 89(16): 8651–8656

[126] Wang L, Shi W, Joyce MG, Modjarrad K, Zhang Y, Leung K, Lees CR, Zhou T, Yassine HM, Kanekiyo M, Yang ZY, Chen X, Becker MM, Freeman M, Vogel L, Johnson JC, Olinger G, Todd JP, Bagci U, Solomon J, Mollura DJ, Hensley L, Jahrling P, Denison MR, Rao SS, Subbarao K, Kwong PD, Mascola JR, Kong WP, Graham BS. Evaluation of candidate vaccine approaches for MERS-CoV. Nat Commun 2015; 6: 7712

[127] Zhao J, Perera RA, Kayali G, Meyerholz D, Perlman S, Peiris M. Passive immunotherapy with dromedary immune serum in an experimental animal model for Middle East respiratory syndrome coronavirus infection. J Virol 2015; 89(11): 6117–6120

[128] Corti D, Zhao J, Pedotti M, Simonelli L, Agnihothram S, Fett C, Fernandez-Rodriguez B, Foglierini M, Agatic G, Vanzetta F, Gopal R, Langrish CJ, Barrett NA, Sallusto F, Baric RS, Varani L, Zambon M, Perlman S, Lanzavecchia A. Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus. Proc Natl Acad Sci USA 2015; 112(33): 10473–10478

[129] Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H. Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Sci Rep 2013; 3: 1686

[130] Frausto SD, Lee E, Tang H. Cyclophilins as modulators of viral replication. Viruses 2013; 5(7): 1684–1701

[131] Chan JF, Chan KH, Kao RY, To KK, Zheng BJ, Li CP, Li PT, Dai J, Mok FK, Chen H, Hayden FG, Yuen KY. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect 2013; 67(6): 606–616

[132] Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP, Brining D, Bushmaker T, Martellaro C, Baseler L, Benecke AG, Katze MG, Munster VJ, Feldmann H. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 2013; 19(10): 1313–1317

[133] Al-Tawfiq JA, Momattin H, Dib J, Memish ZA. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis 2014; 20: 42–46

[134] Omrani AS, Saad MM, Baig K, Bahloul A, Abdul-Matin M, Alaidaroos AY, Almakhlafi GA, Albarrak MM, Memish ZA, Albarrak AM. Ribavirin and interferon α-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis 2014; 14(11): 1090–1095

[135] Josset L, Menachery VD, Gralinski LE, Agnihothram S, Sova P, Carter VS, Yount BL, Graham RL, Baric RS, Katze MG. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. MBio 2013; 4(3): e00165–e13

[136] Kindrachuk J, Ork B, Hart BJ, Mazur S, Holbrook MR, Frieman MB, Traynor D, Johnson RF, Dyall J, Kuhn JH, Olinger GG, Hensley LE, Jahrling PB. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis. Antimicrob Agents Chemother 2015; 59(2): 1088–1099

[137] Liu Q, Xia S, Sun Z, Wang Q, Du L, Lu L, Jiang S. Testing of Middle East respiratory syndrome coronavirus replication inhibitors for the ability to block viral entry. Antimicrob Agents Chemother 2015; 59(1): 742–744

[138] de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, van den Hoogen BG, Neyts J, Snijder EJ. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 2014; 58(8): 4875–4884

[139] Hart BJ, Dyall J, Postnikova E, Zhou H, Kindrachuk J, Johnson RF, Olinger GG Jr, Frieman MB, Holbrook MR, Jahrling PB, Hensley L. Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol 2014; 95(Pt 3): 571–577

[140] Chan JF, Yao Y, Yeung ML, Deng W, Bao L, Jia L, Li F, Xiao C, Gao H, Yu P, Cai JP, Chu H, Zhou J, Chen H, Qin C, Yuen KY. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis 2015; 212(12): 1904–1913

[141] Wu A, Wang Y, Zeng C, Huang X, Xu S, Su C, Wang M, Chen Y, Guo D. Prediction and biochemical analysis of putative cleavage sites of the 3C-like protease of Middle East respiratory syndrome coronavirus. Virus Res 2015; 208: 56–65

[142] Kilianski A, Mielech AM, Deng X, Baker SC. Assessing activity and inhibition of Middle East respiratory syndrome coronavirus papain-like and 3C-like proteases using luciferase-based biosensors. J Virol 2013; 87(21): 11955–11962

[143] Adedeji AO, Singh K, Kassim A, Coleman CM, Elliott R, Weiss SR, Frieman MB, Sarafianos SG. Evaluation of SSYA10-001 as a replication inhibitor of severe acute respiratory syndrome, mouse hepatitis, and Middle East respiratory syndrome coronaviruses. Antimicrob Agents Chemother 2014; 58(8): 4894–4898

[144] Cheng KW, Cheng SC, Chen WY, Lin MH, Chuang SJ, Cheng IH, Sun CY, Chou CY. Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res 2015; 115: 9–16

[145] Ren Z, Yan L, Zhang N, Guo Y, Yang C, Lou Z, Rao Z. The newly emerged SARS-like coronavirus HCoV-EMC also has an “Achilles’ heel”: current effective inhibitor targeting a 3C-like protease. Protein Cell 2013; 4(4): 248–250

[146] Ohnuma K, Haagmans BL, Hatano R, Raj VS, Mou H, Iwata S, Dang NH, Bosch BJ, Morimoto C. Inhibition of Middle East respiratory syndrome coronavirus infection by anti-CD26 monoclonal antibody. J Virol 2013; 87(24): 13892–13899

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg