MERS coronavirus outbreak: Implications for emerging viral infections
Identifieur interne : 001310 ( Pmc/Corpus ); précédent : 001309; suivant : 001311MERS coronavirus outbreak: Implications for emerging viral infections
Auteurs : Awad Al-Omari ; Ali A. Rabaan ; Samer Salih ; Jaffar A. Al-Tawfiq ; Ziad A. MemishSource :
- Diagnostic Microbiology and Infectious Disease [ 0732-8893 ] ; 2018.
Abstract
In September 2012, a novel coronavirus was isolated from a patient who died in Saudi Arabia after presenting with acute respiratory distress and acute kidney injury. Analysis revealed the disease to be due to a novel virus which was named Middle East Respiratory Coronavirus (MERS-CoV). There have been several MERS-CoV hospital outbreaks in KSA, continuing to the present day, and the disease has a mortality rate in excess of 35%. Since 2012, the World Health Organization has been informed of 2220 laboratory-confirmed cases resulting in at least 790 deaths. Cases have since arisen in 27 countries, including an outbreak in the Republic of Korea in 2015 in which 36 people died, but more than 80% of cases have occurred in Saudi Arabia.. Human-to-human transmission of MERS-CoV, particularly in healthcare settings, initially caused a ‘media panic’, however human-to-human transmission appears to require close contact and thus far the virus has not achieved epidemic potential. Zoonotic transmission is of significant importance and evidence is growing implicating the dromedary camel as the major animal host in spread of disease to humans. MERS-CoV is now included on the WHO list of priority blueprint diseases for which there which is an urgent need for accelerated research and development as they have the potential to cause a public health emergency while there is an absence of efficacious drugs and/or vaccines. In this review we highlight epidemiological, clinical, and infection control aspects of MERS-CoV as informed by the Saudi experience. Attention is given to recommended treatments and progress towards vaccine development.
Url:
DOI: 10.1016/j.diagmicrobio.2018.10.011
PubMed: 30413355
PubMed Central: 7127703
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">MERS coronavirus outbreak: Implications for emerging viral infections</title><author><name sortKey="Al Omari, Awad" sort="Al Omari, Awad" uniqKey="Al Omari A" first="Awad" last="Al-Omari">Awad Al-Omari</name><affiliation><nlm:aff id="af0005">Critical Care and Infection Control Department, Dr. Sulaiman Al-Habib Medical Group, and Al-Faisal University, Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Rabaan, Ali A" sort="Rabaan, Ali A" uniqKey="Rabaan A" first="Ali A." last="Rabaan">Ali A. Rabaan</name><affiliation><nlm:aff id="af0010">Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Salih, Samer" sort="Salih, Samer" uniqKey="Salih S" first="Samer" last="Salih">Samer Salih</name><affiliation><nlm:aff id="af0015">Internal Medicine Department, Dr.Sulaiman Al-Habib Medical Group, Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Tawfiq, Jaffar A" sort="Al Tawfiq, Jaffar A" uniqKey="Al Tawfiq J" first="Jaffar A." last="Al-Tawfiq">Jaffar A. Al-Tawfiq</name><affiliation><nlm:aff id="af0020">Medical Department, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff></affiliation></author><author><name sortKey="Memish, Ziad A" sort="Memish, Ziad A" uniqKey="Memish Z" first="Ziad A." last="Memish">Ziad A. Memish</name><affiliation><nlm:aff id="af0025">College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30413355</idno><idno type="pmc">7127703</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127703</idno><idno type="RBID">PMC:7127703</idno><idno type="doi">10.1016/j.diagmicrobio.2018.10.011</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">001310</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001310</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">MERS coronavirus outbreak: Implications for emerging viral infections</title><author><name sortKey="Al Omari, Awad" sort="Al Omari, Awad" uniqKey="Al Omari A" first="Awad" last="Al-Omari">Awad Al-Omari</name><affiliation><nlm:aff id="af0005">Critical Care and Infection Control Department, Dr. Sulaiman Al-Habib Medical Group, and Al-Faisal University, Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Rabaan, Ali A" sort="Rabaan, Ali A" uniqKey="Rabaan A" first="Ali A." last="Rabaan">Ali A. Rabaan</name><affiliation><nlm:aff id="af0010">Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Salih, Samer" sort="Salih, Samer" uniqKey="Salih S" first="Samer" last="Salih">Samer Salih</name><affiliation><nlm:aff id="af0015">Internal Medicine Department, Dr.Sulaiman Al-Habib Medical Group, Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Al Tawfiq, Jaffar A" sort="Al Tawfiq, Jaffar A" uniqKey="Al Tawfiq J" first="Jaffar A." last="Al-Tawfiq">Jaffar A. Al-Tawfiq</name><affiliation><nlm:aff id="af0020">Medical Department, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA</nlm:aff></affiliation></author><author><name sortKey="Memish, Ziad A" sort="Memish, Ziad A" uniqKey="Memish Z" first="Ziad A." last="Memish">Ziad A. Memish</name><affiliation><nlm:aff id="af0025">College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia</nlm:aff></affiliation></author></analytic><series><title level="j">Diagnostic Microbiology and Infectious Disease</title><idno type="ISSN">0732-8893</idno><idno type="eISSN">1879-0070</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>In September 2012, a novel coronavirus was isolated from a patient who died in Saudi Arabia after presenting with acute respiratory distress and acute kidney injury. Analysis revealed the disease to be due to a novel virus which was named Middle East Respiratory Coronavirus (MERS-CoV). There have been several MERS-CoV hospital outbreaks in KSA, continuing to the present day, and the disease has a mortality rate in excess of 35%. Since 2012, the World Health Organization has been informed of 2220 laboratory-confirmed cases resulting in at least 790 deaths. Cases have since arisen in 27 countries, including an outbreak in the Republic of Korea in 2015 in which 36 people died, but more than 80% of cases have occurred in Saudi Arabia.. Human-to-human transmission of MERS-CoV, particularly in healthcare settings, initially caused a ‘media panic’, however human-to-human transmission appears to require close contact and thus far the virus has not achieved epidemic potential. Zoonotic transmission is of significant importance and evidence is growing implicating the dromedary camel as the major animal host in spread of disease to humans. MERS-CoV is now included on the WHO list of priority blueprint diseases for which there which is an urgent need for accelerated research and development as they have the potential to cause a public health emergency while there is an absence of efficacious drugs and/or vaccines. In this review we highlight epidemiological, clinical, and infection control aspects of MERS-CoV as informed by the Saudi experience. Attention is given to recommended treatments and progress towards vaccine development.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Agrawal, A S" uniqKey="Agrawal A">A.S. Agrawal</name></author><author><name sortKey="Ying, T" uniqKey="Ying T">T. Ying</name></author><author><name sortKey="Tao, X" uniqKey="Tao X">X. Tao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ahmed, A E" uniqKey="Ahmed A">A.E. Ahmed</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Al Johani, S" uniqKey="Al Johani S">S. Al Johani</name></author><author><name sortKey="Hajeer, A H" uniqKey="Hajeer A">A.H. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Diagn Microbiol Infect Dis</journal-id><journal-id journal-id-type="iso-abbrev">Diagn. Microbiol. Infect. Dis</journal-id><journal-title-group><journal-title>Diagnostic Microbiology and Infectious Disease</journal-title></journal-title-group><issn pub-type="ppub">0732-8893</issn><issn pub-type="epub">1879-0070</issn><publisher><publisher-name>Elsevier Inc.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30413355</article-id><article-id pub-id-type="pmc">7127703</article-id><article-id pub-id-type="publisher-id">S0732-8893(18)30502-9</article-id><article-id pub-id-type="doi">10.1016/j.diagmicrobio.2018.10.011</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>MERS coronavirus outbreak: Implications for emerging viral infections</article-title></title-group><contrib-group><contrib contrib-type="author" id="au0005"><name><surname>Al-Omari</surname><given-names>Awad</given-names></name><xref rid="af0005" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au0010"><name><surname>Rabaan</surname><given-names>Ali A.</given-names></name><email>arabaan@gmail.com</email><email>ali.rabaan@jhah.com</email><xref rid="af0010" ref-type="aff">b</xref><xref rid="cr0005" ref-type="corresp">⁎</xref></contrib><contrib contrib-type="author" id="au0015"><name><surname>Salih</surname><given-names>Samer</given-names></name><xref rid="af0015" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au0020"><name><surname>Al-Tawfiq</surname><given-names>Jaffar A.</given-names></name><xref rid="af0020" ref-type="aff">d</xref></contrib><contrib contrib-type="author" id="au0025"><name><surname>Memish</surname><given-names>Ziad A.</given-names></name><xref rid="af0025" ref-type="aff">e</xref></contrib></contrib-group><aff id="af0005"><label>a</label>Critical Care and Infection Control Department, Dr. Sulaiman Al-Habib Medical Group, and Al-Faisal University, Riyadh, Saudi Arabia</aff><aff id="af0010"><label>b</label>Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia</aff><aff id="af0015"><label>c</label>Internal Medicine Department, Dr.Sulaiman Al-Habib Medical Group, Riyadh, Saudi Arabia</aff><aff id="af0020"><label>d</label>Medical Department, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA</aff><aff id="af0025"><label>e</label>College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia</aff><author-notes><corresp id="cr0005"><label>⁎</label>Corresponding author. Tel.: +966-13-877-6670; fax: +966-13-877-6741. <email>arabaan@gmail.com</email><email>ali.rabaan@jhah.com</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>18</day><month>10</month><year>2018</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>3</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>18</day><month>10</month><year>2018</year></pub-date><volume>93</volume><issue>3</issue><fpage>265</fpage><lpage>285</lpage><history><date date-type="received"><day>21</day><month>7</month><year>2018</year></date><date date-type="rev-recd"><day>28</day><month>9</month><year>2018</year></date><date date-type="accepted"><day>11</day><month>10</month><year>2018</year></date></history><permissions><copyright-statement>© 2018 Elsevier Inc. All rights reserved.</copyright-statement><copyright-year>2018</copyright-year><copyright-holder>Elsevier Inc.</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="ab0005"><p>In September 2012, a novel coronavirus was isolated from a patient who died in Saudi Arabia after presenting with acute respiratory distress and acute kidney injury. Analysis revealed the disease to be due to a novel virus which was named Middle East Respiratory Coronavirus (MERS-CoV). There have been several MERS-CoV hospital outbreaks in KSA, continuing to the present day, and the disease has a mortality rate in excess of 35%. Since 2012, the World Health Organization has been informed of 2220 laboratory-confirmed cases resulting in at least 790 deaths. Cases have since arisen in 27 countries, including an outbreak in the Republic of Korea in 2015 in which 36 people died, but more than 80% of cases have occurred in Saudi Arabia.. Human-to-human transmission of MERS-CoV, particularly in healthcare settings, initially caused a ‘media panic’, however human-to-human transmission appears to require close contact and thus far the virus has not achieved epidemic potential. Zoonotic transmission is of significant importance and evidence is growing implicating the dromedary camel as the major animal host in spread of disease to humans. MERS-CoV is now included on the WHO list of priority blueprint diseases for which there which is an urgent need for accelerated research and development as they have the potential to cause a public health emergency while there is an absence of efficacious drugs and/or vaccines. In this review we highlight epidemiological, clinical, and infection control aspects of MERS-CoV as informed by the Saudi experience. Attention is given to recommended treatments and progress towards vaccine development.</p></abstract><abstract abstract-type="author-highlights" id="ab0010"><title>Highlights</title><p><list list-type="simple" id="l0005"><list-item id="li0005"><label>•</label><p id="p0005">2220 laboratory-confirmed cases of MERS-CoV resulting in at least 790 deaths since 2012</p></list-item><list-item id="li0010"><label>•</label><p id="p0010">MERS-CoV is on the WHO list of priority blueprint diseases</p></list-item><list-item id="li0015"><label>•</label><p id="p0015">Zoonotic and human-to-human transmission modes need further clarification.</p></list-item><list-item id="li0020"><label>•</label><p id="p0020">No specific therapy has yet been approved.</p></list-item><list-item id="li0025"><label>•</label><p id="p0025">There is a need for well-controlled clinical trials on potential direct therapies.</p></list-item></list></p></abstract><kwd-group id="ks0005"><title>Keywords</title><kwd>Coronavirus</kwd><kwd>MERS</kwd><kwd>Respiratory</kwd><kwd>Infection</kwd><kwd>Transmission</kwd><kwd>Saudi Arabia</kwd><kwd>Middle East</kwd></kwd-group></article-meta></front><body><sec id="s0005"><label>1</label><title>Introduction</title><p id="p0030">Middle East Respiratory Syndrome (MERS) arises from infection with the MERS-coronavirus (MERS-CoV), a beta coronavirus. Since the first confirmed case in June 2012, the World Health Organization (WHO) have been informed of 2220 laboratory-confirmed cases resulting in at least 790 deaths (<xref rid="bb0775" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV), 2018</xref>; <xref rid="bb1180" ref-type="bibr">Zaki et al., 2012</xref>). Although cases have arisen in 27 countries to date, including a major outbreak in the Republic of Korea in 2015, the overwhelming burden of infection has occurred in the Middle East and most particularly in the Kingdom of Saudi Arabia (KSA), where more than 80% of cases have occurred according to WHO estimates (<xref rid="bb0775" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV), 2018</xref>; <xref rid="bb0805" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV). Fact sheet, 2018</xref>; <xref rid="bb0840" ref-type="bibr">Nishiura et al., 2016a</xref>, <xref rid="bb0845" ref-type="bibr">Nishiura et al., 2016b</xref>, <xref rid="bb0885" ref-type="bibr">Park et al., 2015</xref>). In this review, we consider current knowledge of MERS-CoV virology, molecular biology, immunology, epidemiology, diagnosis, transmission, therapy and vaccinology with special reference to the impact on the Middle East and KSA in particular.</p></sec><sec id="s0010"><label>2</label><title>Epidemiology</title><p id="p0035">The first confirmed case of Middle East Respiratory Syndrome (MERS) was in June 2012. A previously healthy 60-year old Saudi male was hospitalized on 10th June 2012 in Bisha in the Kingdom of Saudi Arabia (KSA) with acute community-acquired pneumonia and was subsequently transferred to a private hospital in Jeddah on 13th June 2012, where he died on 24th June due to respiratory and renal failure (<xref rid="bb1180" ref-type="bibr">Zaki et al., 2012</xref>). Indirect immunofluorescence assays on day 1 sputum samples were negative for influenza A and B, parainfluenza 1 to 3, respiratory syncytial virus and adenovirus, however cytopathic changes in LLC-MK2 and Vero cells inoculated with the patient's sputum indicated the likelihood of viral replication (<xref rid="bb1180" ref-type="bibr">Zaki et al., 2012</xref>). PCR testing was negative for adenovirus, enterovirus, metapneumovirus, herpesviruses, and paramyxoviruses but positive for detection of coronaviruses (<xref rid="bb1180" ref-type="bibr">Zaki et al., 2012</xref>). Sequencing of the PCR products confirmed the identification of a new virus belonging in lineage C of the betacoronavirus genus and initially named human coronavirus EMC (HCoV-EMC) (<xref rid="bb1180" ref-type="bibr">Zaki et al., 2012</xref>). In September 2012, the same virus was identified in a 49-year-old man who had been transferred from a hospital in Qatar to London with an unexplained, severe respiratory illness which required intubation and ventilation (<xref rid="bb0155" ref-type="bibr">Bermingham et al., 2012</xref>). Importantly, this man had a history of travel in KSA, where he had experienced a mild undiagnosed respiratory illness in August 2012 (<xref rid="bb0155" ref-type="bibr">Bermingham et al., 2012</xref>). The first cluster of human cases was retrospectively confirmed from a group of 13 people who had become ill with an unexplained respiratory illness in a public hospital in Zarqa city in Jordan in April 2012 (<xref rid="bb0505" ref-type="bibr">Hijawi et al., 2013</xref>).</p><p id="p0040">Since then, most outbreaks have occurred in KSA. These include a cluster of 25 cases in Al-Hasa between April 1st and May 23rd 2013 (<xref rid="bb0110" ref-type="bibr">Assiri et al., 2013a</xref>), 255 laboratory-confirmed cases in Jeddah between January 1st and May 16th, 2014 (<xref rid="bb0365" ref-type="bibr">Drosten et al., 2015</xref>, <xref rid="bb0865" ref-type="bibr">Oboho et al., 2015</xref>), 45 cases in King Fahad Medical City in Riyadh between March 29th and May 21st, 2014, with contemporaneous outbreaks in other Riyadh hospitals between March and April 2014 (<xref rid="bb0045" ref-type="bibr">Almekhlafi et al., 2016</xref>, <xref rid="bb0390" ref-type="bibr">Fagbo et al., 2015</xref>), and 130 cases at King Abulaziz Medical City in Riyadh during late June–late August 2015 (<xref rid="bb0130" ref-type="bibr">Balkhy et al., 2016a</xref>). An exception was the major outbreak that occurred in in the Republic of Korea between 20 May and 27 July 2015 (<xref rid="bb0840" ref-type="bibr">Nishiura et al., 2016a</xref>, <xref rid="bb0845" ref-type="bibr">Nishiura et al., 2016b</xref>, <xref rid="bb0885" ref-type="bibr">Park et al., 2015</xref>). This outbreak encompassed 186 MERS-CoV cases, and resulted in 36 deaths (<xref rid="bb0780" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV) – Republic of Korea, 2015</xref>; <xref rid="bb0840" ref-type="bibr">Nishiura et al., 2016a</xref>, <xref rid="bb0845" ref-type="bibr">Nishiura et al., 2016b</xref>). However, in common with cases that have arisen in other countries outside the Middle East, the Korean outbreak began with a man with a preceding travel history to Middle Eastern countries. According to reports made to WHO and the Centers of Disease Control and Prevention (CDC), laboratory-confirmed cases of MERS have occurred in Middle Eastern countries including KSA, Bahrain, Iran, Jordan, Kuwait, Lebanon, Oman, Qatar, United Arab Emirates (UAE), and Yemen, as well as in countries outside the Middle East including Algeria, Austria, China, Egypt, France, Germany, Greece, Italy, Malaysia, Netherlands, Philippines, Republic of Korea, Thailand, Tunisia, Turkey, United Kingdom (UK), and United States of America (USA), but associated with individuals with a travel history in the Middle East.</p><p id="p0045">MERS-CoV is now included on the WHO list of priority blueprint diseases for which there which is an urgent need for accelerated research and development as they have the potential to cause a public health emergency while there is an absence of efficacious drugs and/or vaccines (<xref rid="bb0635" ref-type="bibr">List of Blueprint priority diseases, 2018</xref>). Cases continue to arise in KSA and exact a high mortality rate, including 20 cases from 11 areas of the country reported to WHO by the National IHR Focal Point between December 2017 and 17 January 2018, resulting in 9 deaths (<xref rid="bb0795" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV) – Saudi Arabia, 2018</xref>). Frequent small outbreaks include 2 clusters of cases in the Al Jawf Region of KSA, <italic>i.e.</italic> a cluster of 13 cases in a hospital between 2nd and 11th August 2017, among them 8 healthcare workers (HCWs), and 7 cases in Dawmet Aljandal City between 24th and 31st August 2017 (<xref rid="bb0785" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV) – Saudi Arabia, 2017a</xref>, <xref rid="bb0790" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV) – Saudi Arabia, 2017b</xref>). In 3 clusters in 3 Riyadh hospitals in June 2017, 2 of which were related, 49 individuals were infected of whom 10 died (<xref rid="bb0315" ref-type="bibr">Coronavirus infections, 2017</xref>).</p><p id="p0050">Clearly, MERS-CoV is a serious public health issue in KSA. Extended outbreaks of the disease have been focused on healthcare facilities, with transmission apparently dependent on close human-to-human contact (<xref rid="bb0045" ref-type="bibr">Almekhlafi et al., 2016</xref>, <xref rid="bb0110" ref-type="bibr">Assiri et al., 2013a</xref>, <xref rid="bb0130" ref-type="bibr">Balkhy et al., 2016a</xref>, <xref rid="bb0365" ref-type="bibr">Drosten et al., 2015</xref>, <xref rid="bb0390" ref-type="bibr">Fagbo et al., 2015</xref>, <xref rid="bb0865" ref-type="bibr">Oboho et al., 2015</xref>). The emergence of this disease has therefore had a profound impact on infection control and prevention procedures in KSA as outbreaks in healthcare facilities have been associated with defective or inadequate infection prevention and control measures (<xref rid="bb0135" ref-type="bibr">Balkhy et al., 2016b</xref>, <xref rid="bb0180" ref-type="bibr">Butt et al., 2016</xref>, <xref rid="bb0325" ref-type="bibr">Cotten et al., 2014</xref>, <xref rid="bb0480" ref-type="bibr">Hastings et al., 2016</xref>).</p></sec><sec id="s0015"><label>3</label><title>Infection prevention and control measures in Saudi Arabia</title><p id="p0055">Public health authorities in KSA worked with WHO in identifying shortcomings in infection and control procedures in healthcare facilities which contributed to MERS-CoV transmission (<xref rid="bb0775" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV), 2018</xref>). Problems which were identified included emergency room overcrowding and neglect of basic infection and prevention control measures such as handwashing (<xref rid="bb0775" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV), 2018</xref>). The KSA Ministry of Health updated guidelines for infection prevention and control in line with WHO recommendations (<xref rid="bb0180" ref-type="bibr">Butt et al., 2016</xref>, <xref rid="bb0480" ref-type="bibr">Hastings et al., 2016</xref>). The Ministry of Health now specifies that “Standard Precautions” should be adhered to in all patient interactions within hospitals, and that these should be further supplemented with the specific precautions for suspected or confirmed MERS-CoV cases (<xref rid="bb1000" ref-type="bibr">Scientific Advisory Board, Ministry of Health, Kingdom of Saudi Arabia, n.d.</xref>). Infection prevention and control measures include comprehensive basic procedures such as hand hygiene, including application of ‘my 5 moments for hand hygiene’ (<xref rid="bb0005" ref-type="bibr">About SAVE LIVES: Clean Your Hands, 2018</xref>), respiratory precautions, contacts control, and use of personal protective equipment (PPE), which comprises surgical or correctly fitted and sealed N95 mask, gloves and gown, and goggles/face shield where indicated, and prevention of overcrowding in emergency rooms. More advanced precautions for care of patients with acute respiratory infections include use of effective triage, droplet and airborne precautions, safe patient transport and continuous training and education of healthcare workers. Frequent and thorough cleaning of MERS patient rooms with special attention to frequently touched surfaces, preferably by designated, well-trained housekeeping staff and with a clearly defined scope for cleaning of patient-care equipment, is also recommended (<xref rid="bb1000" ref-type="bibr">Scientific Advisory Board, Ministry of Health, Kingdom of Saudi Arabia, n.d.</xref>). Ministry of Health guidelines should also be followed for cleaning and disinfection after MERS patient discharge, handling of textiles, use of disposable dishes and eating utensils for MERS-CoV patients and diposal of medical waste (<xref rid="bb1000" ref-type="bibr">Scientific Advisory Board, Ministry of Health, Kingdom of Saudi Arabia, n.d.</xref>). Detailed guidelines are included on management of contacts of MERS-CoV patients, including household contacts, healthcare workers and patients; contact monitoring for 14 days after date of exposure is recommended (<xref rid="bb1000" ref-type="bibr">Scientific Advisory Board, Ministry of Health, Kingdom of Saudi Arabia, n.d.</xref>). Home isolation procedures and duration of isolation precautions should be based on laboratory testing if available to assure absence of viral shedding; appropriate duration of isolation is an area that is still being researched (<xref rid="bb1000" ref-type="bibr">Scientific Advisory Board, Ministry of Health, Kingdom of Saudi Arabia, n.d.</xref>). Handling of bodies in the mortuary, as well as guidelines for extracorporeal membrane oxygenation (ECMO), which is available in designated MERS-CoV centers in Riyadh, Jeddah and Dammam, but which is of uncertain benefit for MERS-CoV treatment, are also detailed (<xref rid="bb1000" ref-type="bibr">Scientific Advisory Board, Ministry of Health, Kingdom of Saudi Arabia, n.d.</xref>).</p><p id="p0060">Implementation of these infection prevention and control guidelines for MERS-CoV in line with most up-to-date case definition and surveillance guidance have resulted in a decline in cases in KSA (<xref rid="bb1000" ref-type="bibr">Scientific Advisory Board, Ministry of Health, Kingdom of Saudi Arabia, n.d.</xref>). However, diligence in needed in maintaining surveillance standards and furthering understanding of transmission patterns within KSA and elsewhere. Comparison of epidemiology of KSA outbreaks to that of the Republic of Korea 2015 outbreak suggests that while there are similarities in terms of mean age of infected individuals (51 and 54 y respectively) and the higher risk of infection or death for older males (≥70 y), nevertheless there is evidence that transmission patterns and risk factors are different in KSA (<xref rid="bb0230" ref-type="bibr">Chen et al., 2017</xref>). While in Korea the transmission pattern was almost exclusively nosocomial, in KSA zoonotic transmission, human-to-human transmission and unknown pathways were all present in addition to nosocomial infection (<xref rid="bb0230" ref-type="bibr">Chen et al., 2017</xref>). In some 59.9% of cases in KSA outbreaks, exposure risk was unknown (<xref rid="bb0230" ref-type="bibr">Chen et al., 2017</xref>). Thus in addition to the infection prevention and control guidelines for healthcare facilities, WHO has also issued guidance on potential zoonotic transmission in the community, in particular with respect to dromedary camels which are recognized as a major MERS-CoV host reservoir and animal source for human infection (<xref rid="bb0805" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV). Fact sheet, 2018</xref>). In KSA it is recommended that people visiting places where dromedary camels are present should practice general hygiene measures and avoid contact with sick animals. Furthermore, consumption of raw or uncooked meat, milk or urine from dromedaries is discouraged, with pasteurization, cooking, or other heat treatments recommended for rendering these products fit for consumption (<xref rid="bb0805" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV). Fact sheet, 2018</xref>). Immunocompromised people and other vulnerable groups such as people with diabetes, renal failure or chronic lung disease are advised to avoid contact with dromedaries in general and not to consume camel food products that have not been pasteurized or adequately cooked (<xref rid="bb0805" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV). Fact sheet, 2018</xref>). Recent studies, including those based on serological evidence, support the role of dromedary camels as important zoonotic sources of human MERS-CoV infection. MERS-CoV antibodies are present in more than 90% of dromedary camels tested in the Middle East and in many African countries (<xref rid="bb0040" ref-type="bibr">Ali et al., 2017a</xref>, <xref rid="bb0255" ref-type="bibr">Chu et al., 2015</xref>, <xref rid="bb0405" ref-type="bibr">Farag et al., 2015</xref>, <xref rid="bb0500" ref-type="bibr">Hemida et al., 2013</xref>, <xref rid="bb0490" ref-type="bibr">Hemida et al., 2014</xref>, <xref rid="bb0485" ref-type="bibr">Hemida et al., 2017a</xref>, <xref rid="bb0820" ref-type="bibr">Müller et al., 2015</xref>, <xref rid="bb0955" ref-type="bibr">Reusken et al., 2014</xref>). Dromedary camel exposure within 2 weeks of illness onset has been identified as a significant risk factor in a study examining MERS-CoV infection cases documented between May and November 2014 in KSA (<xref rid="bb0055" ref-type="bibr">Alraddadi et al., 2016a</xref>). Changes in dromedary camel production and farming practices, including intensification and location close to cities, may have contributed to zoonotic transmission in KSA (<xref rid="bb0430" ref-type="bibr">Gossner et al., 2016</xref>). Thus, in KSA the emergence of MERS-CoV has had an impact on the agricultural, animal husbandry, food production and veterinary fields, as well as infection and prevention control procedures in healthcare settings (<xref rid="bb0495" ref-type="bibr">Hemida et al., 2017b</xref>). For example, the association between the calving season and MERS-CoV infection in dromedary camels and the highest risk of MERS-CoV infection in calves compared to adult cows, has led to suggestions that weaning of calves could be delayed to reduce the opportunity for human exposure to calves (<xref rid="bb0490" ref-type="bibr">Hemida et al., 2014</xref>, <xref rid="bb0485" ref-type="bibr">Hemida et al., 2017a</xref>, <xref rid="bb0495" ref-type="bibr">Hemida et al., 2017b</xref>). Furthermore, there is a need to increase understanding of the implications in terms of MERS-CoV transmission and spread, as well as viral exchange, amplification and dissemination, of the economically important bidirectional movement of camels between African countries and the Middle East, including KSA (<xref rid="bb0495" ref-type="bibr">Hemida et al., 2017b</xref>).</p><p id="p0065">Meanwhile, when a case of MERS-CoV is suspected, effective identification is achieved by molecular methods. The currently WHO-recommended methods used in KSA are based on polymerase chain reaction (PCR) targeting of a number of MERS-CoV genes, which has been made possible by development in understanding of MERS-CoV classification and genomics.</p></sec><sec id="s0020"><label>4</label><title>General virology</title><sec id="s0025"><label>4.1</label><title>Classification</title><p id="p0070">In the 1960s, the first human respiratory illness-causing coronaviruses, (HCoVs) 229E and HCoV-OC43, were discovered (<xref rid="bb0150" ref-type="bibr">Becker et al., 1967</xref>, <xref rid="bb0470" ref-type="bibr">Hamre and Procknow, 1966</xref>). In 2003, a new CoV named Severe Acute Respiratory Syndrome (SARS)-CoV SARS was involved in a series of international outbreaks causing close to 800 deaths (<xref rid="bb0695" ref-type="bibr">Marra et al., 2003</xref>, <xref rid="bb0905" ref-type="bibr">Peiris et al., 2003</xref>, <xref rid="bb0970" ref-type="bibr">Rota et al., 2003</xref>). The NL63 and HKU1 human coronaviruses were discovered in 2004, both of which also cause human respiratory illness (<xref rid="bb0420" ref-type="bibr">Fouchier et al., 2004</xref>, <xref rid="bb0345" ref-type="bibr">van der Hoek et al., 2004</xref>). MERS-CoV was first isolated in September 2012, and initially named human coronavirus EMC (<xref rid="bb1180" ref-type="bibr">Zaki et al., 2012</xref>).The coronavirus study group later renamed this novel virus as the Middle East respiratory syndrome coronavirus (MERS-CoV), reflecting its origin (<xref rid="bb0440" ref-type="bibr">de Groot et al., 2013</xref>).</p><p id="p0075">Coronaviruses (CoVs) are members of the <italic>Coronavirinae</italic> subfamily of the <italic>Coronaviridae</italic> family. CoVs infect humans as well as other species. The subfamily is comprised of 4 genera, alpha CoVs, beta CoVs, gamma CoVs, and delta CoVs (<xref rid="f0005" ref-type="fig">Fig. 1</xref>) CoVs are enveloped single-stranded, positive-sense RNA viruses with genomes of 25 to 32 kilobases (kb). HCoV-NL63 and HCoV-229E are alphaCoVs, while SARS-CoV, MERS-CoV, HCoV-HKU1 and HCoV-OC43 are beta coronoaviruses (<xref rid="f0005" ref-type="fig">Fig. 1</xref>). The beta coronavirses can be further subdivided into 4 lineages. MERS-CoV is unique among CoVs infecting humans in belonging to lineage C (lineage 3) of the beta CoVs (<xref rid="f0005" ref-type="fig">Fig. 1</xref>) (<xref rid="bb0215" ref-type="bibr">Chan et al., 2015a</xref>, <xref rid="bb0300" ref-type="bibr">Corman et al., 2014a</xref>, <xref rid="bb0435" ref-type="bibr">de Groot et al., 2012</xref>).<fig id="f0005"><label>Fig. 1</label><caption><p>Taxonomy of the Coronaviridae family.</p></caption><alt-text id="al0005">Fig. 1</alt-text><graphic xlink:href="gr1_lrg"></graphic></fig></p><p id="p0080">Bats are potentially the main MERS-CoV mammalian reservoir, as with other coronaviruses (<xref rid="bb0360" ref-type="bibr">Drexler et al., 2014</xref>). Closely related lineage 3 viruses include the bat viruses NeoCoV, isolated from a <italic>Neoromicia zuluensis</italic> bat in South Africa, and the prototypic lineage c betacoronaviruses, <italic>Tylonycteris</italic> bat virus HKU4 and <italic>Pipistrellus</italic> bat HKU5 virus (<xref rid="f0005" ref-type="fig">Fig. 1</xref>) (<xref rid="bb0800" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV) Fact sheet, 2017</xref>; <xref rid="bb0295" ref-type="bibr">Corman et al., 2014b</xref>, <xref rid="bb0540" ref-type="bibr">Ithete et al., 2013</xref>). Studies on the phylogeny of lineage C betacoronaviruses suggest that evolution of MERS-CoV in camels occurred prior to that in humans and that there was exchange of genetic elements among ancestral viruses either in bats, or within the camel genetic ‘mixing vessel’, leading to MERS-CoV emergence (<xref rid="bb0295" ref-type="bibr">Corman et al., 2014b</xref>). Other potentially important mammalian hosts are members of the <italic>Eulipotyphla</italic> taxon, the closest sister taxon to bats which includes hedgehogs (<xref rid="bb0300" ref-type="bibr">Corman et al., 2014a</xref>). EriCoV, another lineage C virus which is closely related to both MERS-CoV and the bat lineage C coronaviruses, was found to be present in approximately 59% of European hedgehog (<italic>Erinaceus europaeus</italic>) fecal samples in a study in Germany (<xref rid="bb0300" ref-type="bibr">Corman et al., 2014a</xref>).</p></sec><sec id="s0030"><label>4.2</label><title>Genomics</title><p id="p0085">The MERS-CoV has a genome of 30,119 nucleotides comprising 7 predicted open reading frames (ORFs) (1a, 1b, 3, 4a, 4b, 5, 8b) and 4 structural genes encoding the spike (S), nucleocapsid (N), membrane (M) and envelope (E) proteins (<xref rid="f0010" ref-type="fig">Fig. 2</xref>) (<xref rid="bb0415" ref-type="bibr">Forni et al., 2016</xref>, <xref rid="bb0670" ref-type="bibr">Mackay and Arden, 2015</xref>, <xref rid="bb1200" ref-type="bibr">Zhang et al., 2016a</xref>). The overlapping ORF1a and 1b are located at the 5′ end of the single stranded positive RNA alongside a 278 nucleotide un-translated region (UTR) (<xref rid="f0010" ref-type="fig">Fig. 2</xref>). ORF1a and ORF1b comprise the majority of the MERS-CoV genome and are translated into polyproteins pp1a and pp1ab, which are then cleaved by viral proteases to give 16 non-structural proteins termed nsp1 to nsp16 (<xref rid="f0010" ref-type="fig">Fig. 2</xref>). These form the replication-transcription complex (RTC) of the virus. Individual nsp proteins have different roles in viral replication. For example, nsp3 has a papain-like protease (PLpro) activity which mediates the initial processing of pp1a (<xref rid="bb0415" ref-type="bibr">Forni et al., 2016</xref>, <xref rid="bb0465" ref-type="bibr">Hagemeijer et al., 2012</xref>, <xref rid="bb0835" ref-type="bibr">Neuman et al., 2014</xref>). Nsp3 also works with nsp4 and nsp6 to anchor the viral RTC to intracellular membranes and form a reticulovesicular membranous network where the viral RNA can replicate. Meanwhile nsp5 also has a protease activity, 3C-like protease (3CLpro), which also mediates pp1a and pp1ab cleavage into nsp 1–16. Nsp7 to nsp11 medate primer-making activity and regulate nsp12, which is the main viral RNA-dependent RNA polymerase (RdRp) (<xref rid="bb0415" ref-type="bibr">Forni et al., 2016</xref>, <xref rid="bb0465" ref-type="bibr">Hagemeijer et al., 2012</xref>, <xref rid="bb0835" ref-type="bibr">Neuman et al., 2014</xref>). Nsp13 to 16 are involved in viral RNA modification (<xref rid="bb0415" ref-type="bibr">Forni et al., 2016</xref>, <xref rid="bb0465" ref-type="bibr">Hagemeijer et al., 2012</xref>, <xref rid="bb0835" ref-type="bibr">Neuman et al., 2014</xref>).<fig id="f0010"><label>Fig. 2</label><caption><p>Genomic Mapping of MERS-CoV.</p></caption><alt-text id="al0010">Fig. 2</alt-text><graphic xlink:href="gr2_lrg"></graphic></fig></p><p id="p0090">The genes for the S, E, M and N proteins are downstream of ORF1 (<xref rid="f0010" ref-type="fig">Fig. 2</xref>). The S protein is vital in MERS-CoV transmission and host cell infection, determining tropism of the virus and host cell entry. The S protein is a trimeric, envelope protein which can be cleaved by host proteases into S1 (N-terminal) and S2 (C-terminal) subunits (<xref rid="bb0650" ref-type="bibr">Lu et al., 2015</xref>). The S1 subunit contains a receptor binding domain (RBD), which mediates binding of S protein to the host cell human dipeptidyl peptidase 4 (DPP4; CD26) receptor (<xref rid="bb0935" ref-type="bibr">Raj et al., 2013</xref>, <xref rid="bb1095" ref-type="bibr">Wang et al., 2013</xref>). Once the MERS-CoV binds to DPP4 <italic>via</italic> the S1 RBD, endocytosis occurs. Cleavage at the S1/S2 junction then occurs, mediated by host proteases including the serine protease TMPRSS2, the endosomal cathepsin L, and furin protease (<xref rid="bb0810" ref-type="bibr">Millet and Whittaker, 2014</xref>, <xref rid="bb0915" ref-type="bibr">Qian et al., 2013</xref>, <xref rid="bb1020" ref-type="bibr">Shirato et al., 2013</xref>, <xref rid="bb1150" ref-type="bibr">Yang et al., 2015a</xref>, <xref rid="bb1200" ref-type="bibr">Zhang et al., 2016a</xref>), followed by viral fusion with the host cell membrane mediated by the S2 subunit. The S2 subunit contains a fusion peptide, 2 heptad repeat domains HR1 and HR2, and a transmembrane (TM) domain (<xref rid="bb0385" ref-type="bibr">Durai et al., 2015</xref>). Fusion is facilitated by rearrangement of S2 into a 6-helix bundle (6HB) fusion core, centred on a trimer of the HR1 and HR2 dimer. This folding of H1/H2 allows exposure of the fusion peptide and insertion into host cell membrane, and hence fusion (<xref rid="bb0385" ref-type="bibr">Durai et al., 2015</xref>, <xref rid="bb1200" ref-type="bibr">Zhang et al., 2016a</xref>).</p></sec><sec id="s0035"><label>4.3</label><title>DPP4 receptor</title><p id="p0095">The MERS-CoV S protein DPP4 receptor is widely expressed in human cells including lower respiratory tract non ciliated bronchial epithelium, kidney epithelial cells, small intestine cells, T lymphocytes and macrophages (<xref rid="bb0050" ref-type="bibr">Al-Qahtani et al., 2017</xref>, <xref rid="bb0165" ref-type="bibr">Boonacker and Van Noorden, 2003</xref>, <xref rid="bb1060" ref-type="bibr">Tang et al., 2017</xref>, <xref rid="bb1110" ref-type="bibr">Widagdo et al., 2016</xref>). There is limited expression of DPP4 in the upper respiratory tract epithelium in humans when compared to dromedary camels, which may contribute to the limited replication of MERS-CoV in the human upper respiratory tract and to restriction of human-to-human transmission (<xref rid="bb1110" ref-type="bibr">Widagdo et al., 2016</xref>). Infection of macrophages by lentiviral particles pseudotyped with MERS-CoV S protein resulted in attenuation of macrophage responses <italic>via</italic> expression of IRAK-M, a negative regulator of Toll-like receptor (TLR) signaling, and of the transcriptional repressor PPARγ (<xref rid="bb0050" ref-type="bibr">Al-Qahtani et al., 2017</xref>). Use of the DPP4 inhibitor sitagliptin or DPP4-siRNA reduced the effects of MERS-CoV S protein on IRAK-M, PPARγ and IL-10, indicating that the suppression of macrophage immune responses by MERS-CoV is mediated <italic>via</italic> DPP4 (<xref rid="bb0050" ref-type="bibr">Al-Qahtani et al., 2017</xref>). Mathematical modeling suggests that reducing the rate of DPP4 expression would reduce MERS-CoV spread (<xref rid="bb1060" ref-type="bibr">Tang et al., 2017</xref>). Indeed, levels of DPP4 mRNA and protein are higher in lung tissues of smokers and individuals with chronic obstructive pulmonary disease (COPD) compared to never-smokers (<xref rid="bb1005" ref-type="bibr">Seys et al., 2018</xref>); both smoking and COPD are associated with increased susceptibility to MERS-CoV infection. Host species restriction of MERS-CoV infection has been linked to 13 DPP4 residues which are key in interacting with the S protein RBD (<xref rid="bb0650" ref-type="bibr">Lu et al., 2015</xref>, <xref rid="bb0900" ref-type="bibr">Peck et al., 2015</xref>, <xref rid="bb0355" ref-type="bibr">van Doremalen et al., 2014</xref>). Phylogenetic analyses have shown that these residues are either conserved or differ by only one or 2 residues in DPP4 of species that are permissive either <italic>in vitro</italic> or <italic>in vivo</italic>, including camel, macaque, marmoset, goat, pig, civet, and horse (<xref rid="bb0650" ref-type="bibr">Lu et al., 2015</xref>), but to have multiple variations in non-permissive species including mouse, hamster and ferret (<xref rid="bb0900" ref-type="bibr">Peck et al., 2015</xref>).</p><p id="p0100">Other host cell mediators may also be involved along with DPP4 in MERS-CoV S protein binding and viral infection. In a recent virus overlay protein binding assay (VOPBA) study, the carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was identified as a another MERS-CoV cell surface binding target which interacts with the S protein in cell culture (<xref rid="bb0200" ref-type="bibr">Chan et al., 2016</xref>). While over-expression of CEACAM5 could not independently support MERS-CoV entry into non-permissive cells, it did enhance viral attachment, while in permissive cells CEACAM5 over-expression enhanced viral entry in conjunction with DPP4 (<xref rid="bb0200" ref-type="bibr">Chan et al., 2016</xref>). MERS-CoV has also been shown to bind with high specificity but low affinity to sialic acid (Sia) in a hemagglutination assay with human erythrocytes and intact virus (<xref rid="bb0620" ref-type="bibr">Li et al., 2017</xref>). The S1 domain or its S1A subdomain expressed on nanoparticles could bind Sia-dependently to human erythrocytes or mucin, while Sia depletion on the surface of Calu-3 human airway cells reduced MERS-CoV viral entry (<xref rid="bb0620" ref-type="bibr">Li et al., 2017</xref>). Thus in addition to DPP4 expression, Sia may also contribute to MERS-CoV host range and tissue tropism.</p></sec></sec><sec id="s0040"><label>5</label><title>Pathogenesis and immunity</title><sec id="s0045"><label>5.1</label><title>Infection routes</title><p id="p0105">The human respiratory tract is the primary target for infection by MERS-CoV (<xref rid="bb0825" ref-type="bibr">Muller et al., 2012</xref>, <xref rid="bb1245" ref-type="bibr">Zielecki et al., 2013</xref>). DPP4-expressing bronchial epithelial cells, bronchiolar epithelial cells, alveolar epithelial cells and the endothelial cells of pulmonary vessels have all been found to be infected by the virus in <italic>ex vivo</italic> human lung tissue (<xref rid="bb0510" ref-type="bibr">Hocke et al., 2013</xref>, <xref rid="bb0670" ref-type="bibr">Mackay and Arden, 2015</xref>, <xref rid="bb0825" ref-type="bibr">Muller et al., 2012</xref>, <xref rid="bb0935" ref-type="bibr">Raj et al., 2013</xref>, <xref rid="bb1005" ref-type="bibr">Seys et al., 2018</xref>, <xref rid="bb1060" ref-type="bibr">Tang et al., 2017</xref>, <xref rid="bb1110" ref-type="bibr">Widagdo et al., 2016</xref>, <xref rid="bb1245" ref-type="bibr">Zielecki et al., 2013</xref>). The human intestinal tract has been recently proposed to be an alternative route for MERS-CoV infection (<xref rid="bb1230" ref-type="bibr">Zhou et al., 2017</xref>). Human primary intestinal epithelial cells, small intestine explants, and intestinal organoids have all been shown to be susceptible to MERS-CoV infection and replication, while enteric MERS-CoV has been identified in clinical patient stool samples (<xref rid="bb1230" ref-type="bibr">Zhou et al., 2017</xref>). In DPP4-transgenic mice, direct intragastri inoculation with MERS-CoV resulted in lethal infection while histology demonstrated the presence of enteric infection in all inoculated mice, with development of sequential respiratory infection (<xref rid="bb1230" ref-type="bibr">Zhou et al., 2017</xref>). MERS-CoV can target both the innate and adaptive human immune responses in a number of direct and indirect ways. A feature of MERS-CoV infection spread is the occurrence of nosocomial outbreaks. In a recent outbreak which occurred in May/June, 2017, there were 44 reported MERS-CoV cases from 3 simultaneous clusters in 3 different healthcare facilities in Riyadh; 11 cases were fatal (<xref rid="bb0080" ref-type="bibr">Amer et al., 2018</xref>). This outbreak highlights the need to develop rapid point-of-care testing to enable emergency room healthcare staff to rapidly identify MERS-CoV cases as the outbreak was the result of delay in diagnosis of MERS-CoV in a patient who presented with acute renal failure and who directly exposed 120 contacts including healthcare workers and other patients during 14 hours spent in the open area of the emergency department and 2 hemodialysis sessions (<xref rid="bb0080" ref-type="bibr">Amer et al., 2018</xref>).Hospital outbreaks, the fact that up to 50% of MERS-CoV cases in Saudi Arabia have been classified as due to human-to-human transmission through contact with asymptomatic or symptomatic individuals and the difficulty inherent in distinguishing the clinical features of MERS-CoV infection from other respiratory tract infections further highlights the importance of specific point-of-care testing and high degree of clinical awareness among clinical staff in Saudi Arabia (<xref rid="bb0520" ref-type="bibr">Hui et al., 2018</xref>).</p></sec><sec id="s0050"><label>5.2</label><title>Innate immune response: interferon</title><p id="p0110">Detection of positive-stranded RNA viruses such as MERS-CoV by the host innate immune system depends on recognition of pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) (<xref rid="bb0855" ref-type="bibr">tenOever, 2016</xref>). An important PAMP relevant to MERS-CoV is viral double-stranded (ds)-RNA. The host cell innate immune response to ds-RNA involves induction of type I interferon (IFN) expression <italic>via</italic> the RIG-1-like helicases including Rig-1 and MDA-5, as well as other activities including activation of protein kinase R (PKR), which reduces translation in the infected host cell, and activation of the 2′,5′-oligoadenylate synthetase (OAS)/RNaseL pathway, which can degrade viral RNA (<xref rid="bb0995" ref-type="bibr">Schneider et al., 2014</xref>, <xref rid="bb0855" ref-type="bibr">tenOever, 2016</xref>). Importantly, while MERS-CoV is significantly more susceptible to type I interferon (IFN)- mediated innate immune responses than SARS-CoV, it also has strategies for evading these responses. In common with other coronaviruses, the MERS-CoV nsp3 PLpro removes ubiquitin (Ub) (deubiquitination; DUB), and interferon-stimulated gene 15 (ISG15) (deISGylation) from host cell proteins, which in turn blocks production of IFN-β and hence reduces type-1 interferon responses in cell line studies (<xref rid="bb0125" ref-type="bibr">Báez-Santos et al., 2014</xref>, <xref rid="bb0330" ref-type="bibr">Daczkowski et al., 2017</xref>). MERS-CoV nsp15, which contains an endonuclease (EndoU) activity, has also been recently shown in primary cell lines and in macrophages to reduce early innate immune responses by inhibition of MDA-5, PKR and OAS responses and IFN activation (<xref rid="bb0590" ref-type="bibr">Kindler et al., 2017</xref>). Nsp16, a viral 2’O-methyltransferase (2’O-MTase), has also been recently implicated in viral pathogenesis and type I- IFN inhibition in both primary human airway cell cultures and <italic>in vivo</italic> mouse models (<xref rid="bb0745" ref-type="bibr">Menachery et al., 2017a</xref>).</p><p id="p0115">Meanwhile non-structural protein NS3, NS4a, NS4b and NS5, as well as the structural M protein, have been implicated in IFN antagonism and inhibition of the innate immune response in cell culture studies (<xref rid="bb0185" ref-type="bibr">Canton et al., 2018</xref>, <xref rid="bb0705" ref-type="bibr">Matthews et al., 2014</xref>, <xref rid="bb0750" ref-type="bibr">Menachery et al., 2017b</xref>, <xref rid="bb0930" ref-type="bibr">Rabouw et al., 2016</xref>, <xref rid="bb1025" ref-type="bibr">Siu et al., 2014</xref>, <xref rid="bb1075" ref-type="bibr">Thornbrough et al., 2016</xref>, <xref rid="bb1160" ref-type="bibr">Yang et al., 2013</xref>, <xref rid="bb1155" ref-type="bibr">Yang et al., 2015b</xref>). Lack of homology between MERS-CoV and SARS-CoV in their accessory ORF-3, 4a, 4b and 5 genes highlights the fact that immune defense mechanisms may differ between the viruses. Deletion of MERS-CoV ORF-3 to 5 has been shown both <italic>in vitro</italic> and <italic>in vivo</italic> mouse models to impact on viral replication and pathogenesis <italic>via</italic> dysregulation of host cell responses, including increased activation of the type-1 IFN pathway and induction of inflammatory responses (<xref rid="bb0750" ref-type="bibr">Menachery et al., 2017b</xref>). ORF5 has been shown to partially modulate the inflammation-associated NF-κB transcription factor (<xref rid="bb0750" ref-type="bibr">Menachery et al., 2017b</xref>). The ORF4b-encoded NS4b protein has been shown in cell culture studies to inhibit IFN- and NF-κB- mediated signaling, IFN-β production and the (OAS)/RNaseL pathway (<xref rid="bb0705" ref-type="bibr">Matthews et al., 2014</xref>, <xref rid="bb1075" ref-type="bibr">Thornbrough et al., 2016</xref>, <xref rid="bb1155" ref-type="bibr">Yang et al., 2015b</xref>). Presence of NS4b in MERS-CoVinfected cells results in tethering of NF-κB in the cytoplasm while NS4a is located in the nucleus (<xref rid="bb0185" ref-type="bibr">Canton et al., 2018</xref>). However in the absence of NS4b, or in the presence of mutant NS4b lacking a nuclear localization signal (NLS), NF-κB can translocate to the nucleus and induce pro-inflammatory cytokine expression (<xref rid="bb0185" ref-type="bibr">Canton et al., 2018</xref>). NS4b-induced NF-κB translocation inhibition appears to be mediated by its binding to karyopherin-α4 (KPNA4), a protein essential for NF-κB nuclear translocation (<xref rid="bb0185" ref-type="bibr">Canton et al., 2018</xref>). Binding of NS4b to KPNA4 during infection inhibited its interaction with the NF-κB-p65 subunit. NS4a is potentially particularly potent in IFN-inhibition as it targets both IFN-β production and signaling <italic>via</italic> interferon-sensitive response element (ISRE) promoter elements (<xref rid="bb1160" ref-type="bibr">Yang et al., 2013</xref>). NS4a-mediated inhibition of IFN production has been linked <italic>in vitro</italic> to its binding to the host cell ds-RNA-binding protein, interferon-inducible double-stranded RNA-dependent protein kinase activator A (PACT), which is a critical innate immune mediator responsible for activation of Rig-1 and MDA-5 and hence type 1-IFN in response to coronavirus infection (<xref rid="bb1025" ref-type="bibr">Siu et al., 2014</xref>). This is linked to NS4a-mediated inhibition of the PKR-induced stress response, as PACT is a PKR-associated protein (<xref rid="bb0930" ref-type="bibr">Rabouw et al., 2016</xref>). NS4a is a ds-RNA binding protein and hence can effectively mask the viral ds-RNA PAMP from the host innate immune response (<xref rid="bb0145" ref-type="bibr">Batool et al., 2017</xref>).</p></sec><sec id="s0055"><label>5.3</label><title>Innate immune response: cellular targeting</title><p id="p0120">MERS-CoV virus infects and replicates in human macrophages -including alveolar macrophages- and can induce pro-inflammatory and chemotactic cytokines and chemokines expression from the infected macrophages (<xref rid="bb1225" ref-type="bibr">Zhou et al., 2014</xref>, <xref rid="bb1220" ref-type="bibr">Zhou et al., 2015a</xref>). Binding and infection of MERS-CoV is supported by expression of DPP4 receptor on alveolar macrophages (<xref rid="bb0770" ref-type="bibr">Meyerholz et al., 2016</xref>). Levels of DPP4 are higher on alveolar macrophages, as well as on alveolar epithelial cells, in individuals with pre-existing pulmonary disease such as cystic fibrosis or chronic obstructive pulmonary disease, which could predispose them to MERS-CoV morbidity and mortality (<xref rid="bb0770" ref-type="bibr">Meyerholz et al., 2016</xref>). In human monocyte-derived macrophages (MDMs), MERS-CoV productive infection did not induce expression of antiviral IFN-α or IFN-β, but induced similar levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α to SARS-CoV, and significantly higher levels of other proinflammatory cytokines including IL-12 and IFN-γ, and chemokines including IP-10/CXCL-10, MCP-1/CCL-2, MIP-1α/CCL-3, RANTES/CCL-5, and IL-8 (<xref rid="bb1225" ref-type="bibr">Zhou et al., 2014</xref>). This could contribute to the level of pulmonary inflammation and tissue damage associated with MERS-CoV induced progressive pneumonia. On the other hand, recent studies in differentiated THP-1 macrophages infected with lentiviral particles pseudotyped with MERS-CoV S protein suggested that macrophage responses including IL-6 and TNF-α production were reduced, while LPS-induced production of the immunosuppressive IL-10 was increased (<xref rid="bb0050" ref-type="bibr">Al-Qahtani et al., 2017</xref>). This increase in IL-10 production was mediated by DPP4 binding and activation of IRAK-M, a negative regulator of TLR signaling and the transcriptional repressor PPARγ (<xref rid="bb0050" ref-type="bibr">Al-Qahtani et al., 2017</xref>). These results suggest that MERS-CoV may employ IRAK-M and PPARγ to evade destruction by macrophages.</p><p id="p0125"><italic>In vitro</italic> studies on antigen-presenting cells (APCs) have shown that human plasmacytoid dendritic cells (pDCs) could be infected by MERS-CoV and that unlike B cells, macrophages, or monocyte-derived dendritic cells (MDDCs) they secreted type I- and type III- IFNs upon MERS-CoV infection (<xref rid="bb0990" ref-type="bibr">Scheuplein et al., 2015</xref>). This was accompanied by initial steps of viral infection and replication, evidenced by increased N protein RNA in infected cells, but not by productive replication or viral amplification (<xref rid="bb0990" ref-type="bibr">Scheuplein et al., 2015</xref>). Recent studies suggested that while mature MDDCs did not seem to be permissive to MERS-CoV infection, immature MDDCs were permissive but, unlike with macrophages, infection <italic>in vitro</italic> did not result in up-regulation of proinflammatory cytokine and chemokine production (<xref rid="bb0280" ref-type="bibr">Cong et al., 2018</xref>). As dendritic cells enter peripheral tissues and carry antigens to lymphoid tissues, it has been suggested that they may contribute to MERS-CoV dissemination by acting as vehicles, possibly explaining the isolation of MERS-CoV from specimens other than respiratory tract samples such as blood, stool, and urine from MERS-CoV infected patients (<xref rid="bb0370" ref-type="bibr">Drosten et al., 2013</xref>, <xref rid="bb0445" ref-type="bibr">Guery et al., 2013</xref>).</p></sec><sec id="s0060"><label>5.4</label><title>Adaptive immune response</title><p id="p0130">In one cell culture study, MERS-CoV but not SARS-CoV could efficiently infect human primary T cells, including cells from peripheral blood, spleen and tonsils (<xref rid="bb0260" ref-type="bibr">Chu et al., 2016</xref>). CD4 T cells appeared to be more susceptible than CD8 T cells, and infection resulted in DPP4 receptor down-regulation and in T cell apoptosis by both extrinsic and intrinsic pathways (<xref rid="bb0260" ref-type="bibr">Chu et al., 2016</xref>). Spleen and tonsil cells were apparently vulnerable to a higher degree of infection and apoptosis than peripheral blood cells (<xref rid="bb0260" ref-type="bibr">Chu et al., 2016</xref>). Infection of common marmosets with MERS-CoV resulted in dissemination of virus to the spleen and infection of T cells <italic>in vivo (</italic><xref rid="bb0260" ref-type="bibr">Chu et al., 2016</xref>). Results of a recent study on a transgenic mouse model expressing human DPP4 (hDPP4) suggested that depletion of CD8 T cells could actually protect from MERS-CoV-induced pathology and symptoms, whereas depletion of macrophages exacerbated the pathology and symptoms (<xref rid="bb0275" ref-type="bibr">Coleman et al., 2017</xref>). Meanwhile recent <italic>in vitro</italic> studies suggested that, in common with H5N1-VN1203 influenza virus, MERS-CoV can attempt to evade the adaptive immune response by down-regulation of antigen-presentation gene expression, mediated by epigenetic mechanisms (<xref rid="bb0755" ref-type="bibr">Menachery et al., 2018</xref>). Down-regulated genes in the human airway epithelial cell line Calu3 included HLA-A, -B, or –C, whose expression was increased in the presence of SARS-CoV infection, as well as transcription factors (CTIIA) and genes expressing elements of the antigen processing machinery (TAP2 and PDIA3). HLA-A, -B, or –C peptides were also decreased by MERS-CoV infection, although H5N1-VN1203 reduced only HLA-A and-C peptides. In the case of MERS-CoV the major epigenetic mechanism appeared to be DNA methylation whereas H5N1-VN1203 employed a number of mechanisms (<xref rid="bb0755" ref-type="bibr">Menachery et al., 2018</xref>). Results from use of mutant viruses suggested that both host and viral processes were involved in the antigen presentation down-regulation, although this conclusion awaits definitive data (<xref rid="bb0755" ref-type="bibr">Menachery et al., 2018</xref>). In terms of humoral responses to MERS-CoV, the S protein has been shown to be the most immunogenic MERS-CoV antigen and is central to neutralizing antibody and T cell responses to MERS-CoV (<xref rid="bb1190" ref-type="bibr">Zhang et al., 2014</xref>). As a result, the S protein is the target of a number of proposed MERS-CoV vaccines, which we have recently extensively reviewed (<xref rid="bb0925" ref-type="bibr">Rabaan et al., 2017</xref>) and which are considered in more detail below.</p></sec><sec id="s0065"><label>5.5</label><title>Case definition</title><p id="p0135">In the light of the pathogenicity of MERS-CoV, its ability to potentially evade the immune system, and its high mortality rate, it is vital that accurate case definition criteria are established and updated as knowledge of the virus expands. This is of particular concern in KSA, which remains the site of the greatest number of cases. The WHO and the CDC regularly update case definitions in order to help healthcare professionals in recognition and classification of cases. Case definitions categorize patients into either confirmed or probable cases.</p></sec><sec id="s0070"><label>5.6</label><title>Confirmed Case</title><p id="p0140">Both WHO and the CDC define a confirmed case as a patient with a laboratory confirmation of MERS-CoV regardless of clinical presentation (<xref rid="bb0190" ref-type="bibr">Centers for Disease Control and Prevention (CDC), 2017</xref>, <xref rid="bb1140" ref-type="bibr">World Health Organization (WHO), n.d</xref>, <xref rid="bb1135" ref-type="bibr">World Health Organization (WHO), 2018</xref>). Laboratory confirmation as currently defined can be <italic>via</italic> detection of viral nucleic acid or serology. The bases for WHO and CDC definitions are shown in <xref rid="t0005" ref-type="table">Table 1</xref>. Viral nucleic acid confirmation can be either by positive results for nucleic acid amplification assays (NAAT), for example reverse transcription polymerase chain reaction (RT-PCR) directed against a minimum of 2 specific genomic targets (either upstream of the E protein gene (upE) and ORF1a, ORF1b or N gene), or against a single positive target with sequencing of a second target, preferably the RNA-dependent RNA polymerase (RdRp; nsp12) or N genes (<xref rid="bb0020" ref-type="bibr">Al Johani and Hajeer, 2016</xref>, <xref rid="bb0190" ref-type="bibr">Centers for Disease Control and Prevention (CDC), 2017</xref>, <xref rid="bb0290" ref-type="bibr">Corman et al., 2012a</xref>, <xref rid="bb0310" ref-type="bibr">Corman et al., 2014c</xref>, <xref rid="bb1140" ref-type="bibr">World Health Organization (WHO), n.d</xref>, <xref rid="bb1135" ref-type="bibr">World Health Organization (WHO), 2018</xref>). In the USA, an Emergency Use Authorization (EUA) was issued by the FDA to authorize the use of the WHO-approved RealStar® MERS-CoV RT-PCR Kit, as there is currently no FDA-cleared/approved test available for MERS-CoV testing in the USA (<xref rid="bb0190" ref-type="bibr">Centers for Disease Control and Prevention (CDC), 2017</xref>, <xref rid="bb0290" ref-type="bibr">Corman et al., 2012a</xref>, <xref rid="bb0410" ref-type="bibr">Food and Drug Administration, 2016</xref>, <xref rid="bb0660" ref-type="bibr">Lu et al., 2014a</xref>). For serology, WHO case confirmation requires demonstration of sero-conversion in 2 samples, ideally taken at least 14 days apart, by a screening test including enzyme-linked immunosorbent assay (ELISA) or immunofluorescence assay (IFA) and a neutralization assay for confirmation (<xref rid="bb1140" ref-type="bibr">World Health Organization (WHO), n.d</xref>, <xref rid="bb1135" ref-type="bibr">World Health Organization (WHO), 2018</xref>). For the CDC, a 2-phase approach is also adopted, involving one screening test (ELISA) and 2 confirmatory tests (IFA, microneutralization) to detect MERS-CoV antibodies (<xref rid="t0005" ref-type="table">Table 1</xref>) (<xref rid="bb0190" ref-type="bibr">Centers for Disease Control and Prevention, 2017</xref>). The CDC specifies that serology tests are for surveillance or investigational purposes rather than for diagnosis.<table-wrap position="float" id="t0005"><label>Table 1</label><caption><p>WHO and CDC case definitions for MERS-CoV.</p></caption><alt-text id="al0015">Table 1</alt-text><table frame="hsides" rules="groups"><thead><tr><th>Case definition</th><th>WHO</th><th>CDC</th></tr></thead><tbody><tr><td rowspan="2">Confirmed</td><td><bold>Nucleic acid testing</bold><break></break>RT-PCR: 2 specific genomic targets<break></break> • upE31<break></break> • ORF1a, ORF1b or N gene<break></break>OR<break></break>RT-PCR: one specific genomic target and:<break></break>Sequencing of a second target: nsp12 or M gene</td><td><bold>Nucleic acid testing</bold><break></break>RT-PCR: 2 specific genomic targets<break></break> • upE31<break></break> • ORF1a, ORF1b or N gene<break></break>OR<break></break>RT-PCR: one specific genomic target and:<break></break>Sequencing of a second target: nsp12 or M gene</td></tr><tr><td><bold>Serology</bold><break></break>Screening test:<break></break> • ELISA<break></break> • IFA<break></break>Confirmation test:<break></break> • Neutralization</td><td><bold>Serology</bold><break></break>Screening test:<break></break> • ELISA<break></break>Confirmation test:<break></break> • IFA<break></break> • Microneutralization<break></break>Surveillance, investigation<break></break>Not diagnosis</td></tr><tr><td rowspan="3">Probable (WHO)<break></break>or<break></break>Patient under investigation (PUI) (CDC)</td><td>1. Febrile acute respiratory illness with clinical, radiological, or histopathological evidence of pulmonary parenchymal disease AND<break></break>Direct epidemiologic link with a laboratory-confirmed MERS-CoV case AND<break></break>Testing for MERS-CoV is unavailable, negative on a single inadequate specimen or inconclusive</td><td>1. Fever AND pneumonia or acute respiratory distress syndrome AND EITHER:<break></break>history of travel from countries in or near the Arabian Peninsula within 14 days before symptom onset, OR<break></break>close contact with a symptomatic traveler who developed fever and acute respiratory illness (not necessarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula, OR<break></break>a member of a cluster of patients with severe acute respiratory illness of unknown etiology in which MERS-CoV is being evaluated, in consultation with state and local health departments</td></tr><tr><td>2. Febrile acute respiratory illness with clinical, radiological, or histopathological evidence of pulmonary parenchymal disease that cannot be explained fully by any other etiology AND<break></break>Resides or traveled in the Middle East, or in countries where MERS-CoV is known to be circulating in dromedary camels or where human infections have recently occurred AND<break></break>Testing for MERS-CoV is inconclusive</td><td>2. Fever AND symptoms of respiratory illness (not necessarily pneumonia) AND being in a healthcare facility (as a patient, worker, or visitor) within 14 days before symptom onset in a country or territory in or near the Arabian Peninsula in which recent healthcare-associated cases of MERS have been identified.</td></tr><tr><td>3. Acute febrile respiratory illness of any severity AND<break></break>Direct epidemiologic link with a confirmed MERS-CoV case AND<break></break>Testing for MERS-CoV is inconclusive</td><td>3. Fever OR symptoms of respiratory illness (not necessarily pneumonia) AND close contact with a confirmed MERS case while the case was ill.</td></tr></tbody></table></table-wrap></p></sec><sec id="s0075"><label>5.7</label><title>Probable case</title><p id="p0145">There are different possible definitions of probable cases according to WHO criteria, all of which involve a febrile patient with respiratory disease, either with evidence of pulmonary parenchymal disease (<italic>e.g.</italic> pneumonia or Acute Respiratory Distress Syndrome (ARDS)); or of any severity, along with other criteria shown in <xref rid="t0005" ref-type="table">Table 1</xref>, including residence or recent travel in the Middle East, or a direct epidemiological link to a laboratory-confirmed case (<xref rid="bb1140" ref-type="bibr">World Health Organization, n.d.</xref>). The CDC criteria for a probable case or person under investigation (PUI) are also shown in <xref rid="t0005" ref-type="table">Table 1</xref>, and again involve patients who are febrile and/or have evidence of respiratory illness (acute or otherwise), along with criteria including recent travel, or being in a healthcare facility, in or near the Arabian Peninsula, or close contact with a laboratory-confirmed case (<xref rid="bb0190" ref-type="bibr">Centers for Disease Control and Prevention, 2017</xref>).</p></sec></sec><sec id="s0080"><label>6</label><title>Diagnosis</title><sec id="s0085"><label>6.1</label><title>Detection of viral RNA</title><p id="p0150">Several assays for detection of MERS-CoV RNA have been developed using real-time PCR. Corman and colleagues introduced assays that target the region upstream of the E protein (upE), ORF1b, and ORF1a (<xref rid="f0010" ref-type="fig">Fig. 2</xref>) (<xref rid="bb0290" ref-type="bibr">Corman et al., 2012a</xref>, <xref rid="bb0305" ref-type="bibr">Corman et al., 2012b</xref>, <xref rid="bb0310" ref-type="bibr">Corman et al., 2014c</xref>). The high sensitivity of RT-PCR (upE) and RT-PCR (ORF1a) compared to ORF1b rendered them valuable options for screening of MERS-CoV RNA (<xref rid="bb0290" ref-type="bibr">Corman et al., 2012a</xref>, <xref rid="bb0305" ref-type="bibr">Corman et al., 2012b</xref>, <xref rid="bb0310" ref-type="bibr">Corman et al., 2014c</xref>, <xref rid="bb1135" ref-type="bibr">World Health Organization (WHO), 2018</xref>). The CDC validated a suggested alternate testing strategy based on screening of one N gene signature sequence (N2) combined with upE testing for enhanced sensitivity, and a second N gene signature (N3) for confirmation of positive tests (<xref rid="bb0660" ref-type="bibr">Lu et al., 2014a</xref>, <xref rid="bb1135" ref-type="bibr">World Health Organization (WHO), 2018</xref>). Corman and colleagues ultimately developed the upE and ORF1a real-time PCRs into the RealStar® MERS-CoV RT-PCR Kit, which was clinically validated using samples of a German MERS-CoV case and respiratory samples from other respiratory disease patients (<xref rid="bb0310" ref-type="bibr">Corman et al., 2014c</xref>). The RealStar® MERS-CoV RT-PCR Kit has been WHO approved and granted an FDA Emergency Use Authorization (EUA) in the United States (<xref rid="bb0410" ref-type="bibr">Food and Drug Administration, 2016</xref>, <xref rid="bb1140" ref-type="bibr">World Health Organization (WHO), n.d</xref>). The same study group introduced RT-PCR assays for sequencing in RdRp gene (RdRpSeq assay) and in the N gene (NSeq assay) now recommended by the WHO as confirmatory tests (<xref rid="bb0305" ref-type="bibr">Corman et al., 2012b</xref>).</p><p id="p0155">Although the RealStar® MERS-CoV RT-PCR Kit is the only upE and ORF1a-detecting kit approved by WHO and the Conformité Européenne (CE), and permitted FDA Emergency Use Authorization (EUA), several MERS-CoV RNA detection kits have been developed. For example, in a recent study 6 commercially available real-time RT-PCR MERS-CoV RNA detection kits based on upE and ORF1a were analyzed and clinically validated on nasopharyngeal swabs taken during the 2015 outbreak in Korea (<xref rid="bb0580" ref-type="bibr">Kim et al., 2016a</xref>). Results suggested that sensitivity and specificity of all of these assay systems would be sufficient for confirmation of MERS-CoV infection, although use of appropriate internal controls would be important in specimens where PCR inhibition is an issue (<xref rid="bb0580" ref-type="bibr">Kim et al., 2016a</xref>). In another recent study, a MERS-CoV r-gene ® 32 rRT-PCR assay 33 (bioMérieux, France), targeting the S protein gene, was shown to have comparable accuracy to the WHO recommended in-house rRT-PCR assay targeting upE and ORF1a in a set of 130 respiratory samples (<xref rid="bb0610" ref-type="bibr">Lee et al., 2017</xref>). Loop-mediated isothermal amplification RT PCR assays (RT-LAMP) have also been developed for field use given their rapid results with high sensitivity profiles. They require minimal instrumentation, thus they can also be used for portable point-of-care testing (<xref rid="bb0160" ref-type="bibr">Bhadra et al., 2015</xref>). Other assays targeting small RNA molecules (leader sequences) have good sensitivity profiles (<xref rid="bb0205" ref-type="bibr">Chan et al., 2015b</xref>).</p><p id="p0160">Respiratory specimens - nasopharyngeal swabs, sputum, tracheal aspirate and bronchoalveolar lavage (BAL) are commonly used for detection of viral RNA. Results of tests on patients from KSA and elsewhere comparing the viral load and genomic fraction yield among respiratory specimens obtained from different sites have shown that lower respiratory samples (<italic>e.g.</italic> tracheal aspirate and bronchoalveolar lavage) yield significantly higher viral loads and genomic fractions compared with upper respiratory tract samples (<xref rid="bb0370" ref-type="bibr">Drosten et al., 2013</xref>, <xref rid="bb0445" ref-type="bibr">Guery et al., 2013</xref>, <xref rid="bb0720" ref-type="bibr">Memish et al., 2014a</xref>). In the context of MERS-CoV testing in RSA and elsewhere, this means that WHO recommends that lower respiratory tract specimens should be collected whenever possible (<xref rid="bb1135" ref-type="bibr">World Health Organization, 2018</xref>). However, a case series from KSA also showed that there is value in collecting and testing upper respiratory tract specimens such as nasopharyngeal/oropharyngeal swabs so long as nasopharyngeal swabs are taken from the nasopharynx following WHO guidelines, not just from the nostril, and that nasopharyngeal and oropharyngeal swabs are placed in the same tube (<xref rid="bb0105" ref-type="bibr">Assiri et al., 2013b</xref>, <xref rid="bb1130" ref-type="bibr">World Health Organization (WHO), 2006</xref>, <xref rid="bb1135" ref-type="bibr">World Health Organization (WHO), 2018</xref>). Thus WHO recommends that when it is possible, both upper and lower respiratory tract specimens should be collected, while specimens from sites outside the respiratory tract should not be used for routine diagnostic testing (<xref rid="bb1135" ref-type="bibr">World Health Organization, 2018</xref>). WHO further recommends that samples should be collected for symptomatic patients for NAAT testing on presentation, followed by repeat sequential sampling every 2–4 days, until results are negative on 2 sequential samples to confirm viral clearance (<xref rid="bb1135" ref-type="bibr">World Health Organization, 2018</xref>).</p></sec><sec id="s0090"><label>6.2</label><title>Antigen detecting tests</title><p id="p0165">For diagnosis of MERS-CoV in camels, which is highly relevant in the KSA context, molecular testing based on NAAT is not always a feasible option largely due to the expense and impracticality of carrying out large numbers of tests on animal herds in a timely manner. Recognition of the need for a relatively affordable test for use in diagnosis in camels which would also be sensitive and specific led to the development of an immunochromatographic assay (ICA) for the rapid and direct qualitative detection of MERS-CoV antigen (<xref rid="bb1030" ref-type="bibr">Song et al., 2015</xref>). The test was based on use of monoclonal antibodies for detection of N protein at room temperature and was 93.9% and 100% sensitive and specific respectively in relation to UpE and ORF1a real-time RT-PCR-based detection in a study on 571 camel nasal swabs (<xref rid="bb1030" ref-type="bibr">Song et al., 2015</xref>). Another N protein antigen-detection test, this time capture enzyme-linked immunosorbent assay (ELISA) based on 2 N protein-specific monoclonal antibodies (MAbs) has also been developed and shown to be 100% specific in testing of a series of 129 nasopharyngeal aspirates known to be positive for various respiratory viruses (<xref rid="bb0235" ref-type="bibr">Chen et al., 2015</xref>). Such a sensitive and specific ELISA test would be feasible for MERS-CoV detection both in clinical samples, in particular for point-of-care testing, and in dromedaries and other animals, and may have particular utility in field studies in KSA and elsewhere in the Middle East and in mass gathering contexts such as Hajj (<xref rid="bb0220" ref-type="bibr">Chan et al., 2017</xref>, <xref rid="bb0235" ref-type="bibr">Chen et al., 2015</xref>). The relative affordability and lower resource-intensiveness would give it an advantage over RT-PCR based methods in these types of contexts. These antigen-detection tests require further refinement as they have not yet been completely validated for use in human samples and are usually not as sensitive as NAAT, which has limited their use to date (<xref rid="bb0220" ref-type="bibr">Chan et al., 2017</xref>).</p></sec><sec id="s0095"><label>6.3</label><title>Detecting human immune response</title><p id="p0170">Several serological assays have been developed for detection of anti MERS-CoV antibodies, notably against N protein or S protein. While NAAT-based testing is the gold standard for MERS-CoV diagnosis, serological assays have some advantages such as a less restricted time frame for antibody <italic>versus</italic> viral RNA detection, easier application in the field during an outbreak situation, and more economical application in animal testing (<xref rid="bb0425" ref-type="bibr">Fukushi et al., 2018</xref>, <xref rid="bb0760" ref-type="bibr">Meyer et al., 2014a</xref>, <xref rid="bb1085" ref-type="bibr">Trivedi et al., 2018</xref>). However, potential pitfalls of serological testing were exposed during the SARS-CoV outbreak, including the possibility of cross-reactivity to antigens from other coronaviruses (<xref rid="bb0760" ref-type="bibr">Meyer et al., 2014a</xref>). A recent assessment of the utility of ELISA-based detection of MERS-CoV S1 IgG compared to viral RNA detection was carried out on nasopharyngeal.</p><p id="p0175">swab specimens from 174 patients in a hospital in Riyadh, between January 2016 and December 2016, during which a MERS-CoV.</p><p id="p0180">outbreak occurred (<xref rid="bb0030" ref-type="bibr">Alhetheel et al., 2017</xref>). While MERS-CoV RNA was detected in 30 patient samples, only 6 samples were positive by serological testing, including 4 who were recently MERS-CoV RNA-positive and 2 who were MERS-CoV RNA-negative. This lack of correlation between NAAT and serological results suggested that MERS-CoV-IgG testing may not be appropriate for diagnosis of acute infection, estimation of outbreak prevalence, or determination of disease severity (<xref rid="bb0030" ref-type="bibr">Alhetheel et al., 2017</xref>). Nevertheless, serological testing remains one of the approved methods for MERS-CoV case confirmation by both WHO and CDC (<xref rid="bb1140" ref-type="bibr">World Health Organization (WHO), n.d</xref>, <xref rid="bb1135" ref-type="bibr">World Health Organization (WHO), 2018</xref>, <xref rid="bb0190" ref-type="bibr">Centers for Disease Control and Prevention (CDC), 2017</xref>). One recent validation study suggested that combination of indirect MERS-CoV N and S ELISAs in combination with confirmation by microneutralization assay can improve overall detection sensitivity and specificity (<xref rid="bb1085" ref-type="bibr">Trivedi et al., 2018</xref>). Another recent innovation suggests the possibility of using competitive ELISA rather than IgG/IgM ELISAs that rely on a species-specific secondary antibody (<xref rid="bb0425" ref-type="bibr">Fukushi et al., 2018</xref>). In this case, labeled monoclonal antibodies (MAb) against MERS-CoV S protein were developed and used to compete with test serum antibodies for target epitopes, allowing detection of antibodies in a species-independent manner (<xref rid="bb0425" ref-type="bibr">Fukushi et al., 2018</xref>). The competitive ELISA successfully detected MERS-CoV-specific antibodies in sera from infected rats and rabbits immunized with MERS-CoV S protein, and the test was also validated on sera from 66 Ethiopian dromedary camels in comparison to a neutralization test, giving sensitivity and specificity of 98% and 100%, respectively. These results suggest that competitive ELISA might be a useful serological test in epidemiological investigations in KSA and elsewhere in the Middle East (<xref rid="bb0425" ref-type="bibr">Fukushi et al., 2018</xref>). WHO recommends that for serology testing in symptomatic patients, paired samples should be collected within the first week of illness and the second ideally 3 to 4 weeks later (<xref rid="bb1135" ref-type="bibr">World Health Organization, 2018</xref>).</p></sec></sec><sec id="s0100"><label>7</label><title>Clinical manifestations of MERS-CoV</title><sec id="s0105"><label>7.1</label><title>Incubation period</title><p id="p0185">Variable incubation periods for MERS-CoV have been calculated in studies from different countries (<xref rid="bb0105" ref-type="bibr">Assiri et al., 2013b</xref>, <xref rid="bb0675" ref-type="bibr">Mailles et al., 2013</xref>, <xref rid="bb0870" ref-type="bibr">Oh et al., 2015</xref>). A median of 5.2 days (95% CI 1.9–14.7 days) (range 2–13 days) was reported in one study of 47 laboratory confirmed MERS-CoV cases in KSA (<xref rid="bb0105" ref-type="bibr">Assiri et al., 2013b</xref>). Investigators in France reported a longer incubation period of between 9 and 12 days (<xref rid="bb0675" ref-type="bibr">Mailles et al., 2013</xref>). Early during the 2015 Korean outbreak, the median incubation period of MER-CoV was found to be 6.3 days (<xref rid="bb0870" ref-type="bibr">Oh et al., 2015</xref>). Accommodating the range of these observations, it is currently recommended that people who have contact with confirmed cases must be evaluated for a full 14 days from day of contact for any symptoms or signs suggestive of MERS-CoV.</p></sec><sec id="s0110"><label>7.2</label><title>Clinical features</title><p id="p0190">The clinical spectrum of MERS-CoV infection ranges from mild respiratory illness to severe disease with severe acute respiratory distress syndrome, septic shock and multi-organ failure (<xref rid="bb0735" ref-type="bibr">Memish et al., 2013a</xref>, <xref rid="bb0740" ref-type="bibr">Memish et al., 2013b</xref>). Most reported cases do run a severe clinical course. Fever and cough are the predominant symptoms in symptomatic cases. Early in the history of MERS-CoV, analyzing the clinical presentation among 47 confirmed cases in KSA showed fever with temperature above 38 °C in almost 98% of the patients (<xref rid="bb0105" ref-type="bibr">Assiri et al., 2013b</xref>). Fever was also found to be a predictive factor for progression of pneumonia in a study following up the clinical course of 5 confirmed MERS-CoV cases during the Korean outbreak. The progression of pneumonia appeared to slow or even stop after fever subsided (<xref rid="bb0965" ref-type="bibr">Rhee et al., 2016</xref>).</p><p id="p0195">Cough was present in 83% of infected individuals in the KSA study of 47 cases, while gastrointestinal (GI) symptoms including abdominal pain, vomiting and diarrhea were also reported in a significant number of patients included in this study (<xref rid="bb0105" ref-type="bibr">Assiri et al., 2013b</xref>). GI symptoms were also reported in 12.9% of the 186 cases involved in the South Korean MERS-CoV outbreak (<xref rid="bb0595" ref-type="bibr">Korea Centers for Disease Control, and Prevention, 2015</xref>). Arabi et al. reported the clinical manifestation in 12 cases from 2 hospitals in KSA, showing that symptoms could be attributed to the lower respiratory tract (<xref rid="bb0090" ref-type="bibr">Arabi et al., 2014</xref>). Upper respiratory tract symptoms, such as rhinorrhea and sore throat, were found to be uncommon (<xref rid="bb0090" ref-type="bibr">Arabi et al., 2014</xref>). Renal complications are well known to occur in MERS-CoV infection. The first ever reported case suffered from acute kidney injury (<xref rid="bb1180" ref-type="bibr">Zaki et al., 2012</xref>). Proteinuria, hematuria and acute kidney injury (AKI) were noted in a retrospective study of 30 MERS-CoV cases in South Korea, in which diabetes, AKI, and the application of a continuous renal replacement therapy (CRRT) were observed to be risk factors for MERS-CoV-related mortality (<xref rid="bb0195" ref-type="bibr">Cha et al., 2015</xref>). Seizures, DIC, and rhabdomyolysis were also reported as complications related to MERS-CoV infection in a study of seventy patients in a single centre in KSA (<xref rid="bb1010" ref-type="bibr">Shalhoub et al., 2015</xref>).</p><p id="p0200">About 75% of confirmed MERS-CoV infections occur in patients with comorbid disease. Frequent comorbid conditions seen in patients with MERS-CoV infection are diabetes mellitus, obesity, chronic kidney disease, cardiac diseases, and hypertension, as well as respiratory diseases including asthma and COPD (<xref rid="bb0015" ref-type="bibr">Ahmed, 2018</xref>, <xref rid="bb0090" ref-type="bibr">Arabi et al., 2014</xref>, <xref rid="bb0105" ref-type="bibr">Assiri et al., 2013b</xref>, <xref rid="bb0120" ref-type="bibr">Badawi and Ryoo, 2016</xref>, <xref rid="bb0140" ref-type="bibr">Banik et al., 2016</xref>, <xref rid="bb0195" ref-type="bibr">Cha et al., 2015</xref>, <xref rid="bb0595" ref-type="bibr">Korea Centers for Disease Control, and Prevention, 2015</xref>, <xref rid="bb0700" ref-type="bibr">Matsuyama et al., 2016</xref>, <xref rid="bb0890" ref-type="bibr">Park et al., 2018</xref>, <xref rid="bb0975" ref-type="bibr">Saad et al., 2014</xref>, <xref rid="bb1010" ref-type="bibr">Shalhoub et al., 2015</xref>). Disease severity and mortality risk is impacted by comorbidities and age. For example, in one study age >50 years and diabetes were significantly associated with mortality and all patients in this series requiring renal replacement therapy died (<xref rid="bb1010" ref-type="bibr">Shalhoub et al., 2015</xref>). Age >65 years was significantly associated with mortality in another single centre study in KSA (<xref rid="bb0975" ref-type="bibr">Saad et al., 2014</xref>). A study analyzing publicly available data from KSA reported that pre-existing lung disease appeared not to be a significant risk factor for severity and mortality, however this study did not use multivariate risk modeling (<xref rid="bb0015" ref-type="bibr">Ahmed, 2018</xref>, <xref rid="bb0140" ref-type="bibr">Banik et al., 2016</xref>). Other case–control and retrospective observational studies from both KSA and Korea have suggested that smoking and/or comorbid respiratory diseases are significant risk factors for MERS-CoV-related mortality (<xref rid="bb0060" ref-type="bibr">Alraddadi et al., 2016b</xref>, <xref rid="bb0250" ref-type="bibr">Choi et al., 2016</xref>, <xref rid="bb0595" ref-type="bibr">Korea Centers for Disease Control, and Prevention, 2015</xref>, <xref rid="bb0700" ref-type="bibr">Matsuyama et al., 2016</xref>, <xref rid="bb0890" ref-type="bibr">Park et al., 2018</xref>). Higher levels of DPP4 mRNA and protein in lung tissues of smokers and COPD patients compared to never-smokers may predispose these individuals to MERS-CoV infection (<xref rid="bb1005" ref-type="bibr">Seys et al., 2018</xref>). Systematic review and meta-analysis has shown that obesity is present in 16% of MERS-CoV cases and may influence disease severity as with other respiratory conditions (<xref rid="bb0120" ref-type="bibr">Badawi and Ryoo, 2016</xref>). Asymptomatic MERS-CoV infection also occurs in household contacts, healthcare workers and people who have contact with dromedary camel (<xref rid="bb0735" ref-type="bibr">Memish et al., 2013a</xref>, <xref rid="bb0740" ref-type="bibr">Memish et al., 2013b</xref>).</p></sec><sec id="s0115"><label>7.3</label><title>Children</title><p id="p0205">Although older age has been confirmed as a risk factor for MERS-CoV infection and mortality, it is not only a disease of adults but also occurs in children, albeit rarely (<xref rid="bb0070" ref-type="bibr">Al-Tawfiq et al., 2016</xref>, <xref rid="bb0710" ref-type="bibr">Memish et al., 2014b</xref>, <xref rid="bb1070" ref-type="bibr">Thabet et al., 2015</xref>). 80.6% of the 31 pediatric cases reported between June 2012 and April 2016 were from KSA, with a mean age of 9.8 ± 5.4 years, and they were most commonly infected due to household contacts (<xref rid="bb0070" ref-type="bibr">Al-Tawfiq et al., 2016</xref>). Mortality is lower in children than in adults and is commonly associated with underlying comorbid conditions In one study from KSA, MERS-CoV was detected in 11 pediatric patients ranging in age from 2 to 16 years (<xref rid="bb0710" ref-type="bibr">Memish et al., 2014b</xref>). While 9 of the 11 were asymptomatic and were detected during a contacts investigation on older patients, 2 symptomatic patients had underlying conditions and one died (<xref rid="bb0710" ref-type="bibr">Memish et al., 2014b</xref>). Meanwhile a 9-month-old infant with infantile nephrotic syndrome being treated with prednisolone died in the PICU of a Riyadh hospital as result of MERS-CoV infection and his clinical course was complicated by acute renal failure (<xref rid="bb1070" ref-type="bibr">Thabet et al., 2015</xref>).</p></sec><sec id="s0120"><label>7.4</label><title>Pregnancy</title><p id="p0210">Information is limited on the impact of MERS-CoV in pregnancy, but in common with other severe respiratory viral infections the impact appears to be severe both maternally and perinatally. In one study on 5 pregnant women in KSA infected with MERS-CoV, all 5 needed ICU admission (<xref rid="bb0100" ref-type="bibr">Assiri et al., 2016</xref>). While 2 recovered and went on to deliver healthy infants, one of the mothers died due to multiple organ failure related to her infection after delivering a healthy infant at 38 weeks gestation, another died due to complications of her infection a few weeks after her infant was surgically delivered at 24 weeks and died after 4 hours of life, and one infant was stillborn at 34 weeks (<xref rid="bb0100" ref-type="bibr">Assiri et al., 2016</xref>). One case of a second trimester stillbirth during a MERS-CoV outbreak in Jordan was attributed to MERS-CoV on the basis of maternal exposure history and serological testing (<xref rid="bb0895" ref-type="bibr">Payne et al., 2014</xref>). In another case a woman at 32 weeks gestation died due to MERS-CoV-related complications including ARDS and septic shock after delivering a healthy infant by caesarean section (<xref rid="bb0690" ref-type="bibr">Malik et al., 2016</xref>).</p></sec><sec id="s0125"><label>7.5</label><title>Laboratory and radiological manifestation</title><p id="p0215">In a study of 47 cases of MERS-CoV infection in KSA, 14% had leukopenia, 34% had lymphopenia and 11% had lymphocytosis, while thrombocytopenia was present in 36% of cases (<xref rid="bb0105" ref-type="bibr">Assiri et al., 2013b</xref>). Lymphocytopenia and thrombocytopenia have also been detected in other studies, including among members of a KSA MERS-CoV family cluster (<xref rid="bb0735" ref-type="bibr">Memish et al., 2013a</xref>). Impaired liver function findings are a feature of MERS-CoV infection, including the 47-case study which revealed raised concentrations of lactate dehydrogenase (49% of patients), alanine aminotransferase (11% of patients) and aspartate amino transferase (15% of patients), although other liver function tests were normal (<xref rid="bb0105" ref-type="bibr">Assiri et al., 2013b</xref>) and in a retrospective study of 29 confirmed cases of MERS-CoV infections from March to May 2014 at 2 hospitals in the Al-Madinah region of KSA, in which elevated liver enzymes were observed in 50% of cases (<xref rid="bb1015" ref-type="bibr">Sherbini et al., 2017</xref>). Elevation of urea and creatinine levels indicating renal impairment has also been widely observed, including in case series from KSA (<xref rid="bb0090" ref-type="bibr">Arabi et al., 2014</xref>, <xref rid="bb1015" ref-type="bibr">Sherbini et al., 2017</xref>). Animal studies on human DPP4 (hDPP4)-expressing transgenic mouse models infected with MERS-CoV, while not entirely reflective of disease in humans, have shown multi-organ damage, including to liver and kidney as well as brain and spleen (<xref rid="bb1205" ref-type="bibr">Zhao et al., 2015</xref>). However, other studies on a hDPP4 transgenic mouse models have suggested that while infection with 10 LD50 of MERS-CoV resulted in persistent inflammatory infiltrates in the lungs and brain stems 2 and 4 days post-infection respectively, and focal infiltrates in the liver, there was no definite pathology in other organs (<xref rid="bb1065" ref-type="bibr">Tao et al., 2016</xref>). Recently, post-mortem histopathological findings on a 33-year-old male T lymphoma patient who contracted MERS-CoV were reported (<xref rid="bb0065" ref-type="bibr">Alsaad et al., 2018</xref>). Histopathological examination of tissue needle biopsies from multiple sites including brain, heart, lung, liver, kidney and skeletal muscle showed evidence of virally induced pulmonary and extrapulmonary pathological changes. These included necrotising pneumonia, pulmonary diffuse alveolar damage, acute kidney injury, hepatitis and myositis with muscle atrophic changes, however there were no notable findings for brain and heart. For the first time, ultrastructural viral particles were shown in renal cells, as well in pneumocytes, pulmonary macrophages and macrophages infiltrating the skeletal muscles (<xref rid="bb0065" ref-type="bibr">Alsaad et al., 2018</xref>). A wide range of radiological features have been shown on chest X-rays of MERS-CoV infected patients including ground glass opacification, consolidation (either patchy or confluent), reticular opacities, nodular opacities and reticulo-nodular infiltrates (<xref rid="bb0105" ref-type="bibr">Assiri et al., 2013b</xref>, <xref rid="bb0335" ref-type="bibr">Das et al., 2015</xref>, <xref rid="bb0340" ref-type="bibr">Das et al., 2016</xref>). Use of serial chest radiographs can be used to classify disease progression into 4 types ranging from type 1, in which initial radiographic deterioration is followed by improvement, all the way up to type 4, where there is progressive radiographic deterioration (<xref rid="bb0340" ref-type="bibr">Das et al., 2016</xref>). Importantly, in a study of 55 adult patients with acute MERS-CoV infection, chest radiographic score was shown to be an independent predictor of mortality, with mean chest radiographic score significantly higher in patients who died than in those who survived. Pneumothorax, bilateral pleural effusion and type 4 radiographic progression were all significantly higher in patients who died (<xref rid="bb0335" ref-type="bibr">Das et al., 2015</xref>). Bilateral pleural effusion has also been identified as an independent predictor of short-term mortality for community-acquired pneumonia but not SARS (<xref rid="bb0475" ref-type="bibr">Hasley et al., 1996</xref>, <xref rid="bb1125" ref-type="bibr">Wong et al., 2003</xref>). Similar to the radiographic findings, the more sensitive computed tomography (CT) scans also showed ground glass opacity (53% of patients), or consolidation (20% of patients), or both together (33% of patients), as well as pleural effusion (33%) and interlobular thickening (26%) within a week of infection (<xref rid="bb0335" ref-type="bibr">Das et al., 2015</xref>, <xref rid="bb0340" ref-type="bibr">Das et al., 2016</xref>). As disease progressed, bronchial abnormalities and organizing pneumonia emerged on CT scans (<xref rid="bb0335" ref-type="bibr">Das et al., 2015</xref>, <xref rid="bb0340" ref-type="bibr">Das et al., 2016</xref>).</p></sec></sec><sec id="s0130"><label>8</label><title>Source and transmission</title><sec id="s0135"><label>8.1</label><title>Bats</title><p id="p0220">As mentioned above, it has been assumed that bats are the likely main MERS-CoV mammalian source reservoir, as with other coronaviruses, because sequences related to the MERS-CoV were found in samples taken from different bat species (<xref rid="f0005" ref-type="fig">Fig. 1</xref>) (<xref rid="bb0360" ref-type="bibr">Drexler et al., 2014</xref>, <xref rid="bb0730" ref-type="bibr">Memish et al., 2013c</xref>). The HKU4 bat coronavirus RBD in the S protein shares high sequence identity to MERS-CoV and pseudotyped viruses embedding HKU4 S protein can bind human DPP4 and enter cells <italic>in vitro</italic> (<xref rid="bb1100" ref-type="bibr">Wang et al., 2014</xref>). HKU4 S protein binds human DPP4 with only low affinity, however introduction of 2 mutations, N762A and S746R, into the bat S gene enabled HKU4 to bind with higher affinity and more efficiently enter human cells (<xref rid="bb1150" ref-type="bibr">Yang et al., 2015a</xref>). These mutations are part of human protease motifs in the S1/S2 junction in MERS-CoV and thus facilitate S protein cleavage and human cell infection and may have been instrumental in transmission of MERS-CoV from bats to humans (<xref rid="bb1150" ref-type="bibr">Yang et al., 2015a</xref>). However, positing that bats are a direct source of MERS-CoV human infections is difficult given the infrequent contact of human with bats. In a study in KSA, it was found that samples from only one bat found near the home of a MERS-CoV infected patient among 823 samples collected from different bat species had total nucleotide identity with MERS-CoV sequence obtained from the patient (<xref rid="bb0730" ref-type="bibr">Memish et al., 2013c</xref>).</p></sec><sec id="s0140"><label>8.2</label><title>Camels</title><p id="p0225">There is growing evidence that dromedary camels act as the source of MERS-CoV. Dromedary camels' sera from different parts of the world –especially from the Middle East and broad areas of Africa, including Nigeria, Tunisia, Egypt and Ethiopia – have tested positive for anti-MERS-CoV antibodies (<xref rid="bb0035" ref-type="bibr">Ali et al., 2017b</xref>, <xref rid="bb0255" ref-type="bibr">Chu et al., 2015</xref>, <xref rid="bb0405" ref-type="bibr">Farag et al., 2015</xref>, <xref rid="bb0765" ref-type="bibr">Meyer et al., 2014b</xref>, <xref rid="bb0820" ref-type="bibr">Müller et al., 2015</xref>, <xref rid="bb0945" ref-type="bibr">Reusken et al., 2013a</xref>, <xref rid="bb0955" ref-type="bibr">Reusken et al., 2014</xref>, <xref rid="bb0985" ref-type="bibr">Saqib et al., 2017</xref>). Serological studies on camels in Africa and the Middle East within the last 30 years suggest that MERS-CoV was circulating among camels for decades before it was first documented in human beings in 2012 (<xref rid="bb0765" ref-type="bibr">Meyer et al., 2014b</xref>, <xref rid="bb0955" ref-type="bibr">Reusken et al., 2014</xref>). All Canary Islands dromedary camels which have positive serological evidence of MERS-CoV infection were originally imported from Africa 20 years ago or more (<xref rid="bb0455" ref-type="bibr">Gutiérrez et al., 2015</xref>). However, there are lower than expected levels of MERS-CoV human infection in Africa, which suggests there may be under-reporting of human cases, possibly related to limited resources for testing. Extension of sero-surveys among the human population would help in furthering understanding of the extent of levels of MERS-CoV infection in Africa. In one study use of ELISA, IFA and ppNT showed that there was evidence for unrecorded cases of human MERS-CoV in Kenya, similar to previous reports in KSA (<xref rid="bb0630" ref-type="bibr">Liljander et al., 2016</xref>, <xref rid="bb0820" ref-type="bibr">Müller et al., 2015</xref>).</p><p id="p0230">There is some genetic evidence to suggest transmission of MERS-CoV occurs from camels to humans. During one outbreak in Qatar, MERS-CoV sequences obtained from nasopharyngeal swabs from 2 infected human cases residing on a farm and from 3 seropositive camels within the same farm were found to be identical (<xref rid="bb0460" ref-type="bibr">Haagmans et al., 2014</xref>). In another case in Jeddah in KSA, a shared unique single nucleotide polymorphism (SNP) signature was found in both a MERS CoV patient and a MERS-CoV-carrying dromedary camel for which he had been caring (<xref rid="bb0115" ref-type="bibr">Azhar et al., 2014</xref>, <xref rid="bb0725" ref-type="bibr">Memish et al., 2014c</xref>). Comparison of the sequence of the full genome of the MERS-CoV variant associated with the Korean outbreak showed 99.96–99.98% similarity with the full genome of CoVs obtained from a camel in Riyadh, Saudi Arabia (<xref rid="bb0980" ref-type="bibr">Sabir et al., 2016</xref>). In this study RT-PCR testing was carried out on nasal swab samples from 1309 camels. Coronaviruses were identified in 25.3% of samples and 3 different lineages of coronaviruses, including MERS-CoV, betacoronavirus 1 (betacoronavirus, group A); and human CoV 229E (alphacoronavirus) were found to be circulating among dromedary camels (<xref rid="bb0980" ref-type="bibr">Sabir et al., 2016</xref>). The study showed camels aged less than 1 year have the highest rate of infection with coronaviruses compared to older camels (<xref rid="bb0980" ref-type="bibr">Sabir et al., 2016</xref>). The identification of camels as the probable natural zoonotic source for human infection with MERS-CoV has economic implications for countries of the Middle East, including KSA, given the importance of the camel trade between the Middle East and Africa (<xref rid="bb1170" ref-type="bibr">Younan et al., 2016</xref>).</p></sec><sec id="s0145"><label>8.3</label><title>Other animals</title><p id="p0235">There was no evidence of MERS CoV upon testing of other animals such as sheep, goats, cattle, or water buffalo, although results of one study suggests alpaca may be a possible viral reservoir (<xref rid="bb0910" ref-type="bibr">Perera et al., 2013</xref>, <xref rid="bb0960" ref-type="bibr">Reusken et al., 2013b</xref>, <xref rid="bb0950" ref-type="bibr">Reusken et al., 2016</xref>). Detection of MERS-CoV in this New World camelid raises the possibility of zoonotic spread of MERS CoV to areas where alpacas are farmed, including South America and the United States (<xref rid="bb0950" ref-type="bibr">Reusken et al., 2016</xref>).</p></sec><sec id="s0150"><label>8.4</label><title>Human-to-human transmission</title><p id="p0240">Strong evidence of human to human transmission was obtained from epidemiological and genomic studies investigating clustering of cases in hospitals and among household contacts (<xref rid="bb0110" ref-type="bibr">Assiri et al., 2013a</xref>, <xref rid="bb0735" ref-type="bibr">Memish et al., 2013a</xref>, <xref rid="bb0820" ref-type="bibr">Müller et al., 2015</xref>). Investigating a hospital outbreak in the city of Al-Ahsa in the Eastern Province of KSA revealed that all isolates of MERS-CoV infecting the 23 patients were from one monophyletic lineage and 91.3% of cases occurred as a result of person-to-person contact (<xref rid="bb0110" ref-type="bibr">Assiri et al., 2013a</xref>). Human-to-human transmission was also responsible for most of the MERS-CoV cases reported during the outbreak that occurred in Jeddah in 2014 (<xref rid="bb0865" ref-type="bibr">Oboho et al., 2015</xref>). The majority of cases were attributable to contact with a health care facility, other patients, or both, highlighting the role of healthcare facilities in human-to-human transmission that also arose in subsequent outbreaks, including hospital outbreaks in Riyadh and the 2015 outbreak in Korea (<xref rid="bb0865" ref-type="bibr">Oboho et al., 2015</xref>, <xref rid="bb0365" ref-type="bibr">Drosten et al., 2015</xref>, <xref rid="bb0390" ref-type="bibr">Fagbo et al., 2015</xref>, <xref rid="bb0045" ref-type="bibr">Almekhlafi et al., 2016</xref>, <xref rid="bb0130" ref-type="bibr">Balkhy et al., 2016a</xref>; <xref rid="bb0780" ref-type="bibr">Middle East respiratory syndrome coronavirus (MERS-CoV) – Republic of Korea, 2015</xref>). As explained above, healthcare facility human-to-human transmission has been associated with defective or inadequate infection prevention and control measures (<xref rid="bb1000" ref-type="bibr">Scientific Advisory Board, Ministry of Health, Kingdom of Saudi Arabia, 2018</xref>, <xref rid="bb0135" ref-type="bibr">Balkhy et al., 2016b</xref>, <xref rid="bb0180" ref-type="bibr">Butt et al., 2016</xref>, <xref rid="bb0315" ref-type="bibr">Coronavirus infections, 2017</xref>, <xref rid="bb0325" ref-type="bibr">Cotten et al., 2014</xref>, <xref rid="bb0480" ref-type="bibr">Hastings et al., 2016</xref>). The infection tends to be milder in secondary cases, in which a patient is infected as a result of close contact with a primary source, and can even be asymptomatic. The number of cases who get infected from confirmed cases is low; the rate of transmission among household contacts has been calculated to be around 5% in one study done in KSA in 2014 (<xref rid="bb0715" ref-type="bibr">Memish et al., 2014d</xref>). However, epidemiological analysis of the Korean hospital outbreak in 2015 showed that the fatality rate was not significantly different between primary cases and subsequent generations (<xref rid="bb0575" ref-type="bibr">Kim, 2015</xref>). This outbreak highlighted the danger posed by a combination of circumstances including a primary source traveling from the Middle East, infection among secondary and tertiary contacts due to movement of infected individuals between healthcare facilities, and inadequate infection prevention and control measures (<xref rid="bb0840" ref-type="bibr">Nishiura et al., 2016a</xref>, <xref rid="bb0845" ref-type="bibr">Nishiura et al., 2016b</xref>, <xref rid="bb0885" ref-type="bibr">Park et al., 2015</xref>).</p></sec><sec id="s0155"><label>8.5</label><title>Epidemic potential</title><p id="p0245">From the data available to date, MERS-CoV has failed to demonstrate the potential to result in an epidemic. A study based on Bayesian analysis was carried out to estimate the basic MERS-CoV reproduction number (R0), which represents the number of secondary cases for each index case in a fully susceptible population (<xref rid="bb0175" ref-type="bibr">Breban et al., 2013</xref>). Epidemic potential is achieved when R0 is above 1,. R0 for MERS-CoV was estimated to be between 0·60 and 0·69, however these calculations were based on data obtained in June 2013 in advance of many of the important outbreaks and so may be underestimated (<xref rid="bb0175" ref-type="bibr">Breban et al., 2013</xref>). There is in any case no room for complacency, as the potential is always present for viral mutations that could increase zoonotic or human-to-human transmissibility. Thus development of effective directed therapies remains a top priority.</p></sec></sec><sec id="s0160"><label>9</label><title>Vaccination and therapy</title><sec id="s0165"><label>9.1</label><title>Current and potential treatments</title><p id="p0250">In 2015, Public Health England (PHE) and the WHO International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC-WHO) published a position paper on MERS-CoV therapies (<xref rid="bb1080" ref-type="bibr">Treatment of MERS-CoV; information for clinicians, 2015</xref>). They concluded that there was a positive benefit <italic>versus</italic> risk balance for convalescent plasma, lopinavir/ritonavir, interferons and monoclonal/polyclonal antibodies, but a negative balance for ribavirin monotherapy or corticosteroids (<xref rid="bb1080" ref-type="bibr">Treatment of MERS-CoV; information for clinicians, 2015</xref>). It was deemed that there was insufficient information available for interferon/ribavirin combination therapy, nitazoxanide and chloroquine (<xref rid="bb1080" ref-type="bibr">Treatment of MERS-CoV; information for clinicians, 2015</xref>). Currently, no specific evidence-based therapy or vaccine for MERS-CoV is available. We have recently extensively reviewed candidate MERS-CoV therapies and vaccines (<xref rid="bb0925" ref-type="bibr">Rabaan et al., 2017</xref>). <xref rid="t0010" ref-type="table">Table 2</xref>shows a summary of current and proposed therapies and vaccines, including targets, advantages and disadvantages, updated to include some potential agents that have emerged since the publication of our review (<xref rid="bb0025" ref-type="bibr">Alharbi et al., 2017</xref>, <xref rid="bb0555" ref-type="bibr">Jung et al., 2018</xref>, <xref rid="bb0600" ref-type="bibr">Langenmayer et al., 2018</xref>, <xref rid="bb0615" ref-type="bibr">Li et al., 2018</xref>, <xref rid="bb0640" ref-type="bibr">Liu et al., 2018</xref>, <xref rid="bb0850" ref-type="bibr">Niu et al., 2018</xref>, <xref rid="bb0925" ref-type="bibr">Rabaan et al., 2017</xref>, <xref rid="bb1050" ref-type="bibr">Sun et al., 2017</xref>). Development of a targeted anti- MERS-CoV therapy and availability of effective vaccines would require coordinated efforts to carry out properly controlled and organized clinical trials. This would be of particular importance for KSA, given the relatively major impact of MERS-CoV there; availability of reliable directed therapies and the possibility of either a prophylactic vaccine programme or a vaccine that could be rapidly available in the event of a major outbreak would be a major advantage in effectively tackling this disease.<table-wrap position="float" id="t0010"><label>Table 2</label><caption><p>Summary of potential MERS-CoV therapies and vaccines.</p></caption><alt-text id="al0020">Table 2</alt-text><table frame="hsides" rules="groups"><thead><tr><th>Therapeutic target</th><th>Type of therapy</th><th>Therapy/<break></break>Vaccine name</th><th>Study type</th><th>Advantages</th><th>Disadvantages</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="10">S1/DPP4 binding</td><td>Antibody (mouse): S1 RBD</td><td>Mersmab</td><td><italic>In vitro</italic></td><td></td><td></td><td>(<xref rid="bb0380" ref-type="bibr">Du et al., 2014</xref>)</td></tr><tr><td>Antibody<break></break>(human): S1 RBD</td><td>m336, m337, m338</td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse, rabbit- m336)</td><td></td><td></td><td>(<xref rid="bb0010" ref-type="bibr">Agrawal et al., 2016</xref>, <xref rid="bb0515" ref-type="bibr">Houser et al., 2016</xref>, <xref rid="bb1165" ref-type="bibr">Ying et al., 2014</xref>)</td></tr><tr><td>Antibody<break></break>(human): S1 RBD</td><td>MERS-4, MERS-27</td><td><italic>In vitro</italic></td><td></td><td></td><td>(<xref rid="bb0545" ref-type="bibr">Jiang et al., 2014</xref>, <xref rid="bb1175" ref-type="bibr">Yu et al., 2015</xref>)</td></tr><tr><td>Antibody (mouse- humanized): S1 RBD</td><td>4C2</td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse)</td><td>Prophylactic and therapeutic</td><td></td><td>(<xref rid="bb0625" ref-type="bibr">Li et al., 2015</xref>)</td></tr><tr><td>Antibody (mouse- humanized): S1 RBD</td><td>hMS-1</td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse)</td><td></td><td></td><td>(<xref rid="bb0920" ref-type="bibr">Qiu et al., 2016</xref>)</td></tr><tr><td>Antibody<break></break>(human): S1 RBD</td><td>LCA60</td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse)</td><td>Targets both NTD and RBD; stable CHO cell line; prophylactic and therapeutic</td><td></td><td>(<xref rid="bb0320" ref-type="bibr">Corti et al., 2016</xref>)</td></tr><tr><td>Antibody<break></break>(human): S1 RBD</td><td>3B11-N</td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (rhesus monkeys)</td><td>Prophylactic</td><td></td><td>(<xref rid="bb0550" ref-type="bibr">Johnson et al., 2016</xref>)</td></tr><tr><td>Antibody<break></break>(human): S1 RBD</td><td>MERS-GD27<break></break>MERS-GD33</td><td><italic>In vitro</italic></td><td>Synergistic effect; Different epitopes; MERS-GD27 overlaps receptor binding site</td><td></td><td>(<xref rid="bb0850" ref-type="bibr">Niu et al., 2018</xref>)</td></tr><tr><td>Antibody<break></break>(human- anti-DPP4)</td><td>2F9, 1F7, YS110</td><td><italic>In vitro</italic></td><td></td><td></td><td>(<xref rid="bb0875" ref-type="bibr">Ohnuma et al., 2013</xref>)</td></tr><tr><td>RBD-IgG fusion vaccine candidate</td><td>RBD s377–588- Fc IgG fusion</td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse)</td><td>Humoral response in mice; potential intranasal administration; improved by adjuvant; divergent strains/ escape mutants;<break></break>CHO cell line</td><td></td><td>(<xref rid="bb0375" ref-type="bibr">Du et al., 2013</xref>, <xref rid="bb0665" ref-type="bibr">Ma et al., 2014</xref>, <xref rid="bb0860" ref-type="bibr">Nyon et al., 2018</xref>, <xref rid="bb1055" ref-type="bibr">Tai et al., 2017</xref>, <xref rid="bb1195" ref-type="bibr">Zhang et al., 2015</xref>, <xref rid="bb1185" ref-type="bibr">Zhang et al., 2016b</xref>)</td></tr><tr><td>Nanoparticles vehicle (vaccine candidate)</td><td>Full-length S protein proprietary nanoparticles</td><td></td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse)</td><td>Use of adjuvants improves humoral response</td><td>Stable expression of abundant full-length S protein difficult</td><td>(<xref rid="bb0270" ref-type="bibr">Coleman et al., 2014</xref>)</td></tr><tr><td>Nanoparticles and virus vehicle (vaccine candidate)</td><td>Full-length S protein: Ad5/MERS and S protein nanoparticles</td><td>Heterologous prime-boost:</td><td><italic>In vivo</italic> (Mouse)</td><td>T cell and neutralizing antibody responses; potentially prophylactic</td><td></td><td>(<xref rid="bb0555" ref-type="bibr">Jung et al., 2018</xref>)</td></tr><tr><td rowspan="6">Virus vehicle (vaccine candidate)</td><td>MVA expressing full-length S protein</td><td>MVA-MERS-S</td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse, camel)</td><td>T cell and neutralizing antibody responses; entering human clinical trials; potential for veterinary use-</td><td></td><td>(<xref rid="bb0600" ref-type="bibr">Langenmayer et al., 2018</xref>, <xref rid="bb1090" ref-type="bibr">Volz et al., 2015</xref>)</td></tr><tr><td>ad5 or ad41 adenovirus expressing full-length S</td><td></td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse)</td><td>T cell and neutralizing antibody responses</td><td></td><td>(<xref rid="bb0450" ref-type="bibr">Guo et al., 2015</xref>)</td></tr><tr><td>Measles virus expressing full-length S</td><td></td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse)</td><td>T cell and neutralizing antibody responses</td><td></td><td>(<xref rid="bb0685" ref-type="bibr">Malczyk et al., 2015</xref>)</td></tr><tr><td>Chimeric vesicular stomatitis virus (VSV) expressing full-length S</td><td></td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Rhesus monkeys)</td><td>T cell and neutralizing antibody responses</td><td></td><td>(<xref rid="bb0640" ref-type="bibr">Liu et al., 2018</xref>)</td></tr><tr><td>Chimpanzee adenovirus (ChAdOx1) expressing full-length S</td><td></td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (mouse)</td><td>T cell and neutralizing antibody responses; entering human clinical trials; potential for veterinary use</td><td></td><td>(<xref rid="bb0025" ref-type="bibr">Alharbi et al., 2017</xref>)</td></tr><tr><td>Plasmid vaccine</td><td>GLS-5300</td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse, camels, and macaques)<break></break>Human clinical trials</td><td>T cell and neutralizing antibody responses; in phase I clinical trial</td><td></td><td>(<xref rid="bb0535" ref-type="bibr">Inovio, 2016</xref>, <xref rid="bb0830" ref-type="bibr">Muthumani et al., 2015</xref>)</td></tr><tr><td rowspan="3">Viral S2-host membrane fusion</td><td>Anti-HR2 viral peptide</td><td>HR2P</td><td><italic>In vitro</italic></td><td></td><td></td><td>(<xref rid="bb0655" ref-type="bibr">Lu et al., 2014b</xref>)</td></tr><tr><td>Anti-HR2 viral peptide</td><td>HR2P-M2</td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Mouse)</td><td>Blocks 6HB bundle formation; enhances IFN-β effect; potential intranasal treatments</td><td></td><td>(<xref rid="bb0170" ref-type="bibr">Bosch et al., 2004</xref>, <xref rid="bb0225" ref-type="bibr">Channappanavar et al., 2015</xref>, <xref rid="bb0645" ref-type="bibr">Liu et al., 2004</xref>)</td></tr><tr><td>Three HR1 and two HR2 protein</td><td>MERS-5HB</td><td><italic>In vitro</italic></td><td>Inhibits fusion and entry</td><td></td><td>(<xref rid="bb1050" ref-type="bibr">Sun et al., 2017</xref>)</td></tr><tr><td rowspan="5">Immune evasion response</td><td>IFN-α2b and ribavirin</td><td></td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Macaque)</td><td>Combination therapy- reduced dose of each; non-human primate model; 10 different gene pathways</td><td></td><td>(<xref rid="bb0395" ref-type="bibr">Falzarano et al., 2013a</xref>, <xref rid="bb0400" ref-type="bibr">Falzarano et al., 2013b</xref>, <xref rid="bb1215" ref-type="bibr">Zheng and Wang, 2016</xref>)</td></tr><tr><td>IFN-β1b and lopinavir</td><td></td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (Marmoset)</td><td>Combination therapy- reduced dose of each</td><td></td><td>(<xref rid="bb0210" ref-type="bibr">Chan et al., 2015c</xref>)</td></tr><tr><td>IFN combination therapy (ribavirin and/or lopinavir</td><td></td><td>Case studies (human)</td><td></td><td>Only prophylactic or early use; insufficient evidence of clinical efficacy as yet</td><td>(<xref rid="bb0565" ref-type="bibr">Khalid et al., 2015</xref>, <xref rid="bb0585" ref-type="bibr">Kim et al., 2016b</xref>, <xref rid="bb1035" ref-type="bibr">Spanakis et al., 2014</xref>, <xref rid="bb1045" ref-type="bibr">Strayer et al., 2014</xref>)</td></tr><tr><td>IFN combination therapy (ribavirin)</td><td></td><td>Retrospective cohort studies (human)</td><td>Probable benefit of early use in less vulnerable patients; safety and efficacy established for other viral illnesses</td><td>Only prophylactic or early use; insufficient evidence of clinical efficacy as yet</td><td>(<xref rid="bb0075" ref-type="bibr">Al-Tawfiq et al., 2014</xref>, <xref rid="bb1120" ref-type="bibr">de Wilde et al., 2013</xref>, <xref rid="bb0570" ref-type="bibr">Khalid et al., 2014</xref>, <xref rid="bb0605" ref-type="bibr">Lau et al., 2013</xref>, <xref rid="bb0880" ref-type="bibr">Omrani et al., 2014</xref>, <xref rid="bb1010" ref-type="bibr">Shalhoub et al., 2015</xref>)</td></tr><tr><td>IFN combination therapy (cyclosporine)</td><td></td><td><italic>In vitro</italic><break></break>Human <italic>ex-vivo</italic> explant</td><td>Synergistic effect; safety and efficacy established for other viral illnesses</td><td></td><td>(<xref rid="bb0615" ref-type="bibr">Li et al., 2018</xref>)</td></tr><tr><td rowspan="3">S protein host proteases</td><td>TMPRSS2 inhibitor</td><td>Camostat</td><td><italic>In vivo</italic>- mouse, SARS-CoV</td><td>Already in clinical use</td><td></td><td>(<xref rid="bb1240" ref-type="bibr">Zhou et al., 2015b</xref>)</td></tr><tr><td>TMPRSS2 inhibitor</td><td>Nafamostat</td><td>Split-protein-based cell–cell fusion assay</td><td>Already in clinical use</td><td></td><td>(<xref rid="bb1145" ref-type="bibr">Yamamoto et al., 2016</xref>)</td></tr><tr><td>Cathepsin L inhibitor</td><td>Teicoplanin dalbavancin oritavancin telavancin</td><td>High-throughput screening</td><td>Already in clinical use</td><td></td><td>(<xref rid="bb1235" ref-type="bibr">Zhou et al., 2016</xref>)</td></tr><tr><td rowspan="3">Viral proteases</td><td>PL(pro) inhibitor</td><td>6-mercaptopurine (6MP)<break></break>6-thioguanine (6TG)</td><td><italic>In vitro</italic></td><td>Potential for more MERS-specific agents</td><td></td><td>(<xref rid="bb0240" ref-type="bibr">Cheng et al., 2015</xref>)</td></tr><tr><td>PL(pro) inhibitor</td><td>F2124–0890</td><td><italic>In vitro</italic></td><td></td><td>May lose potency in physiological reducing environments</td><td>(<xref rid="bb0265" ref-type="bibr">Clasman et al., 2017</xref>)</td></tr><tr><td>Mpro</td><td>Lopinavir</td><td><italic>In vitro</italic><break></break><italic>In vivo</italic> (marmosets)</td><td>High activity at low micromolar range <italic>in vitro</italic>; better outcomes, in marmosets</td><td>Clinical efficacy not fully established in humans</td><td>(<xref rid="bb0210" ref-type="bibr">Chan et al., 2015</xref>, <xref rid="bb1115" ref-type="bibr">de Wilde et al., 2014</xref>, <xref rid="bb0940" ref-type="bibr">Rambaut, 2014</xref>)</td></tr></tbody></table></table-wrap></p><p id="p0255">The S protein and its binding to DPP4 is the target of many proposed direct MERS-CoV therapies, including a large number of antibodies which target the interaction either from the viral or the host side (<xref rid="bb0010" ref-type="bibr">Agrawal et al., 2016</xref>, <xref rid="bb0320" ref-type="bibr">Corti et al., 2016</xref>, <xref rid="bb0380" ref-type="bibr">Du et al., 2014</xref>, <xref rid="bb0515" ref-type="bibr">Houser et al., 2016</xref>, <xref rid="bb0545" ref-type="bibr">Jiang et al., 2014</xref>, <xref rid="bb0550" ref-type="bibr">Johnson et al., 2016</xref>, <xref rid="bb0625" ref-type="bibr">Li et al., 2015</xref>, <xref rid="bb0850" ref-type="bibr">Niu et al., 2018</xref>, <xref rid="bb0875" ref-type="bibr">Ohnuma et al., 2013</xref>, <xref rid="bb0920" ref-type="bibr">Qiu et al., 2016</xref>, <xref rid="bb1165" ref-type="bibr">Ying et al., 2014</xref>, <xref rid="bb1175" ref-type="bibr">Yu et al., 2015</xref>). Monoclonal antibodies against the RBD of the S1 region have particularly strong neutralizing capacity, although full-length S or S1 targeting antibodies may have greater potential in a vaccine context given their larger number of target epitopes and the reduced chance of escape mutations (<xref rid="bb0010" ref-type="bibr">Agrawal et al., 2016</xref>, <xref rid="bb0320" ref-type="bibr">Corti et al., 2016</xref>, <xref rid="bb0380" ref-type="bibr">Du et al., 2014</xref>, <xref rid="bb0515" ref-type="bibr">Houser et al., 2016</xref>, <xref rid="bb0545" ref-type="bibr">Jiang et al., 2014</xref>, <xref rid="bb0550" ref-type="bibr">Johnson et al., 2016</xref>, <xref rid="bb0625" ref-type="bibr">Li et al., 2015</xref>, <xref rid="bb0850" ref-type="bibr">Niu et al., 2018</xref>, <xref rid="bb0875" ref-type="bibr">Ohnuma et al., 2013</xref>, <xref rid="bb0920" ref-type="bibr">Qiu et al., 2016</xref>, <xref rid="bb1165" ref-type="bibr">Ying et al., 2014</xref>, <xref rid="bb1175" ref-type="bibr">Yu et al., 2015</xref>). A fusion product in which truncated RBD (residues 377–588) was joined to the Fc portion of human IgG could bind human DPP4 and inhibit MERS-CoV infection <italic>in vitro</italic> in cell culture and <italic>in vivo</italic> in infected mice (<xref rid="t0010" ref-type="table">Table 2</xref>) (<xref rid="bb0375" ref-type="bibr">Du et al., 2013</xref>). <italic>In vivo</italic> studies on mice have also indicated that intranasal administration of this fusion product induced comparable sustained IgG humoral responses to subcutaneous injection, and superior cellular immune responses and local mucosal responses in lungs (<xref rid="bb0665" ref-type="bibr">Ma et al., 2014</xref>, <xref rid="bb1195" ref-type="bibr">Zhang et al., 2015</xref>). Use of an adjuvant, particularly MF59 or AddaVax, significantly improved both the humoral and T cell responses in subcutaneously immunized mice (<xref rid="bb1185" ref-type="bibr">Zhang et al., 2016b</xref>). Recently, a high-yield CHO cell line capable of large-scale production of this S1 RBD-Fc fusion product was described, strengthening the possibility of sustainable manufacture and human testing for this potential vaccine antigen (<xref rid="bb0860" ref-type="bibr">Nyon et al., 2018</xref>). Another recent study showed that 5 recombinant RBDs incorporating mutations which arose in different MERS-CoV outbreaks or in camel strains could induce neutralizing antibody responses against several MERS-CoV pseudoviruses (<xref rid="bb1055" ref-type="bibr">Tai et al., 2017</xref>).</p><p id="p0260">A particularly promising antibody candidate for MERS-CoV therapy is the human antibody LCA60, as it targets both the N-terminal domain (NTD) and the RBD of S1 (<xref rid="t0010" ref-type="table">Table 2</xref>) (<xref rid="bb0320" ref-type="bibr">Corti et al., 2016</xref>). LCA60 was isolated from B cells of a MERS-CoV-infected human donor, and has been used to establish a stable CHO cell line from which clinical grade antibody is reliably available (<xref rid="bb0320" ref-type="bibr">Corti et al., 2016</xref>); this type of ready availability would be of particular benefit in KSA for outbreak situations. It had both prophylactic and therapeutic activities against MERS-CoV infection in 2 transgenic mouse models, Ad5/hDPP4 and type I interferon receptor (IFNAR)- KO (<xref rid="bb0320" ref-type="bibr">Corti et al., 2016</xref>). Another human anti-RBD antibody, 3B11-N, has shown promising results in a non-human primate model, <italic>i.e.</italic> rhesus monkeys infected with MERS-CoV, in which it prophylactically reduced lung pathology (<xref rid="bb0550" ref-type="bibr">Johnson et al., 2016</xref>). Recently a suite of potent MERS-CoV-neutralizing anti-S protein antibodies were derived from B cells of an infected patient, specifically from the first imported case in China (<xref rid="bb0850" ref-type="bibr">Niu et al., 2018</xref>). Two of the antibodies in particular, MERS-GD27 and MERS-GD33, had potent and synergistic neutralizing <italic>in vitro</italic> activity against both pseudotyped and live MERS-CoV (<xref rid="t0010" ref-type="table">Table 2</xref>) (<xref rid="bb0850" ref-type="bibr">Niu et al., 2018</xref>). The 2 antibodies targeted different epitopes, with the MERS-GD27 epitope almost entirely overlapping the receptor binding site (<xref rid="bb0850" ref-type="bibr">Niu et al., 2018</xref>). Thus there is a wide range of S protein directed antibodies and fusion products available for potential passive immunization strategies, but thus far they have not entered human clinical trials. Availability of monoclonal antibodies may be of particular use in outbreak situations, which continue to arise in KSA. Other potential S protein-targeting vaccine candidates include nanoparticles expressing full-length S protein (<xref rid="bb0270" ref-type="bibr">Coleman et al., 2014</xref>) and active immunization strategies using vectors including modified vaccinia, adenoviruses or measles viruses or plasmids expressing full-length S protein as potential vaccine candidates, discussed in more detail in the next section (<xref rid="bb0025" ref-type="bibr">Alharbi et al., 2017</xref>, <xref rid="bb0450" ref-type="bibr">Guo et al., 2015</xref>, <xref rid="bb0535" ref-type="bibr">Inovio, 2016</xref>, <xref rid="bb0555" ref-type="bibr">Jung et al., 2018</xref>, <xref rid="bb0600" ref-type="bibr">Langenmayer et al., 2018</xref>, <xref rid="bb0640" ref-type="bibr">Liu et al., 2018</xref>, <xref rid="bb0685" ref-type="bibr">Malczyk et al., 2015</xref>, <xref rid="bb0830" ref-type="bibr">Muthumani et al., 2015</xref>, <xref rid="bb1090" ref-type="bibr">Volz et al., 2015</xref>).</p><p id="p0265">Antiviral peptides that target the HR2 regions of the S protein and hence virus-host cell fusion have also been shown to have potential therapeutic activities in cell culture and transgenic animal studies (<xref rid="bb0170" ref-type="bibr">Bosch et al., 2004</xref>, <xref rid="bb0225" ref-type="bibr">Channappanavar et al., 2015</xref>, <xref rid="bb0645" ref-type="bibr">Liu et al., 2004</xref>, <xref rid="bb0655" ref-type="bibr">Lu et al., 2014b</xref>). The HR2 peptide HR2P, covering residues 1251–1286, reduced viral replication and fusion <italic>in vitro</italic> (<xref rid="bb0655" ref-type="bibr">Lu et al., 2014b</xref>) while its analogue, HR2P-M2, blocked fusion even more potently <italic>in vitro</italic>, and inhibited pseudovirus infection by blocking 6HB bundle formation (<xref rid="bb0170" ref-type="bibr">Bosch et al., 2004</xref>, <xref rid="bb0225" ref-type="bibr">Channappanavar et al., 2015</xref>, <xref rid="bb0645" ref-type="bibr">Liu et al., 2004</xref>). Convenient intranasal administration of HR2P-M2 <italic>in vivo</italic> to Ad5/hDPP4 transgenic mice protected them from MERS-CoV infection, which was enhanced by co-administration of IFN-β (<xref rid="bb0170" ref-type="bibr">Bosch et al., 2004</xref>). Recently a synthetic protein named MERS-5-helix bundle (MERS-5HB) was derived from the 6HB bundle involved in MERS-CoV fusion and was shown to bind strongly to HR2P and to effectively inhibit pseudotyped MERS-CoV fusion and entry in <italic>in vitro</italic> studies (<xref rid="t0010" ref-type="table">Table 2</xref>) (<xref rid="bb1050" ref-type="bibr">Sun et al., 2017</xref>). This represents another potentially useful directed MERS-CoV therapeutic candidate.</p><p id="p0270">At present, combined antiviral therapies tend to be used in patients who develop respiratory illness, based on experience with SARS-CoV therapy, for example pegylated interferon (IFN)-α, ribavirin, and/or lopinavir/ritonavir (<xref rid="bb0075" ref-type="bibr">Al-Tawfiq et al., 2014</xref>, <xref rid="bb1120" ref-type="bibr">de Wilde et al., 2013</xref>, <xref rid="bb0570" ref-type="bibr">Khalid et al., 2014</xref>, <xref rid="bb0565" ref-type="bibr">Khalid et al., 2015</xref>, <xref rid="bb0585" ref-type="bibr">Kim et al., 2016b</xref>, <xref rid="bb0605" ref-type="bibr">Lau et al., 2013</xref>, <xref rid="bb0880" ref-type="bibr">Omrani et al., 2014</xref>, <xref rid="bb1010" ref-type="bibr">Shalhoub et al., 2015</xref>, <xref rid="bb1035" ref-type="bibr">Spanakis et al., 2014</xref>, <xref rid="bb1045" ref-type="bibr">Strayer et al., 2014</xref>). While <italic>in vitro</italic> and animal studies suggested their potential efficacy, <italic>in vivo</italic> and clinical evidence is less well-established (<xref rid="bb0075" ref-type="bibr">Al-Tawfiq et al., 2014</xref>, <xref rid="bb0210" ref-type="bibr">Chan et al., 2015</xref>, <xref rid="bb1120" ref-type="bibr">de Wilde et al., 2013</xref>, <xref rid="bb0395" ref-type="bibr">Falzarano et al., 2013a</xref>, <xref rid="bb0400" ref-type="bibr">Falzarano et al., 2013b</xref>, <xref rid="bb0570" ref-type="bibr">Khalid et al., 2014</xref>, <xref rid="bb0565" ref-type="bibr">Khalid et al., 2015</xref>, <xref rid="bb0585" ref-type="bibr">Kim et al., 2016b</xref>, <xref rid="bb0605" ref-type="bibr">Lau et al., 2013</xref>, <xref rid="bb0880" ref-type="bibr">Omrani et al., 2014</xref>, <xref rid="bb1010" ref-type="bibr">Shalhoub et al., 2015</xref>, <xref rid="bb1035" ref-type="bibr">Spanakis et al., 2014</xref>, <xref rid="bb1045" ref-type="bibr">Strayer et al., 2014</xref>, <xref rid="bb1215" ref-type="bibr">Zheng and Wang, 2016</xref>). Clinical studies have been mainly confined to case studies and case series, and retrospective analyses (<xref rid="bb0075" ref-type="bibr">Al-Tawfiq et al., 2014</xref>, <xref rid="bb1120" ref-type="bibr">de Wilde et al., 2013</xref>, <xref rid="bb0570" ref-type="bibr">Khalid et al., 2014</xref>, <xref rid="bb0565" ref-type="bibr">Khalid et al., 2015</xref>, <xref rid="bb0585" ref-type="bibr">Kim et al., 2016b</xref>, <xref rid="bb0605" ref-type="bibr">Lau et al., 2013</xref>, <xref rid="bb0880" ref-type="bibr">Omrani et al., 2014</xref>, <xref rid="bb1035" ref-type="bibr">Spanakis et al., 2014</xref>, <xref rid="bb1045" ref-type="bibr">Strayer et al., 2014</xref>). Thus there is a need for properly controlled clinical trials of IFN combination therapy in MERS-CoV, preferably early in the illness when it seems to be most effective. These types of therapies function essentially by challenging the immune evasion tactics employed by the virus (<xref rid="bb0075" ref-type="bibr">Al-Tawfiq et al., 2014</xref>, <xref rid="bb0210" ref-type="bibr">Chan et al., 2015</xref>, <xref rid="bb1120" ref-type="bibr">de Wilde et al., 2013</xref>, <xref rid="bb0395" ref-type="bibr">Falzarano et al., 2013a</xref>, <xref rid="bb0400" ref-type="bibr">Falzarano et al., 2013b</xref>, <xref rid="bb0570" ref-type="bibr">Khalid et al., 2014</xref>, <xref rid="bb0565" ref-type="bibr">Khalid et al., 2015</xref>, <xref rid="bb0585" ref-type="bibr">Kim et al., 2016b</xref>, <xref rid="bb0605" ref-type="bibr">Lau et al., 2013</xref>, <xref rid="bb0880" ref-type="bibr">Omrani et al., 2014</xref>, <xref rid="bb1010" ref-type="bibr">Shalhoub et al., 2015</xref>, <xref rid="bb1035" ref-type="bibr">Spanakis et al., 2014</xref>, <xref rid="bb1045" ref-type="bibr">Strayer et al., 2014</xref>, <xref rid="bb1215" ref-type="bibr">Zheng and Wang, 2016</xref>). Recently, results of a study using <italic>in vitro</italic> and human <italic>ex vivo</italic> explant cultures suggested that a combination of IFN-α and cyclosporine had a synergistic effect on reduction of MERS-CoV replication, based on immunomodulation and induction of IFN-stimulated gene expression, suggesting that clinical trials may be warranted (<xref rid="t0010" ref-type="table">Table 2</xref>) (<xref rid="bb0615" ref-type="bibr">Li et al., 2018</xref>). Corticosteroid treatment is also commonly used in treatment of critically ill MERS-CoV patients, despite the findings of the ISARIC-WHO group that its risks may outweigh benefits (<xref rid="bb1080" ref-type="bibr">Treatment of MERS-CoV; information for clinicians, 2015</xref>). A recent marginal structural modeling study was carried out on data from 309 critically ill ICU patients with MERS-CoV, of whom 151 received corticosteroids, from 14 KSA health facilities between September 2012 and October 2015 (<xref rid="bb0095" ref-type="bibr">Arabi et al., 2018</xref>). The results indicated that corticosteroid therapy was not associated with significantly different mortality outcomes when time-varying confounding effects such as worsening condition of the patient were considered, but that it was associated with delayed clearance of viral RNA. These findings suggest that bias in determining potentially harmful effects of therapies can emerge in observational studies if only the baseline characteristics rather than time-variant characteristics of the patients are considered and further highlight the need for properly controlled clinical trial data.</p><p id="p0275">Another useful tactic would be to make use of therapies that have already been clinically approved for other purposes and for which there is a sound scientific rationale for possible use in MERS-CoV therapy. An example would be camostat, which is an inhibitor of TMPRSS2 (<xref rid="bb1020" ref-type="bibr">Shirato et al., 2013</xref>, <xref rid="bb1240" ref-type="bibr">Zhou et al., 2015b</xref>). Camostat has been shown to block infection, viral spread and pathogenesis in a pathogenic mouse model of SARS-CoV and would be likely to have a similar inhibitory effect on MERS-CoV (<xref rid="bb1240" ref-type="bibr">Zhou et al., 2015b</xref>). Camostat is already used clinically for treatment of chronic pancreatitis, and is thus a potentially safe and effective therapeutic option. Another TMPRSS2 inhibitor, nafamostat, has also been identified <italic>in vitro</italic> as a potent inhibitor of MERS-CoV S protein-mediated host-viral membrane fusion and is also already in clinical use as an FDA-approved anticoagulant (<xref rid="bb1145" ref-type="bibr">Yamamoto et al., 2016</xref>). In a screen of FDA-approved drugs, an inhibitor of cathepsin L called teicoplanin has been shown to block cytoplasmic entry of MERS-CoV, SARS-CoV and Ebola pseudoviruses (<xref rid="bb0915" ref-type="bibr">Qian et al., 2013</xref>, <xref rid="bb1235" ref-type="bibr">Zhou et al., 2016</xref>). Teicoplanin is in current clinical use as an antibiotic for serious Gram-positive bacterial infections and its derivatives, including dalbavancin, oritavancin, and telavancin, also block cytoplasmic viral entry. While these therapies all target host proteases, another possibility is targeting of viral proteases. The nsp3 encoded PL(pro) activity, which mediates the initial processing of pp1a (<xref rid="f0010" ref-type="fig">Fig. 2</xref>) (<xref rid="bb0415" ref-type="bibr">Forni et al., 2016</xref>, <xref rid="bb0465" ref-type="bibr">Hagemeijer et al., 2012</xref>, <xref rid="bb0835" ref-type="bibr">Neuman et al., 2014</xref>), can be inhibited <italic>in vitro</italic> by the SARS-CoV PL(pro) inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG) and by a commercial compound F2124–0890 (Life Chemicals) (<xref rid="bb0240" ref-type="bibr">Cheng et al., 2015</xref>, <xref rid="bb0265" ref-type="bibr">Clasman et al., 2017</xref>). The main MERS-CoV protease Mpro/3CLpro, encoded by nsp5 (<xref rid="f0010" ref-type="fig">Fig. 2</xref>) can be targeted <italic>in vitro</italic> and <italic>in vivo</italic> by lopinavir, a protease inhibitor with activity against the SARS-CoV Mpro and which emerged in a screen of a library of 348 FDA-approved drugs as one of 4 compounds that inhibited MERS-CoV viral activity in a low micromolar range (<xref rid="bb0210" ref-type="bibr">Chan et al., 2015</xref>, <xref rid="bb1115" ref-type="bibr">de Wilde et al., 2014</xref>, <xref rid="bb0940" ref-type="bibr">Rambaut, 2014</xref>). However, lopinavir clinical efficacy has not been convincingly established in MERS-CoV treatment as it has generally been used clinically in combination with IFN and data is only available from case studies and series. In marmosets infected with MERS-CoV, it gave favorable clinical outcomes and reduced mortality in combination with ritonavir (<xref rid="bb0210" ref-type="bibr">Chan et al., 2015</xref>).</p><p id="p0280">Early treatment (within 4–5 days of symptoms onset) with convalescent plasma (or hyperimmune IV immunoglobulin (HVIG) from plasma of convalescent donors) has been associated with decreased viral load and reduced mortality for influenza and SARS-CoV infection, although the quality of studies for SARS-CoV has been uneven and there have been few adequate clinical trials (<xref rid="bb0525" ref-type="bibr">Hui and Lee, 2013</xref>, <xref rid="bb0530" ref-type="bibr">Hung et al., 2013</xref>, <xref rid="bb0680" ref-type="bibr">Mair-Jenkins et al., 2015</xref>, <xref rid="bb1040" ref-type="bibr">Stockman et al., 2006</xref>). The PHE and ISARIC-WHO position paper identified convalescent plasma as a potential treatment for MERS-CoV infection, however no clinical trial have yet been completed (<xref rid="bb1080" ref-type="bibr">Treatment of MERS-CoV; information for clinicians, 2015</xref>). A clinical trial in KSA on safety and efficacy of convalescent plasma treatment for critically ill MERS-CoV patients was initiated in May 2014 and is still listed as active but not recruiting [247; <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" id="ir0005">ClinicalTrials.gov</ext-link> Identifier: <ext-link ext-link-type="ClinicalTrials.gov" xlink:href="NCT02190799" id="ir0010">NCT02190799</ext-link>]. It was due to report in June 2017 but in common with many convalescent plasma trials it has been affected by logistical and technical issues, such as availability both of sufficient donors and sufficient levels of MERS-CoV antibodies in the plasma that is collected (<xref rid="bb0085" ref-type="bibr">Arabi et al., 2015</xref>, <xref rid="bb0815" ref-type="bibr">Modjarrad, 2016</xref>). Clinical data is sparse on use of convalescent plasma in treatment of MERS-CoV and is confined to 2 case reports in which its role in patient recovery was unclear (<xref rid="bb0090" ref-type="bibr">Arabi et al., 2014</xref>, <xref rid="bb0560" ref-type="bibr">Kapoor et al., 2014</xref>). Use in marmosets infected with MERS-CoV in a recent study indicated that while convalescent plasma treatment reduced signs of clinical disease, including reduced respiratory tract viral load, it did not induce a decrease in gross pathology (<xref rid="bb0350" ref-type="bibr">van Doremalen et al., 2017</xref>). Thus while convalescent plasma is a possible candidate MERS-CoV therapy, technical and logistical difficulties with its collection and preparation and uncertainty over the extent of its protective effects may undermine its potential usefulness.</p></sec><sec id="s0170"><label>9.2</label><title>Vaccines</title><p id="p0285">Studies from KSA have suggested that while patients who survived MERS-CoV produced anti-MERS-CoV IgG and neutralizing antibodies, these antibody levels only weakly inversely correlated with lower respiratory tract (LRT) viral load and would be insufficient to eliminate LRT virus (<xref rid="bb0285" ref-type="bibr">Corman et al., 2015</xref>). T cell responses to MERS-CoV infection are not yet well-understood, but in a recent study on 21 survivors of MERS-CoV in KSA, both CD4 and CD8 T cell responses developed in all of them (<xref rid="bb1210" ref-type="bibr">Zhao et al., 2017</xref>). MERS-CoV specific neutralizing antibody responses along with memory CD4 T cell but not CD8 T cell responses were shown to correlate with disease severity, while virus-specific CD8 T cell responses were observed in all MERS-CoV survivors, even when serological responses were not observed (<xref rid="bb1210" ref-type="bibr">Zhao et al., 2017</xref>). Robust CD8 T cell responses might therefore be important in early clearance of viral infection and hence antibody and CD4 T cell responses may not develop so strongly. Measurement of T cell responses along with antibodies may also give a more accurate estimate of disease prevalence. <italic>In vitro</italic> studies have shown that MERS-CoV infection down-regulates MHC and antigen presentation molecules <italic>via</italic> a methylation-based mechanism, which could have implications for both T cell and humoral adaptive immune responses [old ref. (<xref rid="bb0755" ref-type="bibr">Menachery et al., 2018</xref>)]. The combination of the apparent inadequacy of the humoral adaptive immune response to clear MERS-CoV and the high mortality rate associated with the disease point up the importance of vaccine development, particularly for the Middle East and KSA in particular. Induction of both antibody and T cell responses would be an important feature of a useful vaccine. WHO have issued guidelines on proposed MERS-CoV vaccines; they will consider prospective vaccines on a case-by-case basis (<xref rid="bb1105" ref-type="bibr">WHO target product profiles for MERS-CoV vaccines, 2017</xref>). WHO distinguished between vaccine types to be aimed at 3 different defined target populations, all of which have direct relevance in the Middle East. The 3 types are: dromedary camel vaccines designed to prevent camel-camel and camel-human transmission; prophylactic human vaccines for individuals who may be at long-term risk, for example healthcare workers and people working with potentially infected animals; and finally human vaccines which would be suitable for use in outbreaks (<xref rid="bb1105" ref-type="bibr">WHO target product profiles for MERS-CoV vaccines, 2017</xref>). WHO have defined preferred and minimally acceptable criteria for each vaccine type. These WHO guidelines are particularly welcome in the context of the difficulties that have prevailed in defining populations who should be targeted in a MERS-CoV vaccination program and/or in randomized clinical trials, especially given the current relatively low incidence of disease in humans, and the difficulties in developing suitable small animal models, depending on transduced or transgenic human DPP4-expressing mouse models (<xref rid="bb0245" ref-type="bibr">Cho et al., 2018</xref>).</p><p id="p0290">As with therapy development, the S protein is the focus of many candidate vaccines (<xref rid="bb0025" ref-type="bibr">Alharbi et al., 2017</xref>, <xref rid="bb0270" ref-type="bibr">Coleman et al., 2014</xref>, <xref rid="bb0450" ref-type="bibr">Guo et al., 2015</xref>, <xref rid="bb0535" ref-type="bibr">Inovio, 2016</xref>, <xref rid="bb0555" ref-type="bibr">Jung et al., 2018</xref>, <xref rid="bb0600" ref-type="bibr">Langenmayer et al., 2018</xref>, <xref rid="bb0640" ref-type="bibr">Liu et al., 2018</xref>, <xref rid="bb0685" ref-type="bibr">Malczyk et al., 2015</xref>, <xref rid="bb0830" ref-type="bibr">Muthumani et al., 2015</xref>, <xref rid="bb1090" ref-type="bibr">Volz et al., 2015</xref>). Vectors including modified vaccinia virus Ankara (MVA), ad5 or ad41-type adenoviruses, measles virus, chimeric vesicular stomatitis virus (VSV) and chimpanzee adenovirus (ChAdOx1) have been successfully used to express MERS-CoV S protein and induce neutralizing antibodies in mice and in other animal models including camels and rhesus monkeys (<xref rid="t0010" ref-type="table">Table 2</xref>) (<xref rid="bb0025" ref-type="bibr">Alharbi et al., 2017</xref>, <xref rid="bb0270" ref-type="bibr">Coleman et al., 2014</xref>, <xref rid="bb0450" ref-type="bibr">Guo et al., 2015</xref>, <xref rid="bb0535" ref-type="bibr">Inovio, 2016</xref>, <xref rid="bb0555" ref-type="bibr">Jung et al., 2018</xref>, <xref rid="bb0600" ref-type="bibr">Langenmayer et al., 2018</xref>, <xref rid="bb0640" ref-type="bibr">Liu et al., 2018</xref>, <xref rid="bb0685" ref-type="bibr">Malczyk et al., 2015</xref>, <xref rid="bb0830" ref-type="bibr">Muthumani et al., 2015</xref>, <xref rid="bb1090" ref-type="bibr">Volz et al., 2015</xref>). These virus vectors have the advantage of good safety profiles in humans. Production of candidate vaccines with potential for veterinary use in dromedary camels in order to reduce cross-species transmission is a welcome development in keeping with the WHO guidelines. These include an S protein-expressing MVA-based vaccine (MVA-MERS-S) which can a strong neutralizing antibody and cytotoxic T lymphocyte response and reduction of viral replication in transduced mice and induce mucosal immunity in MERS-CoV-infected dromedary camels (<xref rid="bb0600" ref-type="bibr">Langenmayer et al., 2018</xref>, <xref rid="bb1090" ref-type="bibr">Volz et al., 2015</xref>). These viruses are due to enter human clinical trials soon as a candidate prophylactic MERS-CoV vaccine. Another potential vaccine due to be evaluated in camels and to enter human clinical trials is a ChAdOx1 MERS vaccine (<xref rid="t0010" ref-type="table">Table 2</xref>) (<xref rid="bb0025" ref-type="bibr">Alharbi et al., 2017</xref>). In mouse studies, a single dose of ChAdOx1 MERS with the leader sequence of the human tissue plasminogen activator gene (tPA) induced an equivalent humoral response to 2 doses of an MVA-based vaccine (<xref rid="bb0025" ref-type="bibr">Alharbi et al., 2017</xref>). Another potentially efficient prophylactic vaccination strategy recently tested in mice involved heterologous prime–boost vaccination regimens using Ad5/MERS in combination with S protein nanoparticles (<xref rid="bb0555" ref-type="bibr">Jung et al., 2018</xref>). Heterologous prime-boost elicited both anti-MERS-CoV neutralizing antibodies and simultaneous Th1 and Th2 responses, while homologous prime–boost regimens did not induce simultaneous Th1 and Th2 responses. Homologous Ad5/MERS also did not induce neutralizing antibody responses, while immunization schedules involving Ad5/MERS did induce Th1 cell activation and those including only S protein nanoparticles did not. Thus overall, heterologous prime–boost schedules gave superior results and are likely to induce more effective and sustained immune responses against MERS-CoV (<xref rid="bb0555" ref-type="bibr">Jung et al., 2018</xref>). This type of vaccine would again be in keeping with WHO guidelines. A DNA-plasmid-based vaccine called GLS-5300 which encodes MERS-CoV S protein and was co-developed by Inovio, GeneOne Life Science Inc. and the Walter Reed Army Institute of Research, is meanwhile the first potential MERS-CoV vaccine to be tested in clinical trials in humans (<xref rid="bb0535" ref-type="bibr">Inovio, 2016</xref>). A phase I clinical trial in healthy volunteers is ongoing to evaluate its safety and its ability to generate sustained humoral and cellular immune responses over a 1 year period (<xref rid="bb0535" ref-type="bibr">Inovio, 2016</xref>). Pre-clinical trials were performed in mice, camels, and macaques, in which the vaccine induced robust immune responses which were effective in preventing viral infection (<xref rid="bb0830" ref-type="bibr">Muthumani et al., 2015</xref>).</p></sec></sec><sec id="s0175"><label>10</label><title>Conclusions</title><p id="p0295">Since its initial description in 2012, MERS-CoV has exacted a high mortality rate particularly in KSA. While epidemic potential has not been evident thus far, the potential exists for viral mutation that could increase zoonotic and/or human-to-human transmission. Outbreaks have tended to occur in healthcare facility settings and infection rates in KSA have been reduced by stringent efforts to improve infection control and prevention standards. However, the inclusion by WHO of MERS-CoV on its list of priority blueprint diseases is a timely reminder of the urgent need for accelerated research and development as this disease has the potential to cause a public health emergency and there are currently no directly efficacious drugs and/or vaccines available (<xref rid="bb0635" ref-type="bibr">List of Blueprint priority diseases, 2018</xref>). The virus clinical spectrum varies from asymptomatic, to mild–moderate disease and potential for severe disease with a high case fatality rate. The impact of asymptomatic cases, including healthcare workers, on transmission is not yet fully understood. Multiple studies have suggested that dromedary camels are the likely main zoonotic source of MERS-CoV infection in humans, and this has major implications for the valuable camel trade between the Middle East and Africa. The apparently lower than expected numbers of human cases in Africa may be attributable to inadequacies in surveillance systems that should be addressed. The role of other animals such as bats and hedgehogs also needs further clarification, and the possible emergence of alpacas as a potential zoonotic source deserves attention. While NAAT detection systems are highly sensitive and specific, further attention is needed to the most effective and feasible detection systems that can be employed in the field. A major ongoing issue is the lack of any accepted specific treatment for MERS-CoV infection. Current treatment guidelines are too much based on experience with SARS-CoV therapy, despite numerous key differences between these coronaviruses, and there is an urgent need to move from <italic>in vitro</italic> and <italic>in vivo</italic> models and clinical case studies to properly managed randomized control trials on some of the numerous direct therapeutic and vaccine candidates that have been identified. Further clarification of issues such as duration of isolation of patients with MERS-CoV infection is also needed. Thus in our view, priorities include further clarification of transmission modes, for example the role of asymptomatic individuals in disease spread, ongoing vigilance in monitoring possible cross-species transmission, the ongoing need for well-validated human and animal sera panels, and the need to add some urgency to the clinical response progress, including advancement of possible direct therapies to human clinical trials. While progress has undoubtedly been made in our understanding of MERS-CoV, much remains to be done to reduce the impact of this disease, particularly in KSA, and to ensure that any future outbreaks can be effectively contained.</p></sec><sec id="s0180"><title>Compliance with Ethics Guidelines</title><p id="p0300">This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee. Special thanks to research center, Dr. Sulaiman Al-Habib Medical Group for supporting this research project.</p></sec></body><back><ref-list id="bi0005"><title>References</title><ref id="bb0005"><element-citation publication-type="book" id="rf0005"><chapter-title>About SAVE LIVES: Clean Your Hands</chapter-title><source>My 5 Moments for Hand Hygiene</source><year>2018</year><publisher-name>World Health Organization (WHO)</publisher-name><comment>[cited 2018 September 27]. 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