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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Passive immunotherapy for Middle East Respiratory Syndrome coronavirus infection with equine immunoglobulin or immunoglobulin fragments in a mouse model</title><author><name sortKey="Zhao, Yongkun" sort="Zhao, Yongkun" uniqKey="Zhao Y" first="Yongkun" last="Zhao">Yongkun Zhao</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Wang, Chong" sort="Wang, Chong" uniqKey="Wang C" first="Chong" last="Wang">Chong Wang</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China</nlm:aff></affiliation></author><author><name sortKey="Qiu, Boning" sort="Qiu, Boning" uniqKey="Qiu B" first="Boning" last="Qiu">Boning Qiu</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">College of Veterinary Medicine, Jilin University, Changchun, China</nlm:aff></affiliation></author><author><name sortKey="Li, Chufang" sort="Li, Chufang" uniqKey="Li C" first="Chufang" last="Li">Chufang Li</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Wang, Hualei" sort="Wang, Hualei" uniqKey="Wang H" first="Hualei" last="Wang">Hualei Wang</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Jin, Hongli" sort="Jin, Hongli" uniqKey="Jin H" first="Hongli" last="Jin">Hongli Jin</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation></author><author><name sortKey="Gai, Weiwei" sort="Gai, Weiwei" uniqKey="Gai W" first="Weiwei" last="Gai">Weiwei Gai</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">College of Veterinary Medicine, Jilin University, Changchun, China</nlm:aff></affiliation></author><author><name sortKey="Zheng, Xuexing" sort="Zheng, Xuexing" uniqKey="Zheng X" first="Xuexing" last="Zheng">Xuexing Zheng</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation></author><author><name sortKey="Wang, Tiecheng" sort="Wang, Tiecheng" uniqKey="Wang T" first="Tiecheng" last="Wang">Tiecheng Wang</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Sun, Weiyang" sort="Sun, Weiyang" uniqKey="Sun W" first="Weiyang" last="Sun">Weiyang Sun</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Yan, Feihu" sort="Yan, Feihu" uniqKey="Yan F" first="Feihu" last="Yan">Feihu Yan</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation></author><author><name sortKey="Gao, Yuwei" sort="Gao, Yuwei" uniqKey="Gao Y" first="Yuwei" last="Gao">Yuwei Gao</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Wang, Qian" sort="Wang, Qian" uniqKey="Wang Q" first="Qian" last="Wang">Qian Wang</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Yan, Jinghua" sort="Yan, Jinghua" uniqKey="Yan J" first="Jinghua" last="Yan">Jinghua Yan</name><affiliation><nlm:aff id="aff7">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Academy of Sciences, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Chen, Ling" sort="Chen, Ling" uniqKey="Chen L" first="Ling" last="Chen">Ling Chen</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation><nlm:aff id="aff4">Departments of Microbiology, University of Iowa, Iowa City, USA</nlm:aff></affiliation></author><author><name sortKey="Zhong, Nanshan" sort="Zhong, Nanshan" uniqKey="Zhong N" first="Nanshan" last="Zhong">Nanshan Zhong</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Zhao, Jincun" sort="Zhao, Jincun" uniqKey="Zhao J" first="Jincun" last="Zhao">Jincun Zhao</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Yang, Songtao" sort="Yang, Songtao" uniqKey="Yang S" first="Songtao" last="Yang">Songtao Yang</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Xia, Xianzhu" sort="Xia, Xianzhu" uniqKey="Xia X" first="Xianzhu" last="Xia">Xianzhu Xia</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27890674</idno><idno type="pmc">7113855</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113855</idno><idno type="RBID">PMC:7113855</idno><idno type="doi">10.1016/j.antiviral.2016.11.016</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000A72</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A72</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Passive immunotherapy for Middle East Respiratory Syndrome coronavirus infection with equine immunoglobulin or immunoglobulin fragments in a mouse model</title><author><name sortKey="Zhao, Yongkun" sort="Zhao, Yongkun" uniqKey="Zhao Y" first="Yongkun" last="Zhao">Yongkun Zhao</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Wang, Chong" sort="Wang, Chong" uniqKey="Wang C" first="Chong" last="Wang">Chong Wang</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China</nlm:aff></affiliation></author><author><name sortKey="Qiu, Boning" sort="Qiu, Boning" uniqKey="Qiu B" first="Boning" last="Qiu">Boning Qiu</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">College of Veterinary Medicine, Jilin University, Changchun, China</nlm:aff></affiliation></author><author><name sortKey="Li, Chufang" sort="Li, Chufang" uniqKey="Li C" first="Chufang" last="Li">Chufang Li</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Wang, Hualei" sort="Wang, Hualei" uniqKey="Wang H" first="Hualei" last="Wang">Hualei Wang</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Jin, Hongli" sort="Jin, Hongli" uniqKey="Jin H" first="Hongli" last="Jin">Hongli Jin</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation></author><author><name sortKey="Gai, Weiwei" sort="Gai, Weiwei" uniqKey="Gai W" first="Weiwei" last="Gai">Weiwei Gai</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">College of Veterinary Medicine, Jilin University, Changchun, China</nlm:aff></affiliation></author><author><name sortKey="Zheng, Xuexing" sort="Zheng, Xuexing" uniqKey="Zheng X" first="Xuexing" last="Zheng">Xuexing Zheng</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation></author><author><name sortKey="Wang, Tiecheng" sort="Wang, Tiecheng" uniqKey="Wang T" first="Tiecheng" last="Wang">Tiecheng Wang</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Sun, Weiyang" sort="Sun, Weiyang" uniqKey="Sun W" first="Weiyang" last="Sun">Weiyang Sun</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Yan, Feihu" sort="Yan, Feihu" uniqKey="Yan F" first="Feihu" last="Yan">Feihu Yan</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation></author><author><name sortKey="Gao, Yuwei" sort="Gao, Yuwei" uniqKey="Gao Y" first="Yuwei" last="Gao">Yuwei Gao</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Wang, Qian" sort="Wang, Qian" uniqKey="Wang Q" first="Qian" last="Wang">Qian Wang</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Yan, Jinghua" sort="Yan, Jinghua" uniqKey="Yan J" first="Jinghua" last="Yan">Jinghua Yan</name><affiliation><nlm:aff id="aff7">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Academy of Sciences, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Chen, Ling" sort="Chen, Ling" uniqKey="Chen L" first="Ling" last="Chen">Ling Chen</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation><nlm:aff id="aff4">Departments of Microbiology, University of Iowa, Iowa City, USA</nlm:aff></affiliation></author><author><name sortKey="Zhong, Nanshan" sort="Zhong, Nanshan" uniqKey="Zhong N" first="Nanshan" last="Zhong">Nanshan Zhong</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Zhao, Jincun" sort="Zhao, Jincun" uniqKey="Zhao J" first="Jincun" last="Zhao">Jincun Zhao</name><affiliation><nlm:aff id="aff5">State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Yang, Songtao" sort="Yang, Songtao" uniqKey="Yang S" first="Songtao" last="Yang">Songtao Yang</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Xia, Xianzhu" sort="Xia, Xianzhu" uniqKey="Xia X" first="Xianzhu" last="Xia">Xianzhu Xia</name><affiliation><nlm:aff id="aff1">Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff6">Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</nlm:aff></affiliation></author></analytic><series><title level="j">Antiviral Research</title><idno type="ISSN">0166-3542</idno><idno type="eISSN">1872-9096</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Middle East Respiratory Syndrome (MERS) is a highly lethal pulmonary infection caused by a coronavirus (CoV), MERS-CoV. With the continuing spread of MERS-CoV, prophylactic and therapeutic treatments are urgently needed. In this study, we prepared purified equine F(ab’)<sub>2</sub> from horses immunized with MERS-CoV virus-like particles (VLPs) expressing MERS-CoV S, M and E proteins. Both IgG and F(ab’)<sub>2</sub> efficiently neutralized MERS-CoV replication in tissue culture. Passive transfer of equine immune antibodies significantly reduced virus titers and accelerated virus clearance from the lungs of MERS-CoV infected mice. Our data show that horses immunized with MERS-CoV VLPs can serve as a primary source of protective F(ab’)<sub>2</sub> for potential use in the prophylactic or therapeutic treatment of exposed or infected patients.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Assiri, A" uniqKey="Assiri A">A. Assiri</name></author><author><name sortKey="Al Tawfiq, J A" uniqKey="Al Tawfiq J">J.A. Al-Tawfiq</name></author><author><name sortKey="Al Rabeeah, A A" uniqKey="Al Rabeeah A">A.A. Al-Rabeeah</name></author><author><name sortKey="Al Rabiah, F A" uniqKey="Al Rabiah F">F.A. Al-Rabiah</name></author><author><name sortKey="Al Hajjar, S" uniqKey="Al Hajjar S">S. Al-Hajjar</name></author><author><name sortKey="Al Barrak, A" uniqKey="Al Barrak A">A. Al-Barrak</name></author><author><name sortKey="Flemban, H" uniqKey="Flemban H">H. Flemban</name></author><author><name sortKey="Al Nassir, W N" uniqKey="Al Nassir W">W.N. Al-Nassir</name></author><author><name sortKey="Balkhy, H H" uniqKey="Balkhy H">H.H. Balkhy</name></author><author><name sortKey="Al Hakeem, R F" uniqKey="Al Hakeem R">R.F. Al-Hakeem</name></author><author><name sortKey="Makhdoom, H Q" uniqKey="Makhdoom H">H.Q. Makhdoom</name></author><author><name sortKey="Zumla, A I" uniqKey="Zumla A">A.I. Zumla</name></author><author><name sortKey="Memish, Z A" uniqKey="Memish Z">Z.A. Memish</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Assiri, A" uniqKey="Assiri A">A. Assiri</name></author><author><name sortKey="Mcgeer, A" uniqKey="Mcgeer A">A. McGeer</name></author><author><name sortKey="Perl, T M" uniqKey="Perl T">T.M. Perl</name></author><author><name sortKey="Price, C S" uniqKey="Price C">C.S. Price</name></author><author><name sortKey="Al Rabeeah, A A" uniqKey="Al Rabeeah A">A.A. Al Rabeeah</name></author><author><name sortKey="Cummings, D A" uniqKey="Cummings D">D.A. Cummings</name></author><author><name sortKey="Alabdullatif, Z N" uniqKey="Alabdullatif Z">Z.N. Alabdullatif</name></author><author><name sortKey="Assad, M" uniqKey="Assad M">M. Assad</name></author><author><name sortKey="Almulhim, A" uniqKey="Almulhim A">A. Almulhim</name></author><author><name sortKey="Makhdoom, H" uniqKey="Makhdoom H">H. Makhdoom</name></author><author><name sortKey="Madani, H" uniqKey="Madani H">H. Madani</name></author><author><name sortKey="Alhakeem, R" uniqKey="Alhakeem R">R. Alhakeem</name></author><author><name sortKey="Al Tawfiq, J A" uniqKey="Al Tawfiq J">J.A. Al-Tawfiq</name></author><author><name sortKey="Cotten, M" uniqKey="Cotten M">M. Cotten</name></author><author><name sortKey="Watson, S J" uniqKey="Watson S">S.J. Watson</name></author><author><name sortKey="Kellam, P" uniqKey="Kellam P">P. Kellam</name></author><author><name sortKey="Zumla, A I" uniqKey="Zumla A">A.I. Zumla</name></author><author><name sortKey="Memish, Z A" uniqKey="Memish Z">Z.A. Memish</name></author><author><name sortKey="Team, K M C I" uniqKey="Team K">K.M.-C.I. Team</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Both, L" uniqKey="Both L">L. Both</name></author><author><name sortKey="Banyard, A C" uniqKey="Banyard A">A.C. Banyard</name></author><author><name sortKey="Van Dolleweerd, C" uniqKey="Van Dolleweerd C">C. van Dolleweerd</name></author><author><name sortKey="Horton, D L" uniqKey="Horton D">D.L. Horton</name></author><author><name sortKey="Ma, J K" uniqKey="Ma J">J.K. Ma</name></author><author><name sortKey="Fooks, A R" uniqKey="Fooks A">A.R. Fooks</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Corti, D" uniqKey="Corti D">D. Corti</name></author><author><name sortKey="Zhao, J" uniqKey="Zhao J">J. Zhao</name></author><author><name sortKey="Pedotti, M" uniqKey="Pedotti M">M. Pedotti</name></author><author><name sortKey="Simonelli, L" uniqKey="Simonelli L">L. Simonelli</name></author><author><name sortKey="Agnihothram, S" uniqKey="Agnihothram S">S. Agnihothram</name></author><author><name sortKey="Fett, C" uniqKey="Fett C">C. Fett</name></author><author><name sortKey="Fernandez Rodriguez, B" uniqKey="Fernandez Rodriguez B">B. Fernandez-Rodriguez</name></author><author><name sortKey="Foglierini, M" uniqKey="Foglierini M">M. Foglierini</name></author><author><name sortKey="Agatic, G" uniqKey="Agatic G">G. Agatic</name></author><author><name sortKey="Vanzetta, F" uniqKey="Vanzetta F">F. Vanzetta</name></author><author><name sortKey="Gopal, R" uniqKey="Gopal R">R. Gopal</name></author><author><name sortKey="Langrish, C J" uniqKey="Langrish C">C.J. Langrish</name></author><author><name sortKey="Barrett, N A" uniqKey="Barrett N">N.A. Barrett</name></author><author><name sortKey="Sallusto, F" uniqKey="Sallusto F">F. Sallusto</name></author><author><name sortKey="Baric, R S" uniqKey="Baric R">R.S. Baric</name></author><author><name sortKey="Varani, L" uniqKey="Varani L">L. Varani</name></author><author><name sortKey="Zambon, M" uniqKey="Zambon M">M. Zambon</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S. Perlman</name></author><author><name sortKey="Lanzavecchia, A" uniqKey="Lanzavecchia A">A. Lanzavecchia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Drosten, C" uniqKey="Drosten C">C. Drosten</name></author><author><name sortKey="Meyer, B" uniqKey="Meyer B">B. Meyer</name></author><author><name sortKey="Muller, M A" uniqKey="Muller M">M.A. Muller</name></author><author><name sortKey="Corman, V M" uniqKey="Corman V">V.M. Corman</name></author><author><name sortKey="Al Masri, M" uniqKey="Al Masri M">M. Al-Masri</name></author><author><name sortKey="Hossain, R" uniqKey="Hossain R">R. Hossain</name></author><author><name sortKey="Madani, H" uniqKey="Madani H">H. Madani</name></author><author><name sortKey="Sieberg, A" uniqKey="Sieberg A">A. Sieberg</name></author><author><name sortKey="Bosch, B J" uniqKey="Bosch B">B.J. Bosch</name></author><author><name sortKey="Lattwein, E" uniqKey="Lattwein E">E. Lattwein</name></author><author><name sortKey="Alhakeem, R F" uniqKey="Alhakeem R">R.F. Alhakeem</name></author><author><name sortKey="Assiri, A M" uniqKey="Assiri A">A.M. Assiri</name></author><author><name sortKey="Hajomar, W" uniqKey="Hajomar W">W. Hajomar</name></author><author><name sortKey="Albarrak, A M" uniqKey="Albarrak A">A.M. Albarrak</name></author><author><name sortKey="Al Tawfiq, J A" uniqKey="Al Tawfiq J">J.A. Al-Tawfiq</name></author><author><name sortKey="Zumla, A I" uniqKey="Zumla A">A.I. Zumla</name></author><author><name sortKey="Memish, Z A" uniqKey="Memish Z">Z.A. Memish</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Drosten, C" uniqKey="Drosten C">C. Drosten</name></author><author><name sortKey="Seilmaier, M" uniqKey="Seilmaier M">M. Seilmaier</name></author><author><name sortKey="Corman, V M" uniqKey="Corman V">V.M. Corman</name></author><author><name sortKey="Hartmann, W" uniqKey="Hartmann W">W. Hartmann</name></author><author><name sortKey="Scheible, G" uniqKey="Scheible G">G. Scheible</name></author><author><name sortKey="Sack, S" uniqKey="Sack S">S. Sack</name></author><author><name sortKey="Guggemos, W" uniqKey="Guggemos W">W. Guggemos</name></author><author><name sortKey="Kallies, R" uniqKey="Kallies R">R. Kallies</name></author><author><name sortKey="Muth, D" uniqKey="Muth D">D. Muth</name></author><author><name sortKey="Junglen, S" uniqKey="Junglen S">S. Junglen</name></author><author><name sortKey="Muller, M A" uniqKey="Muller M">M.A. Muller</name></author><author><name sortKey="Haas, W" uniqKey="Haas W">W. Haas</name></author><author><name sortKey="Guberina, H" uniqKey="Guberina H">H. Guberina</name></author><author><name sortKey="Rohnisch, T" uniqKey="Rohnisch T">T. Rohnisch</name></author><author><name sortKey="Schmid Wendtner, M" uniqKey="Schmid Wendtner M">M. Schmid-Wendtner</name></author><author><name sortKey="Aldabbagh, S" uniqKey="Aldabbagh S">S. Aldabbagh</name></author><author><name sortKey="Dittmer, U" uniqKey="Dittmer U">U. Dittmer</name></author><author><name sortKey="Gold, H" uniqKey="Gold H">H. Gold</name></author><author><name sortKey="Graf, P" uniqKey="Graf P">P. Graf</name></author><author><name sortKey="Bonin, F" uniqKey="Bonin F">F. Bonin</name></author><author><name sortKey="Rambaut, A" uniqKey="Rambaut A">A. Rambaut</name></author><author><name sortKey="Wendtner, C M" uniqKey="Wendtner C">C.M. Wendtner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Du, L" uniqKey="Du L">L. Du</name></author><author><name sortKey="Zhao, G" uniqKey="Zhao G">G. Zhao</name></author><author><name sortKey="Kou, Z" uniqKey="Kou Z">Z. Kou</name></author><author><name sortKey="Ma, C" uniqKey="Ma C">C. Ma</name></author><author><name sortKey="Sun, S" uniqKey="Sun S">S. Sun</name></author><author><name sortKey="Poon, V K" uniqKey="Poon V">V.K. Poon</name></author><author><name sortKey="Lu, L" uniqKey="Lu L">L. Lu</name></author><author><name sortKey="Wang, L" uniqKey="Wang L">L. Wang</name></author><author><name sortKey="Debnath, A K" uniqKey="Debnath A">A.K. Debnath</name></author><author><name sortKey="Zheng, B J" uniqKey="Zheng B">B.J. Zheng</name></author><author><name sortKey="Zhou, Y" uniqKey="Zhou Y">Y. Zhou</name></author><author><name sortKey="Jiang, S" uniqKey="Jiang S">S. Jiang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gutierrez, J M" uniqKey="Gutierrez J">J.M. Gutierrez</name></author><author><name sortKey="Lomonte, B" uniqKey="Lomonte B">B. Lomonte</name></author><author><name sortKey="Sanz, L" uniqKey="Sanz L">L. Sanz</name></author><author><name sortKey="Calvete, J J" uniqKey="Calvete J">J.J. Calvete</name></author><author><name sortKey="Pla, D" uniqKey="Pla D">D. Pla</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hayden, F G" uniqKey="Hayden F">F.G. Hayden</name></author><author><name sortKey="Farrar, J" uniqKey="Farrar J">J. Farrar</name></author><author><name sortKey="Peiris, J S M" uniqKey="Peiris J">J.S.M. Peiris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="He, Y" uniqKey="He Y">Y. He</name></author><author><name sortKey="Zhu, Q" uniqKey="Zhu Q">Q. Zhu</name></author><author><name sortKey="Liu, S" uniqKey="Liu S">S. Liu</name></author><author><name sortKey="Zhou, Y" uniqKey="Zhou Y">Y. Zhou</name></author><author><name sortKey="Yang, B" uniqKey="Yang B">B. Yang</name></author><author><name sortKey="Li, J" uniqKey="Li J">J. Li</name></author><author><name sortKey="Jiang, S" uniqKey="Jiang S">S. Jiang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, Y" uniqKey="Li Y">Y. Li</name></author><author><name sortKey="Wan, Y" uniqKey="Wan Y">Y. Wan</name></author><author><name sortKey="Liu, P" uniqKey="Liu P">P. Liu</name></author><author><name sortKey="Zhao, J" uniqKey="Zhao J">J. Zhao</name></author><author><name sortKey="Lu, G" uniqKey="Lu G">G. Lu</name></author><author><name sortKey="Qi, J" uniqKey="Qi J">J. Qi</name></author><author><name sortKey="Wang, Q" uniqKey="Wang Q">Q. Wang</name></author><author><name sortKey="Lu, X" uniqKey="Lu X">X. Lu</name></author><author><name sortKey="Wu, Y" uniqKey="Wu Y">Y. Wu</name></author><author><name sortKey="Liu, W" uniqKey="Liu W">W. Liu</name></author><author><name sortKey="Zhang, B" uniqKey="Zhang B">B. Zhang</name></author><author><name sortKey="Yuen, K Y" uniqKey="Yuen K">K.Y. Yuen</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S. Perlman</name></author><author><name sortKey="Gao, G F" uniqKey="Gao G">G.F. Gao</name></author><author><name sortKey="Yan, J" uniqKey="Yan J">J. Yan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lu, J" uniqKey="Lu J">J. Lu</name></author><author><name sortKey="Guo, Z" uniqKey="Guo Z">Z. Guo</name></author><author><name sortKey="Pan, X" uniqKey="Pan X">X. Pan</name></author><author><name sortKey="Wang, G" uniqKey="Wang G">G. Wang</name></author><author><name sortKey="Zhang, D" uniqKey="Zhang D">D. Zhang</name></author><author><name sortKey="Li, Y" uniqKey="Li Y">Y. Li</name></author><author><name sortKey="Tan, B" uniqKey="Tan B">B. Tan</name></author><author><name sortKey="Ouyang, L" uniqKey="Ouyang L">L. Ouyang</name></author><author><name sortKey="Yu, X" uniqKey="Yu X">X. Yu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Luke, T" uniqKey="Luke T">T. Luke</name></author><author><name sortKey="Wu, H" uniqKey="Wu H">H. Wu</name></author><author><name sortKey="Zhao, J" uniqKey="Zhao J">J. Zhao</name></author><author><name sortKey="Channappanavar, R" uniqKey="Channappanavar R">R. Channappanavar</name></author><author><name sortKey="Coleman, C M" uniqKey="Coleman C">C.M. Coleman</name></author><author><name sortKey="Jiao, J A" uniqKey="Jiao J">J.A. Jiao</name></author><author><name sortKey="Matsushita, H" uniqKey="Matsushita H">H. Matsushita</name></author><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y. Liu</name></author><author><name sortKey="Postnikova, E N" uniqKey="Postnikova E">E.N. Postnikova</name></author><author><name sortKey="Ork, B L" uniqKey="Ork B">B.L. Ork</name></author><author><name sortKey="Glenn, G" uniqKey="Glenn G">G. Glenn</name></author><author><name sortKey="Flyer, D" uniqKey="Flyer D">D. Flyer</name></author><author><name sortKey="Defang, G" uniqKey="Defang G">G. Defang</name></author><author><name sortKey="Raviprakash, K" uniqKey="Raviprakash K">K. Raviprakash</name></author><author><name sortKey="Kochel, T" uniqKey="Kochel T">T. Kochel</name></author><author><name sortKey="Wang, J" uniqKey="Wang J">J. Wang</name></author><author><name sortKey="Nie, W" uniqKey="Nie W">W. Nie</name></author><author><name sortKey="Smith, G" uniqKey="Smith G">G. Smith</name></author><author><name sortKey="Hensley, L E" uniqKey="Hensley L">L.E. Hensley</name></author><author><name sortKey="Olinger, G G" uniqKey="Olinger G">G.G. Olinger</name></author><author><name sortKey="Kuhn, J H" uniqKey="Kuhn J">J.H. Kuhn</name></author><author><name sortKey="Holbrook, M R" uniqKey="Holbrook M">M.R. Holbrook</name></author><author><name sortKey="Johnson, R F" uniqKey="Johnson R">R.F. Johnson</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S. Perlman</name></author><author><name sortKey="Sullivan, E" uniqKey="Sullivan E">E. Sullivan</name></author><author><name sortKey="Frieman, M B" uniqKey="Frieman M">M.B. Frieman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mair Jenkins, J" uniqKey="Mair Jenkins J">J. Mair-Jenkins</name></author><author><name sortKey="Saavedra Campos, M" uniqKey="Saavedra Campos M">M. Saavedra-Campos</name></author><author><name sortKey="Baillie, J K" uniqKey="Baillie J">J.K. Baillie</name></author><author><name sortKey="Cleary, P" uniqKey="Cleary P">P. Cleary</name></author><author><name sortKey="Khaw, F M" uniqKey="Khaw F">F.M. Khaw</name></author><author><name sortKey="Lim, W S" uniqKey="Lim W">W.S. Lim</name></author><author><name sortKey="Makki, S" uniqKey="Makki S">S. Makki</name></author><author><name sortKey="Rooney, K D" uniqKey="Rooney K">K.D. Rooney</name></author><author><name sortKey="Beck, C R" uniqKey="Beck C">C.R. Beck</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mou, H" uniqKey="Mou H">H. Mou</name></author><author><name sortKey="Raj, V S" uniqKey="Raj V">V.S. Raj</name></author><author><name sortKey="Van Kuppeveld, F J" uniqKey="Van Kuppeveld F">F.J. van Kuppeveld</name></author><author><name sortKey="Rottier, P J" uniqKey="Rottier P">P.J. Rottier</name></author><author><name sortKey="Haagmans, B L" uniqKey="Haagmans B">B.L. Haagmans</name></author><author><name sortKey="Bosch, B J" uniqKey="Bosch B">B.J. Bosch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peiris, J S" uniqKey="Peiris J">J.S. Peiris</name></author><author><name sortKey="Guan, Y" uniqKey="Guan Y">Y. Guan</name></author><author><name sortKey="Yuen, K Y" uniqKey="Yuen K">K.Y. Yuen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sabir, J S" uniqKey="Sabir J">J.S. Sabir</name></author><author><name sortKey="Lam, T T" uniqKey="Lam T">T.T. Lam</name></author><author><name sortKey="Ahmed, M M" uniqKey="Ahmed M">M.M. Ahmed</name></author><author><name sortKey="Li, L" uniqKey="Li L">L. Li</name></author><author><name sortKey="Shen, Y" uniqKey="Shen Y">Y. Shen</name></author><author><name sortKey="Abo Aba, S E" uniqKey="Abo Aba S">S.E. Abo-Aba</name></author><author><name sortKey="Qureshi, M I" uniqKey="Qureshi M">M.I. Qureshi</name></author><author><name sortKey="Abu Zeid, M" uniqKey="Abu Zeid M">M. Abu-Zeid</name></author><author><name sortKey="Zhang, Y" uniqKey="Zhang Y">Y. Zhang</name></author><author><name sortKey="Khiyami, M A" uniqKey="Khiyami M">M.A. Khiyami</name></author><author><name sortKey="Alharbi, N S" uniqKey="Alharbi N">N.S. Alharbi</name></author><author><name sortKey="Hajrah, N H" uniqKey="Hajrah N">N.H. Hajrah</name></author><author><name sortKey="Sabir, M J" uniqKey="Sabir M">M.J. Sabir</name></author><author><name sortKey="Mutwakil, M H" uniqKey="Mutwakil M">M.H. Mutwakil</name></author><author><name sortKey="Kabli, S A" uniqKey="Kabli S">S.A. Kabli</name></author><author><name sortKey="Alsulaimany, F A" uniqKey="Alsulaimany F">F.A. Alsulaimany</name></author><author><name sortKey="Obaid, A Y" uniqKey="Obaid A">A.Y. Obaid</name></author><author><name sortKey="Zhou, B" uniqKey="Zhou B">B. Zhou</name></author><author><name sortKey="Smith, D K" uniqKey="Smith D">D.K. Smith</name></author><author><name sortKey="Holmes, E C" uniqKey="Holmes E">E.C. Holmes</name></author><author><name sortKey="Zhu, H" uniqKey="Zhu H">H. Zhu</name></author><author><name sortKey="Guan, Y" uniqKey="Guan Y">Y. Guan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, C Z X" uniqKey="Wang C">C.Z.X. Wang</name></author><author><name sortKey="Gai, W" uniqKey="Gai W">W. Gai</name></author><author><name sortKey="Zhao, Y" uniqKey="Zhao Y">Y. Zhao</name></author><author><name sortKey="Wang, H" uniqKey="Wang H">H. Wang</name></author><author><name sortKey="Wang, H" uniqKey="Wang H">H. Wang</name></author><author><name sortKey="Feng, N" uniqKey="Feng N">N. Feng</name></author><author><name sortKey="Chi, H" uniqKey="Chi H">H. Chi</name></author><author><name sortKey="Qiu, B" uniqKey="Qiu B">B. Qiu</name></author><author><name sortKey="Li, N" uniqKey="Li N">N. Li</name></author><author><name sortKey="Wang, T" uniqKey="Wang T">T. Wang</name></author><author><name sortKey="Gao, Y" uniqKey="Gao Y">Y. Gao</name></author><author><name sortKey="Yang, S" uniqKey="Yang S">S. Yang</name></author><author><name sortKey="Xia, X" uniqKey="Xia X">X. Xia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zaki, A M" uniqKey="Zaki A">A.M. Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S. van Boheemen</name></author><author><name sortKey="Bestebroer, T M" uniqKey="Bestebroer T">T.M. Bestebroer</name></author><author><name sortKey="Osterhaus, A D" uniqKey="Osterhaus A">A.D. Osterhaus</name></author><author><name sortKey="Fouchier, R A" uniqKey="Fouchier R">R.A. Fouchier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zaki, A M" uniqKey="Zaki A">A.M. Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S. van Boheemen</name></author><author><name sortKey="Bestebroer, T M" uniqKey="Bestebroer T">T.M. Bestebroer</name></author><author><name sortKey="Osterhaus, A D M E" uniqKey="Osterhaus A">A.D.M.E. Osterhaus</name></author><author><name sortKey="Fouchier, R A M" uniqKey="Fouchier R">R.A.M. Fouchier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, J" uniqKey="Zhao J">J. Zhao</name></author><author><name sortKey="Li, K" uniqKey="Li K">K. Li</name></author><author><name sortKey="Wohlford Lenane, C" uniqKey="Wohlford Lenane C">C. Wohlford-Lenane</name></author><author><name sortKey="Agnihothram, S S" uniqKey="Agnihothram S">S.S. Agnihothram</name></author><author><name sortKey="Fett, C" uniqKey="Fett C">C. Fett</name></author><author><name sortKey="Gale, M J" uniqKey="Gale M">M.J. Gale</name></author><author><name sortKey="Baric, R S" uniqKey="Baric R">R.S. Baric</name></author><author><name sortKey="Enjuanes, L" uniqKey="Enjuanes L">L. Enjuanes</name></author><author><name sortKey="Gallagher, T" uniqKey="Gallagher T">T. Gallagher</name></author><author><name sortKey="Mccray, P B" uniqKey="Mccray P">P.B. McCray</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S. Perlman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, J" uniqKey="Zhao J">J. Zhao</name></author><author><name sortKey="Perera, R A" uniqKey="Perera R">R.A. Perera</name></author><author><name sortKey="Kayali, G" uniqKey="Kayali G">G. Kayali</name></author><author><name sortKey="Meyerholz, D" uniqKey="Meyerholz D">D. Meyerholz</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S. Perlman</name></author><author><name sortKey="Peiris, M" uniqKey="Peiris M">M. Peiris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zheng, X" uniqKey="Zheng X">X. Zheng</name></author><author><name sortKey="Wong, G" uniqKey="Wong G">G. Wong</name></author><author><name sortKey="Zhao, Y" uniqKey="Zhao Y">Y. Zhao</name></author><author><name sortKey="Wang, H" uniqKey="Wang H">H. Wang</name></author><author><name sortKey="He, S" uniqKey="He S">S. He</name></author><author><name sortKey="Bi, Y" uniqKey="Bi Y">Y. Bi</name></author><author><name sortKey="Chen, W" uniqKey="Chen W">W. Chen</name></author><author><name sortKey="Jin, H" uniqKey="Jin H">H. Jin</name></author><author><name sortKey="Gai, W" uniqKey="Gai W">W. Gai</name></author><author><name sortKey="Chu, D" uniqKey="Chu D">D. Chu</name></author><author><name sortKey="Cao, Z" uniqKey="Cao Z">Z. Cao</name></author><author><name sortKey="Wang, C" uniqKey="Wang C">C. Wang</name></author><author><name sortKey="Fan, Q" uniqKey="Fan Q">Q. Fan</name></author><author><name sortKey="Chi, H" uniqKey="Chi H">H. Chi</name></author><author><name sortKey="Gao, Y" uniqKey="Gao Y">Y. Gao</name></author><author><name sortKey="Wang, T" uniqKey="Wang T">T. Wang</name></author><author><name sortKey="Feng, N" uniqKey="Feng N">N. Feng</name></author><author><name sortKey="Yan, F" uniqKey="Yan F">F. Yan</name></author><author><name sortKey="Huang, G" uniqKey="Huang G">G. Huang</name></author><author><name sortKey="Zheng, Y" uniqKey="Zheng Y">Y. Zheng</name></author><author><name sortKey="Li, N" uniqKey="Li N">N. Li</name></author><author><name sortKey="Li, Y" uniqKey="Li Y">Y. Li</name></author><author><name sortKey="Qian, J" uniqKey="Qian J">J. Qian</name></author><author><name sortKey="Zou, Y" uniqKey="Zou Y">Y. Zou</name></author><author><name sortKey="Kobinger, G" uniqKey="Kobinger G">G. Kobinger</name></author><author><name sortKey="Gao, G F" uniqKey="Gao G">G.F. Gao</name></author><author><name sortKey="Qiu, X" uniqKey="Qiu X">X. Qiu</name></author><author><name sortKey="Yang, S" uniqKey="Yang S">S. Yang</name></author><author><name sortKey="Xia, X" uniqKey="Xia X">X. Xia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, L" uniqKey="Zhou L">L. Zhou</name></author><author><name sortKey="Ni, B" uniqKey="Ni B">B. Ni</name></author><author><name sortKey="Luo, D" uniqKey="Luo D">D. Luo</name></author><author><name sortKey="Zhao, G" uniqKey="Zhao G">G. Zhao</name></author><author><name sortKey="Jia, Z" uniqKey="Jia Z">Z. Jia</name></author><author><name sortKey="Zhang, L" uniqKey="Zhang L">L. Zhang</name></author><author><name sortKey="Lin, Z" uniqKey="Lin Z">Z. Lin</name></author><author><name sortKey="Wang, L" uniqKey="Wang L">L. Wang</name></author><author><name sortKey="Zhang, S" uniqKey="Zhang S">S. Zhang</name></author><author><name sortKey="Xing, L" uniqKey="Xing L">L. Xing</name></author><author><name sortKey="Li, J" uniqKey="Li J">J. Li</name></author><author><name sortKey="Liang, Y" uniqKey="Liang Y">Y. Liang</name></author><author><name sortKey="Shi, X" uniqKey="Shi X">X. Shi</name></author><author><name sortKey="Zhao, T" uniqKey="Zhao T">T. Zhao</name></author><author><name sortKey="Zhou, L" uniqKey="Zhou L">L. Zhou</name></author><author><name sortKey="Wu, Y" uniqKey="Wu Y">Y. Wu</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X. Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zumla, A" uniqKey="Zumla A">A. Zumla</name></author><author><name sortKey="Hui, D S" uniqKey="Hui D">D.S. Hui</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S. Perlman</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Antiviral Res</journal-id><journal-id journal-id-type="iso-abbrev">Antiviral Res</journal-id><journal-title-group><journal-title>Antiviral Research</journal-title></journal-title-group><issn pub-type="ppub">0166-3542</issn><issn pub-type="epub">1872-9096</issn><publisher><publisher-name>Published by Elsevier B.V.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27890674</article-id><article-id pub-id-type="pmc">7113855</article-id><article-id pub-id-type="publisher-id">S0166-3542(16)30392-8</article-id><article-id pub-id-type="doi">10.1016/j.antiviral.2016.11.016</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Passive immunotherapy for Middle East Respiratory Syndrome coronavirus infection with equine immunoglobulin or immunoglobulin fragments in a mouse model</article-title></title-group><contrib-group><contrib contrib-type="author" id="au1"><name><surname>Zhao</surname><given-names>Yongkun</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff6" ref-type="aff">f</xref><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author" id="au2"><name><surname>Wang</surname><given-names>Chong</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff2" ref-type="aff">b</xref><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author" id="au3"><name><surname>Qiu</surname><given-names>Boning</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff3" ref-type="aff">c</xref><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author" id="au4"><name><surname>Li</surname><given-names>Chufang</given-names></name><xref rid="aff5" ref-type="aff">e</xref><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author" id="au5"><name><surname>Wang</surname><given-names>Hualei</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff6" ref-type="aff">f</xref></contrib><contrib contrib-type="author" id="au6"><name><surname>Jin</surname><given-names>Hongli</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au7"><name><surname>Gai</surname><given-names>Weiwei</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au8"><name><surname>Zheng</surname><given-names>Xuexing</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au9"><name><surname>Wang</surname><given-names>Tiecheng</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff6" ref-type="aff">f</xref></contrib><contrib contrib-type="author" id="au10"><name><surname>Sun</surname><given-names>Weiyang</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff6" ref-type="aff">f</xref></contrib><contrib contrib-type="author" id="au11"><name><surname>Yan</surname><given-names>Feihu</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au12"><name><surname>Gao</surname><given-names>Yuwei</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff6" ref-type="aff">f</xref></contrib><contrib contrib-type="author" id="au13"><name><surname>Wang</surname><given-names>Qian</given-names></name><xref rid="aff5" ref-type="aff">e</xref></contrib><contrib contrib-type="author" id="au14"><name><surname>Yan</surname><given-names>Jinghua</given-names></name><xref rid="aff7" ref-type="aff">g</xref></contrib><contrib contrib-type="author" id="au15"><name><surname>Chen</surname><given-names>Ling</given-names></name><xref rid="aff5" ref-type="aff">e</xref></contrib><contrib contrib-type="author" id="au16"><name><surname>Perlman</surname><given-names>Stanley</given-names></name><xref rid="aff4" ref-type="aff">d</xref></contrib><contrib contrib-type="author" id="au17"><name><surname>Zhong</surname><given-names>Nanshan</given-names></name><xref rid="aff5" ref-type="aff">e</xref></contrib><contrib contrib-type="author" id="au18"><name><surname>Zhao</surname><given-names>Jincun</given-names></name><email>zhaojincun@gird.cn</email><xref rid="aff5" ref-type="aff">e</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib><contrib contrib-type="author" id="au19"><name><surname>Yang</surname><given-names>Songtao</given-names></name><email>yst62041@163.com</email><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff6" ref-type="aff">f</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author" id="au20"><name><surname>Xia</surname><given-names>Xianzhu</given-names></name><email>xiaxzh@cae.cn</email><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff6" ref-type="aff">f</xref><xref rid="cor3" ref-type="corresp">∗∗∗</xref></contrib></contrib-group><aff id="aff1"><label>a</label>Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun, China</aff><aff id="aff2"><label>b</label>State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China</aff><aff id="aff3"><label>c</label>College of Veterinary Medicine, Jilin University, Changchun, China</aff><aff id="aff4"><label>d</label>Departments of Microbiology, University of Iowa, Iowa City, USA</aff><aff id="aff5"><label>e</label>State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China</aff><aff id="aff6"><label>f</label>Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China</aff><aff id="aff7"><label>g</label>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Academy of Sciences, Beijing, China</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author. Department of Virology, Institute of Military Veterinary, Academy of Military Medical Sciences, 666 Liuying West Road, Changchun, Jilin, 130012, China. <email>yst62041@163.com</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author. State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China. <email>zhaojincun@gird.cn</email></corresp><corresp id="cor3"><label>∗∗∗</label>Corresponding author. Department of Virology, Institute of Military Veterinary, Academy of Military Medical Sciences, 666 Liuying West Road, Changchun, Jilin, 130012, China. <email>xiaxzh@cae.cn</email></corresp><fn id="fn1"><label>1</label><p id="ntpara0010">These authors contributed equally to this paper.</p></fn></author-notes><pub-date pub-type="pmc-release"><day>24</day><month>11</month><year>2016</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>1</month><year>2017</year></pub-date><pub-date pub-type="epub"><day>24</day><month>11</month><year>2016</year></pub-date><volume>137</volume><fpage>125</fpage><lpage>130</lpage><history><date date-type="received"><day>18</day><month>7</month><year>2016</year></date><date date-type="rev-recd"><day>23</day><month>11</month><year>2016</year></date><date date-type="accepted"><day>23</day><month>11</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 Published by Elsevier B.V.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder></copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract id="abs0010"><p>Middle East Respiratory Syndrome (MERS) is a highly lethal pulmonary infection caused by a coronavirus (CoV), MERS-CoV. With the continuing spread of MERS-CoV, prophylactic and therapeutic treatments are urgently needed. In this study, we prepared purified equine F(ab’)<sub>2</sub> from horses immunized with MERS-CoV virus-like particles (VLPs) expressing MERS-CoV S, M and E proteins. Both IgG and F(ab’)<sub>2</sub> efficiently neutralized MERS-CoV replication in tissue culture. Passive transfer of equine immune antibodies significantly reduced virus titers and accelerated virus clearance from the lungs of MERS-CoV infected mice. Our data show that horses immunized with MERS-CoV VLPs can serve as a primary source of protective F(ab’)<sub>2</sub> for potential use in the prophylactic or therapeutic treatment of exposed or infected patients.</p></abstract><abstract abstract-type="author-highlights" id="abs0015"><title>Highlights</title><p><list list-type="simple" id="ulist0010"><list-item id="u0010"><label>•</label><p id="p0010">Healthy horses immunized with MERS-CoV virus-like particles rapidly generate high titers of virus neutralizing antibodies.</p></list-item><list-item id="u0015"><label>•</label><p id="p0015">Passive transfer of equine immune antibodies significantly reduced virus titers from the lungs of MERS-CoV infected mice.</p></list-item><list-item id="u0020"><label>•</label><p id="p0020">F(ab’)<sub>2</sub> fragments prepared by digestion of antibody with pepsin to reduce possible allergic responses.</p></list-item><list-item id="u0025"><label>•</label><p id="p0025">Equine immune antibodies are polyclonal and recognize more antigen determinants in MERS-CoV spike protein.</p></list-item></list></p></abstract><kwd-group id="kwrds0010"><title>Keywords</title><kwd>Middle East Respiratory Syndrome coronavirus</kwd><kwd>Equine immune serum</kwd><kwd>Immunoglobulin</kwd><kwd>F(ab’)<sub>2</sub> fragment</kwd><kwd>Animal model</kwd></kwd-group></article-meta></front><body><sec id="sec1"><label>1</label><title>Introduction</title><p id="p0030">Middle East Respiratory Syndrome (MERS)-CoV is an emerging pathogen that causes severe pneumonia in humans in the Arabian Peninsula and in travelers from this region (<xref rid="bib1" ref-type="bibr">Assiri et al., 2013a</xref>, <xref rid="bib20" ref-type="bibr">Zaki et al., 2012b</xref>, <xref rid="bib25" ref-type="bibr">Zumla et al., 2015</xref>). Human-to-human spread has been documented (<xref rid="bib2" ref-type="bibr">Assiri et al., 2013b</xref>). While infections of immunocompetent patients generally present with only mild symptoms, the elderly and patients with pre-existing illnesses such as diabetes or renal failure are likely to develop more severe disease (<xref rid="bib1" ref-type="bibr">Assiri et al., 2013a</xref>). As of September 21, 2016, 1806 cases with 643 deaths (35.6% mortality) had been reported to the World Health Organization, although the actual number of infections could be much larger since mild, asymptomatic or undiagnosed cases are likely to be common (<xref rid="bib5" ref-type="bibr">Drosten et al., 2014</xref>).</p><p id="p0035">As yet there are neither licensed vaccines nor any prophylactic or therapeutic treatments effective against MERS-CoV. Given the ability of coronaviruses to rapidly adapt to new hosts, a major public health concern is that MERS-CoV will further adapt to replication in humans, triggering a global severe acute respiratory syndrome (SARS)-like pandemic (<xref rid="bib16" ref-type="bibr">Peiris et al., 2004</xref>, <xref rid="bib19" ref-type="bibr">Zaki et al., 2012a</xref>).</p><p id="p0040">As of now, the most promising treatment is the passive administration of anti-MERS-CoV neutralizing antibodies. Several research groups have developed and produced anti-MERS patient-derived or humanized monoclonal neutralizing antibodies <italic>in vitro</italic> that were able to protect MERS-CoV infected mice (<xref rid="bib4" ref-type="bibr">Corti et al., 2015</xref>, <xref rid="bib11" ref-type="bibr">Li et al., 2015</xref>, <xref rid="bib21" ref-type="bibr">Zhao et al., 2014</xref>). However, since these antibodies react with a single epitope on the MERS-CoV spike (S) protein and since coronaviruses are prone to mutate, this approach has raised concerns about possible antibody escape (<xref rid="bib4" ref-type="bibr">Corti et al., 2015</xref>, <xref rid="bib17" ref-type="bibr">Sabir et al., 2016</xref>).</p><p id="p0045">Recently, we showed that sera from Middle East dromedary camels contained high levels of anti-MERS-CoV neutralizing antibodies. Passive immunotherapy with sera from these animals significantly reduced virus loads and accelerated virus clearance from the lungs of MERS-CoV infected mice (<xref rid="bib22" ref-type="bibr">Zhao et al., 2015</xref>). This provides proof of concept that immune animal sera are potentially useful in the treatment of patients with MERS (<xref rid="bib9" ref-type="bibr">Hayden et al., 2014</xref>). Passive immunotherapy with animal sera or antibodies has been successfully used to prevent rabies and to neutralize snake venom (<xref rid="bib3" ref-type="bibr">Both et al., 2012</xref>, <xref rid="bib8" ref-type="bibr">Gutierrez et al., 2014</xref>). Convalescent plasma used to treat patients with SARS has been found safe and has demonstrated some efficacy in a study with a small number of patients (<xref rid="bib14" ref-type="bibr">Mair-Jenkins et al., 2015</xref>). However, neutralizing antibody titers in MERS patients are generally low and the limited number of MERS survivors makes this approach impractical (<xref rid="bib6" ref-type="bibr">Drosten et al., 2013</xref>).</p><p id="p0050">Here, we show that immunization of healthy horses with MERS-CoV virus-like particles (VLPs) expressing MERS-CoV S, M and E proteins induces strong polyclonal neutralizing antibodies against MERS-CoV. Since administration of whole antibodies can induce allergic responses in some humans, we further tested F(ab’)<sub>2</sub> fragments prepared by digestion of antibody with pepsin. Prophylactic or therapeutic treatment of MERS-CoV infected mice with either IgG or F(ab’)<sub>2</sub> significantly decreased the virus load in their lungs.</p></sec><sec id="sec2"><label>2</label><title>Materials and methods</title><sec id="sec2.1"><label>2.1</label><title>Antigen preparation</title><p id="p0055">MERS-CoV VLPs were produced and purified as previously described (<xref rid="bib18" ref-type="bibr">Wang et al., 2016</xref>). In brief, army worm Sf9 cells were infected with a single recombinant baculoviruses co-expressing MERS-CoV structural protein genes S, M, and E, at a multiplicity of infection (MOI) of 0.5. Culture supernatants were harvested at 96 h post-infection and centrifuged at 2000 g for 30 min to remove cell debris. Following centrifugation of the clarified supernatants at 100,000 g for 1 h at 4 °C the resulting VLP pellets were resuspended in PBS and loaded onto a 30–40–50% discontinuous sucrose gradient. After an additional centrifugation at 100,000 g for 1.5 h at 4 °C, bands between 30 and 40% sucrose containing MERS-CoV VLP were collected.</p></sec><sec id="sec2.2"><label>2.2</label><title>Animal immunization</title><p id="p0060">Four 4-year-old healthy horses received multi-point intramuscular injections of 0.5, 1.5, 2, 3, and 5 mg MERS-CoV VLPs in 4 ml PBS at weeks 0, 2, 4, 6, and 8, respectively. Freund's complete adjuvant (Sigma) was included in the first dose, and incomplete adjuvant in the remaining ones. Sera were collected from the jugular vein 2 weeks after each injection, and stored at −20 °C before further analysis.</p></sec><sec id="sec2.3"><label>2.3</label><title>MERS-CoV specific antibody measurement</title><p id="p0065">MERS-CoV specific antibodies in the sera were measured by an indirect enzyme-linked immunosorbent assay (ELISA) using purified MERS-CoV receptor-binding domain (RBD) protein (i.e., S protein residues 358–662 cloned into the pET-30a expression vector and purified by Ni-NTA affinity chromatograph column). Briefly, 96-well microtitration plates (Corning Costar, USA) were pre-coated with 100 μL purified RBD antigen diluted in 0.05 mol/L carbonate sodium buffer (pH 9.6) to a final concentration of 1 μg/mL and incubated at 4 °C overnight. After blocking with skimmed milk for 2 h at 37 °C, 100 μL twofold serially diluted serum samples were added to the wells, and incubated at 37 °C for 1 h. The plates were washed three times with PBS containing 0.05% Tween-20 (PBST), before addition of 100 μL HRP-labeled rabbit antibody against horse IgG (Bioss, China; 1:20,000) and incubation at 37 °C for 1 h. After washing with PBST, 100 μL 3, 3′, 3, 5’-tetramethylbenzidine (TMB) (Sigma, USA) as substrate was added to each well and incubated for 30 min. The reaction was stopped with 50 μL 2 M H<sub>2</sub>SO<sub>4</sub>. Optical densities at 450 nm were measured in an ELISA plate reader (Bio-Rad, USA).</p></sec><sec id="sec2.4"><label>2.4</label><title>Immunoglobulin purification</title><p id="p0070">Horse antiserum was diluted with 2 vol of normal saline (0.9% NaCl) and a half volume of saturated ammonium sulfate was then added and mixed gently at room temperature for 30 min before centrifugation at 5000 g for 20 min. The resulting sediment was redissolved in saline and mixed with a one-third volume of saturated ammonium sulfate. After incubation at ambient temperature for 30 min and centrifugation at 5000 g for 20 min, the second sediments were dissolved in normal saline and dialyzed against normal saline to remove any remaining ammonium salt.</p></sec><sec id="sec2.5"><label>2.5</label><title>Immunoaffinity chromatography</title><p id="p0075">Immunoaffinity resins were prepared by coupling 10 mg RBD protein to 0.02 M sodium periodate-activated Sepharose 4B (4 g), and then incubating with 150 μL sodium borohydride for 30 min. After reaction with 1 M Tris (pH 7.5) for 30 min, a purified IgG sample was diluted 9-fold with PBS and incubated with the RBD resin overnight at 4 °C with constant rotation. The flowthroughs (anti-RBD depleted) were collected, and then the flowthroughs were tested against the RBD protein by ELISA to ensure RBD-specific IgG all bound with the RBD Sepharose 4B. After washing with PBS, the bound antibodies (anti-RBD) were eluted in 0.2 M glycine-HCl buffer (pH 2.7). The eluates were neutralized with 1 M Tris buffer (pH 9.0), and then dialyzed against PBS. All samples were adjusted to the same protein concentration and sterilized by passage through microspin filters (0.2 μm pore size; Millipore). Neutralizing activity of the IgG, RBD-specific IgG, and flowthroughs were tested.</p></sec><sec id="sec2.6"><label>2.6</label><title>F(ab')<sub>2</sub> preparation</title><p id="p0080">The pH of the horse antiserum was adjusted to 3.3 with 1 mol/L HCl. Following incubation with pepsin (10000 IU/mL) at 30 °C for 2.5 h, the reaction was stopped by adjusting the pH to 7.2 with 1 mol/L NaOH. The solution was then applied to Protein-A and Protein-G columns sequentially to remove whole immunoglobulins. The purity of the resulting F(ab’)<sub>2</sub> protein was assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) followed by Coomassie blue staining and the target fraction in the gel was analyzed in a thin layer chromatography scanner (transmission, zigzag scan, dual wavelength, swing width:8 mm, delta Y: 0.1 mm) (CS-9301, Shimadzu).</p></sec><sec id="sec2.7"><label>2.7</label><title>Mice and virus</title><p id="p0085">Specific pathogen-free 6 week old BALB/c mice were purchased from Charles River Laboratories International and maintained in the Animal Care Facility, University of Iowa. Briefly, all mice were housed in Thoren individually ventilated cages. Caging and bedding were autoclaved. Irradiated diet was fed. Filtered water (0.2 μm filter) was provided with Edstrom automatic watering system. HEPA-filtered cage changing stations were used. All persons entering animal rooms worn autoclaved gowns, gloves, hair bonnets, face masks, and shoe covers. All protocols were approved by the University of Iowa Institutional Animal Care and Use Committee. The EMC/2012 strain of MERS-CoV (passage 8, designated MERS-CoV), kindly provided by Drs. Bart Haagmans and Ron Fouchier (Erasmus Medical Center, Rotterdam, Holland), was passaged once in Vero 81 cells and titrated in the same cell line. All work with MERS-CoV was conducted in the University of Iowa Biosafety Level 3 (BSL-3) Laboratory.</p></sec><sec id="sec2.8"><label>2.8</label><title>MERS-CoV plaque reduction neutralization assay</title><p id="p0090">Serum samples, purified IgG or F(ab’)<sub>2</sub> were serially diluted in DMEM and mixed with an equal volume of MERS-CoV containing 80 PFU. Following incubation at 37 °C for 1 h, aliquots were added to cultures of Vero 81 cells in 48 well plates and incubated at 37 °C in 5% CO<sub>2</sub> for 1 h with gentle rocking every 15 min. Plates were then overlaid with 1.2% agarose/DMEM/2% calf serum. After further incubation for 3 days, agarose plugs were removed using a small spatula, and the remaining plaques were visualized by staining with 0.1% crystal violet.</p></sec><sec id="sec2.9"><label>2.9</label><title>Antibody treatment and MERS-CoV infection of mice</title><p id="p0095">Six-week-old female BALB/c mice were lightly anesthetized with isoflurane and transduced intranasally with 2.5 × 10<sup>8</sup> PFU of Ad5-hDPP4 in 75 μL DMEM as described elsewhere (<xref rid="bib21" ref-type="bibr">Zhao et al., 2014</xref>). Five days post transduction, mice were infected intranasally with MERS-CoV (1 × 10<sup>5</sup> PFU) in a total volume of 50 μL DMEM. Mice were monitored daily for morbidity (weight loss) and mortality. All work with MERS-CoV was conducted in the University of Iowa Biosafety Level 3 (BSL-3) Laboratory. Separate groups were injected with 200 μL horse antiserum or 500 μg IgG or F(ab’)<sub>2</sub> intraperitoneally (IP) 1 day before or after intranasal infection with 1 × 10<sup>5</sup> PFU MERS-CoV. Control mice were given an equal volume of normal horse serum (Sigma).</p></sec><sec id="sec2.10"><label>2.10</label><title>Virus titers</title><p id="p0100">To obtain virus titers, Lungs were harvested from subgroups of 3 animals at the indicated time points (see Results) and homogenized into 3 mL of phosphate buffered saline (PBS), using a manual homogenizer. Lung homogenates were aliquoted into micro tubes and kept in −80 °C. Virus was titered on Vero 81 cells. Cells were fixed with 10% formaldehyde and stained with crystal violet three days post-infection (p.i.). Viral titers are expressed as PFU/g tissue for MERS-CoV (<xref rid="bib21" ref-type="bibr">Zhao et al., 2014</xref>).</p></sec></sec><sec id="sec3"><label>3</label><title>Results and discussion</title><p id="p0105">Due to the biosafety risk, MERS-CoV must be handled in a BSL-3 laboratory, whereas VLPs can be rapidly generated under BSL-2 conditions as an immunogen inducing high antibody titers. In addition, the horse provides little risk to humans and produces high antibody yields, making these animals an effective source for production of hyperimmune sera (<xref rid="bib23" ref-type="bibr">Zheng et al., 2016</xref>).</p><sec id="sec3.1"><label>3.1</label><title>Evaluation of equine antibodies</title><p id="p0110">RBD-specific IgG titers in the sera were all above 1:20,480 after five immunizations (<xref rid="fig1" ref-type="fig">Fig. 1</xref>) as assessed by ELISA. RBD contains the major neutralizing epitopes of the S protein, as shown by the observation that absorption of SARS patient convalescent sera with SARS-CoV RBD removes the majority of neutralizing antibodies (<xref rid="bib10" ref-type="bibr">He et al., 2005</xref>). Independent research groups have also shown more directly that the MERS-CoV RBD sequence contains the major antigenic determinants for inducing neutralizing antibodies, and that neutralizing epitopes within MERS-CoV S1 are also localized primarily in the RBD region (<xref rid="bib7" ref-type="bibr">Du et al., 2013</xref>, <xref rid="bib15" ref-type="bibr">Mou et al., 2013</xref>). Here, we have demonstrated that anti-RBD antibodies function as major components of neutralizing antibodies. We found that RBD-specific IgG neutralized MERS-CoV infection with half maximal inhibitory concentration of 15.74 μg/mL, and 2.612 × 10<sup>3</sup> μg/mL for flowthroughs (<xref rid="fig2" ref-type="fig">Fig. 2</xref>), suggesting that the RBD of S protein act as an important neutralization determinant of MERS-CoV. Our results demonstrate that equine antibodies are polyclonal and recognize more antigen determinants in MERS-CoV S protein than single mAbs, which could potentially prevent antibody escape.<fig id="fig1"><label>Fig. 1</label><caption><p><bold>Robust MERS-CoV RBD-specific antibody in immunized horse sera</bold>. Horses (n = 4) were injected intramuscularly with MERS-CoV VLPs and boosted every two weeks an additional 4 times. Sera were collected 2 weeks after each immunization. RBD-specific antibodies in immunized horse sera were detected using ELISA.</p></caption><alt-text id="alttext0010">Fig. 1</alt-text><graphic xlink:href="gr1_lrg"></graphic></fig><fig id="fig2"><label>Fig. 2</label><caption><p><bold>Neutralizing activity of the RBD-specific antibodies in IgG</bold>. <italic>In vitro</italic> neutralization tests of total IgG, RBD-specific IgG, and flowthroughs, were determined in a series of 2-fold dilutions and 50% neutralization was calculated using Graphpad Prism.</p></caption><alt-text id="alttext0015">Fig. 2</alt-text><graphic xlink:href="gr2_lrg"></graphic></fig></p></sec><sec id="sec3.2"><label>3.2</label><title>Generation of IgG and F(ab’)<sub>2</sub></title><p id="p0115">The integrity of IgG and F(ab’)<sub>2</sub> fragments was evaluated using an SDS-PAGE gel (<xref rid="fig3" ref-type="fig">Fig. 3</xref>A). The purity of the F(ab’)<sub>2</sub> fragments after Protein-A/G chromatography was >91% after gel electrophoresis (<xref rid="fig3" ref-type="fig">Fig. 3</xref>B). Passive transfer of blood products from other humans poses a safety concern, with possible contamination with agents of blood-borne diseases (e.g., HIV, hepatitis). Heterologous antibody carries a potential risk of allergic reaction, but generation of F(ab’)<sub>2</sub> fragments, results in antibodies being less immunoreactive and safer for use in humans.<fig id="fig3"><label>Fig. 3</label><caption><p><bold>Generation and purification of IgG and F(ab’)</bold><sub><bold>2</bold></sub>. Saturated ammonium sulfate was added to serum to precipitate the IgG, and F(ab’)<sub>2</sub> was generated by digestion of the IgG with pepsin, followed by Protein-A/G chromatography. (<bold>A</bold>) SDS-PAGE electrophoresis and Coomassie blue staining of IgG before dialysis, IgG and F(ab’)<sub>2</sub>. (<bold>B</bold>) The purity of F(ab’)<sub>2</sub> was 91.3%.</p></caption><alt-text id="alttext0020">Fig. 3</alt-text><graphic xlink:href="gr3_lrg"></graphic></fig></p></sec><sec id="sec3.3"><label>3.3</label><title>Equine antibodies neutralized MERS-CoV in cell culture</title><p id="p0120">While we successfully generated equine antibodies against MERS-CoV VLPs, their protective effect against authentic MERS-CoV infection remained untested. Using a plaque reduction neutralizing assay, we confirmed that immune sera significantly neutralized MERS-CoV infection <italic>in vitro</italic>, with a half effective maximal dilution of 1: 20,900 (<xref rid="fig4" ref-type="fig">Fig. 4</xref>A, B). Further, we found that equine IgG and F(ab’)<sub>2</sub> also neutralized MERS-CoV infection with half effective maximal concentrations (EC<sub>50</sub>) of 2.16 μg/mL and 2.60 μg/mL for IgG and F(ab’)<sub>2</sub>, respectively (<xref rid="fig4" ref-type="fig">Fig. 4</xref>C, D). Collectively, these results show that equine antibody products exhibit highly potent neutralizing activity against MERS-CoV.<fig id="fig4"><label>Fig. 4</label><caption><p><bold>Immune horse serum, purified IgG and F(ab’)</bold><sub><bold>2</bold></sub><bold>neutralized MERS-CoV <italic>in vitro</italic></bold>. (<bold>A</bold>) Serum or (<bold>C</bold>) antibody samples were serially diluted in DMEM and mixed 1:1 with 80 PFU MERS-CoV. After a 1 h incubation at 37 °C, the mixture was added to Vero 81 cell monolayers for an additional 1 h. Following removal of the supernatants, the cells were then overlaid with 1.2% agarose/containing DMEM/2% calf serum. After a further incubation of 3 days, agarose plugs were removed for virus tiration. Plaques were visualized by staining with 0.1% crystal violet. (<bold>B</bold>) Dilutions or (<bold>D</bold>) concentrations for 50% of maximal neutralizing effect are shown.</p></caption><alt-text id="alttext0025">Fig. 4</alt-text><graphic xlink:href="gr4_lrg"></graphic></fig></p></sec><sec id="sec3.4"><label>3.4</label><title>Passive transfer of equine antibodies protected MERS-CoV infected mice</title><p id="p0125">Next we asked if adoptive transfer of equine antibodies could protect mice from MERS-CoV infection prophylactically and therapeutically. By using a mouse model we previously generated (<xref rid="bib21" ref-type="bibr">Zhao et al., 2014</xref>), we injected animals with immune serum (<xref rid="fig5" ref-type="fig">Fig. 5</xref>A, B), purified IgG (<xref rid="fig5" ref-type="fig">Fig. 5</xref>C, D) or F(ab’)<sub>2</sub> (<xref rid="fig5" ref-type="fig">Fig. 5</xref>E, F) i.p. 1 day before (<xref rid="fig5" ref-type="fig">Fig. 5</xref>A, C, E) or after (<xref rid="fig5" ref-type="fig">Fig. 5</xref>B, D, F) MERS-CoV challenge. In both prophylactic and therapeutic settings, passive transfer of equine immune antibodies resulted in a 2–4 log reduction of virus titers in the lungs of MERS-CoV infected mice, and accelerated virus clearance in the serum treated group (<xref rid="fig5" ref-type="fig">Fig. 5</xref>A, B). We did not observe any difference in body weight loss and pathologic changes on the exterior surface of the lungs in treated and untreated mice after infeciton, since in this model, mice only develope mild lung disease. Rapid virus replication and inflammatory cell infiltration in the infected lungs are the major parameters to measure (<xref rid="bib21" ref-type="bibr">Zhao et al., 2014</xref>). Since the half-life of F(ab’)<sub>2</sub><italic>in vivo</italic> is relatively short and MERS-CoV is cleared within 6 days in this model (<xref rid="bib21" ref-type="bibr">Zhao et al., 2014</xref>), we did not inject F(ab’)<sub>2</sub> antibodies before day −1 or after day 1 p.i.<fig id="fig5"><label>Fig. 5</label><caption><p><bold>Immune horse serum, purified IgG and F(ab’)</bold><sub><bold>2</bold></sub><bold>protected MERS-CoV infected mice</bold>. Ad5-hDPP4 transduced BALB/c mice (6wks, female) were injected intraperitoneally with 200 μL horse serum (<bold>A, B</bold>), 500 μg purified horse immune IgG <bold>(C, D)</bold> or purified horse immune F(ab’)<sub>2</sub><bold>(E, F)</bold> 1 day before <bold>(A, C, E)</bold> or after <bold>(B, D, F)</bold> intranasal infection with 1 × 10<sup>5</sup> PFU MERS-CoV. Virus titers in the lungs were measured at the indicated time points. Titers are expressed as PFU/g tissue. n = 3 mice/group/time point. *P values of <0.05 as compared to control group.</p></caption><alt-text id="alttext0030">Fig. 5</alt-text><graphic xlink:href="gr5_lrg"></graphic></fig></p><p id="p0130">Of note, the purified IgG seemed to have lower protective potency than that of the immune serum <italic>in vivo</italic> (<xref rid="fig5" ref-type="fig">Fig. 5</xref>). The concentration of IgG in serum is > 10 mg/mL. We used 200 μL of immune serum (equal to 2 mg IgG) per mouse which is much higher than the immune IgG we used (500 μg/mice). The other reason could be we purified immune IgG using saturated ammonium sulfate precipitation method, which needed to be performed under room temperature. We speculated that some IgGs were degraded or misfolded, and unable to bind to MERS-CoV spike protein under this circumstance. While, immune sera were properly stored at −20 °C and contained high concentration of BSA and other proteins, which made the antiserum more stable.</p><p id="p0135">To date, there are several anti-MERS-CoV antibodies developed from different origins. Each antibody contains its own advantages and disadvantages. For monoclonal antibodies, mouse-derived monoclonal antibody needs to be humanized before human use (<xref rid="bib11" ref-type="bibr">Li et al., 2015</xref>); a human neutralizing antibody derived from a convalescent MERS patient can be produced in large amount from CHO cells (<xref rid="bib4" ref-type="bibr">Corti et al., 2015</xref>). However, the single clone antibody raises the concern of viral escape mutant when applied to human. Administration of transchromosomic bovine human immunoglobulins (<xref rid="bib13" ref-type="bibr">Luke et al., 2016</xref>) or dromedary immune serum (<xref rid="bib22" ref-type="bibr">Zhao et al., 2015</xref>) resulted in rapidly viral clearance in infected mouse lungs. The disadvantage of these antibodies is that these animals are not readily available. Compared to the antibodies described above, the administration of equine IgG-derived F(ab’)<sub>2</sub> fragment proved to be a versatile and feasible method (<xref rid="bib12" ref-type="bibr">Lu et al., 2006</xref>, <xref rid="bib24" ref-type="bibr">Zhou et al., 2007</xref>). It provides a useful platform to produce therapeutics against emerging infectious diseases.</p><p id="p0140">In summary, by immunizing healthy horses with MERS-CoV VLPs, we have successfully developed the first equine IgG-derived F(ab’)<sub>2</sub> fragment that neutralizes MERS-CoV <italic>in vitro</italic> and <italic>in vivo</italic>. Both prophylactic and therapeutic treatments decreased virus loads and accelerated virus clearance in the lungs of MERS-CoV-infected mice. Therefore, horses immunized with MERS-CoV VLPs can serve as a useful initial source for developing protective F(ab’)<sub>2</sub> fragments, for the purpose of preparedness and to serve as a strategic reserve for a potential MERS epidemic and other emergent pathogens.</p></sec></sec><sec id="sec4"><title>Potential conflicts of interest disclosure</title><p id="p0145">The authors declare no competing interests.</p></sec></body><back><ref-list id="cebib0010"><title>References</title><ref id="bib1"><element-citation publication-type="journal" id="sref1"><person-group person-group-type="author"><name><surname>Assiri</surname><given-names>A.</given-names></name><name><surname>Al-Tawfiq</surname><given-names>J.A.</given-names></name><name><surname>Al-Rabeeah</surname><given-names>A.A.</given-names></name><name><surname>Al-Rabiah</surname><given-names>F.A.</given-names></name><name><surname>Al-Hajjar</surname><given-names>S.</given-names></name><name><surname>Al-Barrak</surname><given-names>A.</given-names></name><name><surname>Flemban</surname><given-names>H.</given-names></name><name><surname>Al-Nassir</surname><given-names>W.N.</given-names></name><name><surname>Balkhy</surname><given-names>H.H.</given-names></name><name><surname>Al-Hakeem</surname><given-names>R.F.</given-names></name><name><surname>Makhdoom</surname><given-names>H.Q.</given-names></name><name><surname>Zumla</surname><given-names>A.I.</given-names></name><name><surname>Memish</surname><given-names>Z.A.</given-names></name></person-group><article-title>Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study</article-title><source>Lancet Infect. Dis.</source><volume>13</volume><year>2013</year><fpage>752</fpage><lpage>761</lpage><pub-id pub-id-type="pmid">23891402</pub-id></element-citation></ref><ref id="bib2"><element-citation publication-type="journal" id="sref2"><person-group person-group-type="author"><name><surname>Assiri</surname><given-names>A.</given-names></name><name><surname>McGeer</surname><given-names>A.</given-names></name><name><surname>Perl</surname><given-names>T.M.</given-names></name><name><surname>Price</surname><given-names>C.S.</given-names></name><name><surname>Al Rabeeah</surname><given-names>A.A.</given-names></name><name><surname>Cummings</surname><given-names>D.A.</given-names></name><name><surname>Alabdullatif</surname><given-names>Z.N.</given-names></name><name><surname>Assad</surname><given-names>M.</given-names></name><name><surname>Almulhim</surname><given-names>A.</given-names></name><name><surname>Makhdoom</surname><given-names>H.</given-names></name><name><surname>Madani</surname><given-names>H.</given-names></name><name><surname>Alhakeem</surname><given-names>R.</given-names></name><name><surname>Al-Tawfiq</surname><given-names>J.A.</given-names></name><name><surname>Cotten</surname><given-names>M.</given-names></name><name><surname>Watson</surname><given-names>S.J.</given-names></name><name><surname>Kellam</surname><given-names>P.</given-names></name><name><surname>Zumla</surname><given-names>A.I.</given-names></name><name><surname>Memish</surname><given-names>Z.A.</given-names></name><name><surname>Team</surname><given-names>K.M.-C.I.</given-names></name></person-group><article-title>Hospital outbreak of Middle East respiratory syndrome coronavirus</article-title><source>N. Engl. J. Med.</source><volume>369</volume><year>2013</year><fpage>407</fpage><lpage>416</lpage><pub-id pub-id-type="pmid">23782161</pub-id></element-citation></ref><ref id="bib3"><element-citation publication-type="journal" id="sref3"><person-group person-group-type="author"><name><surname>Both</surname><given-names>L.</given-names></name><name><surname>Banyard</surname><given-names>A.C.</given-names></name><name><surname>van Dolleweerd</surname><given-names>C.</given-names></name><name><surname>Horton</surname><given-names>D.L.</given-names></name><name><surname>Ma</surname><given-names>J.K.</given-names></name><name><surname>Fooks</surname><given-names>A.R.</given-names></name></person-group><article-title>Passive immunity in the prevention of rabies</article-title><source>Lancet Infect. Dis.</source><volume>12</volume><year>2012</year><fpage>397</fpage><lpage>407</lpage><pub-id pub-id-type="pmid">22541629</pub-id></element-citation></ref><ref id="bib4"><element-citation publication-type="journal" id="sref4"><person-group person-group-type="author"><name><surname>Corti</surname><given-names>D.</given-names></name><name><surname>Zhao</surname><given-names>J.</given-names></name><name><surname>Pedotti</surname><given-names>M.</given-names></name><name><surname>Simonelli</surname><given-names>L.</given-names></name><name><surname>Agnihothram</surname><given-names>S.</given-names></name><name><surname>Fett</surname><given-names>C.</given-names></name><name><surname>Fernandez-Rodriguez</surname><given-names>B.</given-names></name><name><surname>Foglierini</surname><given-names>M.</given-names></name><name><surname>Agatic</surname><given-names>G.</given-names></name><name><surname>Vanzetta</surname><given-names>F.</given-names></name><name><surname>Gopal</surname><given-names>R.</given-names></name><name><surname>Langrish</surname><given-names>C.J.</given-names></name><name><surname>Barrett</surname><given-names>N.A.</given-names></name><name><surname>Sallusto</surname><given-names>F.</given-names></name><name><surname>Baric</surname><given-names>R.S.</given-names></name><name><surname>Varani</surname><given-names>L.</given-names></name><name><surname>Zambon</surname><given-names>M.</given-names></name><name><surname>Perlman</surname><given-names>S.</given-names></name><name><surname>Lanzavecchia</surname><given-names>A.</given-names></name></person-group><article-title>Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus</article-title><source>Proc. Natl. Acad. Sci. U. S. A.</source><volume>112</volume><year>2015</year><fpage>10473</fpage><lpage>10478</lpage><pub-id pub-id-type="pmid">26216974</pub-id></element-citation></ref><ref id="bib5"><element-citation publication-type="journal" id="sref5"><person-group person-group-type="author"><name><surname>Drosten</surname><given-names>C.</given-names></name><name><surname>Meyer</surname><given-names>B.</given-names></name><name><surname>Muller</surname><given-names>M.A.</given-names></name><name><surname>Corman</surname><given-names>V.M.</given-names></name><name><surname>Al-Masri</surname><given-names>M.</given-names></name><name><surname>Hossain</surname><given-names>R.</given-names></name><name><surname>Madani</surname><given-names>H.</given-names></name><name><surname>Sieberg</surname><given-names>A.</given-names></name><name><surname>Bosch</surname><given-names>B.J.</given-names></name><name><surname>Lattwein</surname><given-names>E.</given-names></name><name><surname>Alhakeem</surname><given-names>R.F.</given-names></name><name><surname>Assiri</surname><given-names>A.M.</given-names></name><name><surname>Hajomar</surname><given-names>W.</given-names></name><name><surname>Albarrak</surname><given-names>A.M.</given-names></name><name><surname>Al-Tawfiq</surname><given-names>J.A.</given-names></name><name><surname>Zumla</surname><given-names>A.I.</given-names></name><name><surname>Memish</surname><given-names>Z.A.</given-names></name></person-group><article-title>Transmission of MERS-coronavirus in household contacts</article-title><source>N. Engl. J. Med.</source><volume>371</volume><year>2014</year><fpage>828</fpage><lpage>835</lpage><pub-id pub-id-type="pmid">25162889</pub-id></element-citation></ref><ref id="bib6"><element-citation publication-type="journal" id="sref6"><person-group person-group-type="author"><name><surname>Drosten</surname><given-names>C.</given-names></name><name><surname>Seilmaier</surname><given-names>M.</given-names></name><name><surname>Corman</surname><given-names>V.M.</given-names></name><name><surname>Hartmann</surname><given-names>W.</given-names></name><name><surname>Scheible</surname><given-names>G.</given-names></name><name><surname>Sack</surname><given-names>S.</given-names></name><name><surname>Guggemos</surname><given-names>W.</given-names></name><name><surname>Kallies</surname><given-names>R.</given-names></name><name><surname>Muth</surname><given-names>D.</given-names></name><name><surname>Junglen</surname><given-names>S.</given-names></name><name><surname>Muller</surname><given-names>M.A.</given-names></name><name><surname>Haas</surname><given-names>W.</given-names></name><name><surname>Guberina</surname><given-names>H.</given-names></name><name><surname>Rohnisch</surname><given-names>T.</given-names></name><name><surname>Schmid-Wendtner</surname><given-names>M.</given-names></name><name><surname>Aldabbagh</surname><given-names>S.</given-names></name><name><surname>Dittmer</surname><given-names>U.</given-names></name><name><surname>Gold</surname><given-names>H.</given-names></name><name><surname>Graf</surname><given-names>P.</given-names></name><name><surname>Bonin</surname><given-names>F.</given-names></name><name><surname>Rambaut</surname><given-names>A.</given-names></name><name><surname>Wendtner</surname><given-names>C.M.</given-names></name></person-group><article-title>Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection</article-title><source>Lancet Infect. Dis.</source><volume>13</volume><year>2013</year><fpage>745</fpage><lpage>751</lpage><pub-id pub-id-type="pmid">23782859</pub-id></element-citation></ref><ref id="bib7"><element-citation publication-type="journal" id="sref7"><person-group person-group-type="author"><name><surname>Du</surname><given-names>L.</given-names></name><name><surname>Zhao</surname><given-names>G.</given-names></name><name><surname>Kou</surname><given-names>Z.</given-names></name><name><surname>Ma</surname><given-names>C.</given-names></name><name><surname>Sun</surname><given-names>S.</given-names></name><name><surname>Poon</surname><given-names>V.K.</given-names></name><name><surname>Lu</surname><given-names>L.</given-names></name><name><surname>Wang</surname><given-names>L.</given-names></name><name><surname>Debnath</surname><given-names>A.K.</given-names></name><name><surname>Zheng</surname><given-names>B.J.</given-names></name><name><surname>Zhou</surname><given-names>Y.</given-names></name><name><surname>Jiang</surname><given-names>S.</given-names></name></person-group><article-title>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</article-title><source>J. Virology</source><volume>87</volume><year>2013</year><fpage>9939</fpage><lpage>9942</lpage><pub-id pub-id-type="pmid">23824801</pub-id></element-citation></ref><ref id="bib8"><element-citation publication-type="journal" id="sref8"><person-group person-group-type="author"><name><surname>Gutierrez</surname><given-names>J.M.</given-names></name><name><surname>Lomonte</surname><given-names>B.</given-names></name><name><surname>Sanz</surname><given-names>L.</given-names></name><name><surname>Calvete</surname><given-names>J.J.</given-names></name><name><surname>Pla</surname><given-names>D.</given-names></name></person-group><article-title>Immunological profile of antivenoms: preclinical analysis of the efficacy of a polyspecific antivenom through antivenomics and neutralization assays</article-title><source>J. Proteomics</source><volume>105</volume><year>2014</year><fpage>340</fpage><lpage>350</lpage><pub-id pub-id-type="pmid">24583507</pub-id></element-citation></ref><ref id="bib9"><element-citation publication-type="journal" id="sref9"><person-group person-group-type="author"><name><surname>Hayden</surname><given-names>F.G.</given-names></name><name><surname>Farrar</surname><given-names>J.</given-names></name><name><surname>Peiris</surname><given-names>J.S.M.</given-names></name></person-group><article-title>Towards improving clinical management of Middle East respiratory syndrome coronavirus infection</article-title><source>Lancet Infect. Dis.</source><volume>14</volume><year>2014</year><fpage>544</fpage><lpage>546</lpage><pub-id pub-id-type="pmid">24964934</pub-id></element-citation></ref><ref id="bib10"><element-citation publication-type="journal" id="sref10"><person-group person-group-type="author"><name><surname>He</surname><given-names>Y.</given-names></name><name><surname>Zhu</surname><given-names>Q.</given-names></name><name><surname>Liu</surname><given-names>S.</given-names></name><name><surname>Zhou</surname><given-names>Y.</given-names></name><name><surname>Yang</surname><given-names>B.</given-names></name><name><surname>Li</surname><given-names>J.</given-names></name><name><surname>Jiang</surname><given-names>S.</given-names></name></person-group><article-title>Identification of a critical neutralization determinant of severe acute respiratory syndrome (SARS)-associated coronavirus: importance for designing SARS vaccines</article-title><source>Virology</source><volume>334</volume><year>2005</year><fpage>74</fpage><lpage>82</lpage><pub-id pub-id-type="pmid">15749124</pub-id></element-citation></ref><ref id="bib11"><element-citation publication-type="journal" id="sref11"><person-group person-group-type="author"><name><surname>Li</surname><given-names>Y.</given-names></name><name><surname>Wan</surname><given-names>Y.</given-names></name><name><surname>Liu</surname><given-names>P.</given-names></name><name><surname>Zhao</surname><given-names>J.</given-names></name><name><surname>Lu</surname><given-names>G.</given-names></name><name><surname>Qi</surname><given-names>J.</given-names></name><name><surname>Wang</surname><given-names>Q.</given-names></name><name><surname>Lu</surname><given-names>X.</given-names></name><name><surname>Wu</surname><given-names>Y.</given-names></name><name><surname>Liu</surname><given-names>W.</given-names></name><name><surname>Zhang</surname><given-names>B.</given-names></name><name><surname>Yuen</surname><given-names>K.Y.</given-names></name><name><surname>Perlman</surname><given-names>S.</given-names></name><name><surname>Gao</surname><given-names>G.F.</given-names></name><name><surname>Yan</surname><given-names>J.</given-names></name></person-group><article-title>A humanized neutralizing antibody against MERS-CoV targeting the receptor-binding domain of the spike protein</article-title><source>Cell Res.</source><volume>25</volume><year>2015</year><fpage>1237</fpage><lpage>1249</lpage><pub-id pub-id-type="pmid">26391698</pub-id></element-citation></ref><ref id="bib12"><element-citation publication-type="journal" id="sref12"><person-group person-group-type="author"><name><surname>Lu</surname><given-names>J.</given-names></name><name><surname>Guo</surname><given-names>Z.</given-names></name><name><surname>Pan</surname><given-names>X.</given-names></name><name><surname>Wang</surname><given-names>G.</given-names></name><name><surname>Zhang</surname><given-names>D.</given-names></name><name><surname>Li</surname><given-names>Y.</given-names></name><name><surname>Tan</surname><given-names>B.</given-names></name><name><surname>Ouyang</surname><given-names>L.</given-names></name><name><surname>Yu</surname><given-names>X.</given-names></name></person-group><article-title>Passive immunotherapy for influenza A H5N1 virus infection with equine hyperimmune globulin F(ab')2 in mice</article-title><source>Respir. Res.</source><volume>7</volume><year>2006</year><fpage>43</fpage><pub-id pub-id-type="pmid">16553963</pub-id></element-citation></ref><ref id="bib13"><element-citation publication-type="journal" id="sref13"><person-group person-group-type="author"><name><surname>Luke</surname><given-names>T.</given-names></name><name><surname>Wu</surname><given-names>H.</given-names></name><name><surname>Zhao</surname><given-names>J.</given-names></name><name><surname>Channappanavar</surname><given-names>R.</given-names></name><name><surname>Coleman</surname><given-names>C.M.</given-names></name><name><surname>Jiao</surname><given-names>J.A.</given-names></name><name><surname>Matsushita</surname><given-names>H.</given-names></name><name><surname>Liu</surname><given-names>Y.</given-names></name><name><surname>Postnikova</surname><given-names>E.N.</given-names></name><name><surname>Ork</surname><given-names>B.L.</given-names></name><name><surname>Glenn</surname><given-names>G.</given-names></name><name><surname>Flyer</surname><given-names>D.</given-names></name><name><surname>Defang</surname><given-names>G.</given-names></name><name><surname>Raviprakash</surname><given-names>K.</given-names></name><name><surname>Kochel</surname><given-names>T.</given-names></name><name><surname>Wang</surname><given-names>J.</given-names></name><name><surname>Nie</surname><given-names>W.</given-names></name><name><surname>Smith</surname><given-names>G.</given-names></name><name><surname>Hensley</surname><given-names>L.E.</given-names></name><name><surname>Olinger</surname><given-names>G.G.</given-names></name><name><surname>Kuhn</surname><given-names>J.H.</given-names></name><name><surname>Holbrook</surname><given-names>M.R.</given-names></name><name><surname>Johnson</surname><given-names>R.F.</given-names></name><name><surname>Perlman</surname><given-names>S.</given-names></name><name><surname>Sullivan</surname><given-names>E.</given-names></name><name><surname>Frieman</surname><given-names>M.B.</given-names></name></person-group><article-title>Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo</article-title><source>Sci. Transl. Med.</source><volume>8</volume><year>2016</year><fpage>326ra321</fpage></element-citation></ref><ref id="bib14"><element-citation publication-type="journal" id="sref14"><person-group person-group-type="author"><name><surname>Mair-Jenkins</surname><given-names>J.</given-names></name><name><surname>Saavedra-Campos</surname><given-names>M.</given-names></name><name><surname>Baillie</surname><given-names>J.K.</given-names></name><name><surname>Cleary</surname><given-names>P.</given-names></name><name><surname>Khaw</surname><given-names>F.M.</given-names></name><name><surname>Lim</surname><given-names>W.S.</given-names></name><name><surname>Makki</surname><given-names>S.</given-names></name><name><surname>Rooney</surname><given-names>K.D.</given-names></name><name><surname>Beck</surname><given-names>C.R.</given-names></name></person-group><article-title>The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis</article-title><source>J. Infect. Dis.</source><volume>211</volume><year>2015</year><fpage>80</fpage><lpage>90</lpage><pub-id pub-id-type="pmid">25030060</pub-id></element-citation></ref><ref id="bib15"><element-citation publication-type="journal" id="sref15"><person-group person-group-type="author"><name><surname>Mou</surname><given-names>H.</given-names></name><name><surname>Raj</surname><given-names>V.S.</given-names></name><name><surname>van Kuppeveld</surname><given-names>F.J.</given-names></name><name><surname>Rottier</surname><given-names>P.J.</given-names></name><name><surname>Haagmans</surname><given-names>B.L.</given-names></name><name><surname>Bosch</surname><given-names>B.J.</given-names></name></person-group><article-title>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</article-title><source>J. Virology</source><volume>87</volume><year>2013</year><fpage>9379</fpage><lpage>9383</lpage><pub-id pub-id-type="pmid">23785207</pub-id></element-citation></ref><ref id="bib16"><element-citation publication-type="journal" id="sref16"><person-group person-group-type="author"><name><surname>Peiris</surname><given-names>J.S.</given-names></name><name><surname>Guan</surname><given-names>Y.</given-names></name><name><surname>Yuen</surname><given-names>K.Y.</given-names></name></person-group><article-title>Severe acute respiratory syndrome</article-title><source>Nat. Med.</source><volume>10</volume><year>2004</year><fpage>S88</fpage><lpage>S97</lpage><pub-id pub-id-type="pmid">15577937</pub-id></element-citation></ref><ref id="bib17"><element-citation publication-type="journal" id="sref17"><person-group person-group-type="author"><name><surname>Sabir</surname><given-names>J.S.</given-names></name><name><surname>Lam</surname><given-names>T.T.</given-names></name><name><surname>Ahmed</surname><given-names>M.M.</given-names></name><name><surname>Li</surname><given-names>L.</given-names></name><name><surname>Shen</surname><given-names>Y.</given-names></name><name><surname>Abo-Aba</surname><given-names>S.E.</given-names></name><name><surname>Qureshi</surname><given-names>M.I.</given-names></name><name><surname>Abu-Zeid</surname><given-names>M.</given-names></name><name><surname>Zhang</surname><given-names>Y.</given-names></name><name><surname>Khiyami</surname><given-names>M.A.</given-names></name><name><surname>Alharbi</surname><given-names>N.S.</given-names></name><name><surname>Hajrah</surname><given-names>N.H.</given-names></name><name><surname>Sabir</surname><given-names>M.J.</given-names></name><name><surname>Mutwakil</surname><given-names>M.H.</given-names></name><name><surname>Kabli</surname><given-names>S.A.</given-names></name><name><surname>Alsulaimany</surname><given-names>F.A.</given-names></name><name><surname>Obaid</surname><given-names>A.Y.</given-names></name><name><surname>Zhou</surname><given-names>B.</given-names></name><name><surname>Smith</surname><given-names>D.K.</given-names></name><name><surname>Holmes</surname><given-names>E.C.</given-names></name><name><surname>Zhu</surname><given-names>H.</given-names></name><name><surname>Guan</surname><given-names>Y.</given-names></name></person-group><article-title>Co-circulation of three camel coronavirus species and recombination of MERS-CoVs in Saudi Arabia</article-title><source>Science</source><volume>351</volume><year>2016</year><fpage>81</fpage><lpage>84</lpage><pub-id pub-id-type="pmid">26678874</pub-id></element-citation></ref><ref id="bib18"><element-citation publication-type="journal" id="sref18"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>C.Z.X.</given-names></name><name><surname>Gai</surname><given-names>W.</given-names></name><name><surname>Zhao</surname><given-names>Y.</given-names></name><name><surname>Wang</surname><given-names>H.</given-names></name><name><surname>Wang</surname><given-names>H.</given-names></name><name><surname>Feng</surname><given-names>N.</given-names></name><name><surname>Chi</surname><given-names>H.</given-names></name><name><surname>Qiu</surname><given-names>B.</given-names></name><name><surname>Li</surname><given-names>N.</given-names></name><name><surname>Wang</surname><given-names>T.</given-names></name><name><surname>Gao</surname><given-names>Y.</given-names></name><name><surname>Yang</surname><given-names>S.</given-names></name><name><surname>Xia</surname><given-names>X.</given-names></name></person-group><article-title>MERS-CoV virus-like particles produced in insect cells induce specific humoural and cellular imminity in rhesus macaques</article-title><source>Oncotarget</source><year>2016</year><comment>(in press)</comment></element-citation></ref><ref id="bib19"><element-citation publication-type="journal" id="sref19"><person-group person-group-type="author"><name><surname>Zaki</surname><given-names>A.M.</given-names></name><name><surname>van Boheemen</surname><given-names>S.</given-names></name><name><surname>Bestebroer</surname><given-names>T.M.</given-names></name><name><surname>Osterhaus</surname><given-names>A.D.</given-names></name><name><surname>Fouchier</surname><given-names>R.A.</given-names></name></person-group><article-title>Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia</article-title><source>N. Engl. J. Med.</source><volume>367</volume><year>2012</year><fpage>1814</fpage><lpage>1820</lpage><pub-id pub-id-type="pmid">23075143</pub-id></element-citation></ref><ref id="bib20"><element-citation publication-type="journal" id="sref20"><person-group person-group-type="author"><name><surname>Zaki</surname><given-names>A.M.</given-names></name><name><surname>van Boheemen</surname><given-names>S.</given-names></name><name><surname>Bestebroer</surname><given-names>T.M.</given-names></name><name><surname>Osterhaus</surname><given-names>A.D.M.E.</given-names></name><name><surname>Fouchier</surname><given-names>R.A.M.</given-names></name></person-group><article-title>Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia</article-title><source>N. Engl. J. Med.</source><volume>367</volume><year>2012</year><fpage>1814</fpage><lpage>1820</lpage><pub-id pub-id-type="pmid">23075143</pub-id></element-citation></ref><ref id="bib21"><element-citation publication-type="journal" id="sref21"><person-group person-group-type="author"><name><surname>Zhao</surname><given-names>J.</given-names></name><name><surname>Li</surname><given-names>K.</given-names></name><name><surname>Wohlford-Lenane</surname><given-names>C.</given-names></name><name><surname>Agnihothram</surname><given-names>S.S.</given-names></name><name><surname>Fett</surname><given-names>C.</given-names></name><name><surname>Gale</surname><given-names>M.J.</given-names><suffix>Jr.</suffix></name><name><surname>Baric</surname><given-names>R.S.</given-names></name><name><surname>Enjuanes</surname><given-names>L.</given-names></name><name><surname>Gallagher</surname><given-names>T.</given-names></name><name><surname>McCray</surname><given-names>P.B.</given-names><suffix>Jr.</suffix></name><name><surname>Perlman</surname><given-names>S.</given-names></name></person-group><article-title>Rapid generation of a mouse model for Middle East respiratory syndrome</article-title><source>Proc. Natl. Acad. Sci. U. S. A.</source><volume>111</volume><year>2014</year><fpage>4970</fpage><lpage>4975</lpage><pub-id pub-id-type="pmid">24599590</pub-id></element-citation></ref><ref id="bib22"><element-citation publication-type="journal" id="sref22"><person-group person-group-type="author"><name><surname>Zhao</surname><given-names>J.</given-names></name><name><surname>Perera</surname><given-names>R.A.</given-names></name><name><surname>Kayali</surname><given-names>G.</given-names></name><name><surname>Meyerholz</surname><given-names>D.</given-names></name><name><surname>Perlman</surname><given-names>S.</given-names></name><name><surname>Peiris</surname><given-names>M.</given-names></name></person-group><article-title>Passive immunotherapy with dromedary immune serum in an experimental animal model for Middle East respiratory syndrome coronavirus infection</article-title><source>J. virology</source><volume>89</volume><year>2015</year><fpage>6117</fpage><lpage>6120</lpage><pub-id pub-id-type="pmid">25787284</pub-id></element-citation></ref><ref id="bib23"><element-citation publication-type="journal" id="sref23"><person-group person-group-type="author"><name><surname>Zheng</surname><given-names>X.</given-names></name><name><surname>Wong</surname><given-names>G.</given-names></name><name><surname>Zhao</surname><given-names>Y.</given-names></name><name><surname>Wang</surname><given-names>H.</given-names></name><name><surname>He</surname><given-names>S.</given-names></name><name><surname>Bi</surname><given-names>Y.</given-names></name><name><surname>Chen</surname><given-names>W.</given-names></name><name><surname>Jin</surname><given-names>H.</given-names></name><name><surname>Gai</surname><given-names>W.</given-names></name><name><surname>Chu</surname><given-names>D.</given-names></name><name><surname>Cao</surname><given-names>Z.</given-names></name><name><surname>Wang</surname><given-names>C.</given-names></name><name><surname>Fan</surname><given-names>Q.</given-names></name><name><surname>Chi</surname><given-names>H.</given-names></name><name><surname>Gao</surname><given-names>Y.</given-names></name><name><surname>Wang</surname><given-names>T.</given-names></name><name><surname>Feng</surname><given-names>N.</given-names></name><name><surname>Yan</surname><given-names>F.</given-names></name><name><surname>Huang</surname><given-names>G.</given-names></name><name><surname>Zheng</surname><given-names>Y.</given-names></name><name><surname>Li</surname><given-names>N.</given-names></name><name><surname>Li</surname><given-names>Y.</given-names></name><name><surname>Qian</surname><given-names>J.</given-names></name><name><surname>Zou</surname><given-names>Y.</given-names></name><name><surname>Kobinger</surname><given-names>G.</given-names></name><name><surname>Gao</surname><given-names>G.F.</given-names></name><name><surname>Qiu</surname><given-names>X.</given-names></name><name><surname>Yang</surname><given-names>S.</given-names></name><name><surname>Xia</surname><given-names>X.</given-names></name></person-group><article-title>Treatment with hyperimmune equine immunoglobulin or immunoglobulin fragments completely protects rodents from Ebola virus infection</article-title><source>Sci. Rep.</source><volume>6</volume><year>2016</year><fpage>24179</fpage><pub-id pub-id-type="pmid">27067649</pub-id></element-citation></ref><ref id="bib24"><element-citation publication-type="journal" id="sref24"><person-group person-group-type="author"><name><surname>Zhou</surname><given-names>L.</given-names></name><name><surname>Ni</surname><given-names>B.</given-names></name><name><surname>Luo</surname><given-names>D.</given-names></name><name><surname>Zhao</surname><given-names>G.</given-names></name><name><surname>Jia</surname><given-names>Z.</given-names></name><name><surname>Zhang</surname><given-names>L.</given-names></name><name><surname>Lin</surname><given-names>Z.</given-names></name><name><surname>Wang</surname><given-names>L.</given-names></name><name><surname>Zhang</surname><given-names>S.</given-names></name><name><surname>Xing</surname><given-names>L.</given-names></name><name><surname>Li</surname><given-names>J.</given-names></name><name><surname>Liang</surname><given-names>Y.</given-names></name><name><surname>Shi</surname><given-names>X.</given-names></name><name><surname>Zhao</surname><given-names>T.</given-names></name><name><surname>Zhou</surname><given-names>L.</given-names></name><name><surname>Wu</surname><given-names>Y.</given-names></name><name><surname>Wang</surname><given-names>X.</given-names></name></person-group><article-title>Inhibition of infection caused by severe acute respiratory syndrome-associated coronavirus by equine neutralizing antibody in aged mice</article-title><source>Int. Immunopharmacol.</source><volume>7</volume><year>2007</year><fpage>392</fpage><lpage>400</lpage><pub-id pub-id-type="pmid">17276898</pub-id></element-citation></ref><ref id="bib25"><element-citation publication-type="journal" id="sref25"><person-group person-group-type="author"><name><surname>Zumla</surname><given-names>A.</given-names></name><name><surname>Hui</surname><given-names>D.S.</given-names></name><name><surname>Perlman</surname><given-names>S.</given-names></name></person-group><article-title>Middle East respiratory syndrome</article-title><source>Lancet</source><volume>386</volume><year>2015</year><fpage>995</fpage><lpage>1007</lpage><pub-id pub-id-type="pmid">26049252</pub-id></element-citation></ref></ref-list><ack id="ack0010"><title>Acknowledgments</title><p>This work was supported by the <funding-source id="gs1">National Key R&D program</funding-source> (2016YFC1200902), the <funding-source id="gs2">National Science and Technology Major Project of the Ministry of Science and Technology of China</funding-source> (No. 2014ZX09102044-007), the <funding-source id="gs3">Municipal Healthcare Joint-Innovation Major Project of Guangzhou</funding-source> (201604020011) and the <funding-source id="gs4">Open Project of the State Key Laboratory of Respiratory Disease and the National Institutes of Health</funding-source> (SP).</p></ack></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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