Highlights and Conclusions from the Technical Consultative Meeting on Novel Coronavirus Infection, Cairo, Egypt, 14–16 January 2013 C

EMHJ • Vol. 19 Supplement 1 2013 Eastern Mediterranean Health Journal La Revue de Santé de la Méditerranée orientale

Meeting report Highlights and conclusions from the technical consultative meeting on novel coronavirus infection, Cairo, Egypt, 14–16 January 2013 C. Joseph,1 M.R. Malik,2 A.W. Mounts,1 A. R. Mafi,2 S. Briand,1 Z.A. Memish 3,4 and the technical working group for the meeting on novel coronavirus

مقتطفات وخالصات من االجتامع التشاوري التقني حول العدوى بالفريوس التاجي اجلديد؛ القاهرة، مرص، 14-16 كانون الثاين/يناير 2013 كارل جوزيف، مامونار مالك، أنطوين واين ماونت، عيل رضا معايف، سيلفي برياند، زياد ميمش، الفريق العامل لالجتامع عىل رواية الفريوس التاجي اخلالصـة: لقد أدى ظهور ذرية جديدة من الفريوس التاجي Coronavirusيف شبه اجلزيرة العربية إىل إثارة القلق الصحي عىل الصعيد العاملي عام 2012 ؛ وذلك يعود ًجزئياإىل أن معظم حاالت العدوى البرشية كانت مميتة، كام يعود ًجزئيا ًأيضا إىل أهنا من مصدر حيواين عىل ما ُي َفرتض. وقد عقدت منظمة الصحة العاملية يف كانون الثاين/يناير ،2012 ً اجتامعا ًعاجاليف ظل املعلومات الضئيلة املتاحة حول السوابق الطبيعية والوبائية للعدوى هبذا الفريوس اجلديد. وقد استعرض االجتامع ِّالبينات الراهنة، َّوحدد الفجوات احلاسمة يف املعارف والالزمة لتحسي الوصول إىل ٍفهم أفضل ملخاطر الصحة العامة التي ترافق هذا الفريوس بحيث يتم حتسي التأهب كام تتم محاية ووقاية الصحة يف العامل.

ABSTRACT The emergence of a novel strain of coronavirus in the Arabian Peninsula raised a global health concern in 2012, partly because the majority of human infections were fatal and partly due to its presumed animal origin. An urgent meeting of scientific and public health experts was convened by WHO in January 2013 in view of the limited knowledge available on the epidemiological and natural history of infection with this novel virus. The meeting reviewed current evidence and identified critical knowledge gaps to improve better understanding of the public health risk associated with the virus so as to improve preparedness and to safeguard and protect global health.

Faits marquants et conclusions de la réunion de consutlation technique sur l'infection par le nouveau coronavirus, Le Caire (Égypte), 14 - 16 janvier 2013

RÉSUMÉ L'émergence d'une nouvelle souche de coronavirus dans la Péninsule arabique a soulevé des inquiétudes sanitaires à l'échelle mondiale en 2012, d'une part parce que la majorité des infections humaines ont été mortelles et d'autre part parce qu'une origine animale était suspectée. L'Organisation mondiale de la Santé a invité des experts en santé publique et scientifiques à une réunion urgente en janvier 2013, étant donné les connaissances limitées disponibles sur l'évolution épidémiologique et naturelle de l'infection par ce nouveau virus. Pendant la réunion, les données disponibles ont été examinées et des lacunes critiques dans les connaissances ont été identifiées en vue d'améliorer la compréhension du risque pour la santé publique associé à ce virus, d'intensifier la préparation et de préserver et de protéger la santé mondiale.

1Global Influenza Programme, Department of Pandemic and Epidemic Disease. World Health Organization, Geneva, Switzerland. 2Pandemic and Epidemic Disease, Department of Communicable Disease Prevention and Control, World Health Organization Regional Office for the Eastern Mediterranean, Cairo, Egypt (Correspondence to M.R. Malik: [email protected]). 3Ministry of Health, Riyadh, Saudi Arabia. 4College of Medicine, Al Faisal University, Riyadh, Saudi Arabia.

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Introduction scientists who had been involved with sporadic cases were 6 June—10 Oc- the study of the origin of the virus, and tober. The dates of onset for the cases In 2012, a multi-country outbreak of experts who had participated in the within the family cluster were sequen- severe acute respiratory disease in the global public health response to SARS tial and ranged from 5 October to 3 Arabian Peninsula, caused by a novel and the avian influenza epidemic. The November, consistent with human-to- coronavirus (nCoV), raised a global purpose of this meeting was to review human transmission. No community health alert [1–3]. In light of the severity and discuss the scientific and public transmission was reported. of illness seen amongst the laboratory- health understanding of the emer- The investigation of potential en- confirmed cases reported to the World gence of nCoV to date, identify critical vironmental and animal sources of the Health Organization (WHO) by Janu- knowledge gaps in understanding the nCoV carried out in the Bisha area of ary 2013, where the mortality rate was current risk and identify the next steps Saudi Arabia in September 2012 was not over 55% [4], the discovery of this new to improve knowledge and close up conclusive. Bats and dates were the main virus triggered unprecedented global the research gap for public health ac- focus of investigation. Bats were targeted attention. tion at the national and international because of the genetic relatedness of This novel virus brought back mem- level. The meeting was organized in 5 the nCoV to coronaviruses previously ories of the global epidemic of severe thematic sessions and in each of these found in bats in Mexico and elsewhere acute respiratory syndrome (SARS) in sessions, available scientific informa- [9]. Bat CoVHKU9, bovine respiratory 2003 as this new virus was presumed to tion and up-to-date evidence on nCoV CoV and Kenya Idoline bat viruses were be of animal origin and also belonged to were presented and discussed by the detected among the 755 oral, rectal and the same family of Coronoviridae as that participants. The sessions included serological samples from insectivorous of the SARS virus (SARS–CoV). Clini- (i) epidemiological information; (ii) bats collected in the Bisha area of Saudi Arabia and tested in the United States of cal symptoms caused by nCoV infection virological and animal investigation; America (USA) in October. Sequenc- also matched the clinical picture of acute (iii) development of tests for nCoV; ing by nested polymerase chain reaction primary viral pneumonia seen in many (iv) experience from SARS; and (v) (PCR) showed that Saudi bat virus was patients suffering from SARS [5]. risk communication and preparedness. The final session of the meeting on genetically indistinguishable from the The genetic sequence data indicated “knowledge gaps and priorities for re- nCoV identified by the Erasmus Medi- that this new coronavirus was a beta- search” reviewed the currently available cal Center (EMC) of Rotterdam in the coronavirus similar to bat coronaviruses, scientific evidence and identified the Netherlands. No virus was cultured from but not similar to any other coronavirus critical knowledge gaps that needed to the Bisha bats. No microbiological or previously described in humans, includ- be addressed in order to improve global environmental link was made between ing the coronavirus that caused SARS understanding of the risk associated date farming and date consumption for in 2003 [6–8]. The available evidence with this novel virus. This paper summa- the first confirmed case of nCoV infec- related to this nCoV continued to sug- rizes the currently available information tion and no tests were carried out on gest a zoonotic origin for the virus, and on the virus, knowledge gaps and the camels or goats. Though the inability to experience with the SARS–CoV also priority public health research activities culture the virus or extend the sequence showed that any novel virus that is zo- that were discussed in the meeting in makes interpretation of the results dif- onotic in origin has the potential to effi- order to improve global preparedness ficult, it did suggest that the virus may ciently transmit from person to person, for any potential pandemic caused by have been in the environment at very especially in healthcare settings, and this novel virus. low frequency and concentration. It to cause a global pandemic of severe remained unknown whether the virus human illness. was in livestock or another intermediate An urgent meeting of scientific and Highlights host, nor how it may have been transmit- public health experts involved in the ted to humans. national and global investigations of Environmental and The first case reported from Qatar this nCoV infection was convened by epidemiological investigation had onset of illness on 3 September with WHO at its Eastern Mediterranean Re- By December 2012, 6 laboratory- a travel history to Mecca from 29 July to gional Office in Cairo, Egypt, from 14 to confirmed cases of nCoV, including 18 August. He had no known contact 16 January 2013. The meeting brought 3 deaths, had been reported from with sick people. He owns a farm with together WHO, national experts who Saudi Arabia. Three (3) cases occurred camels and sheep which he visited once had been involved in investigations sporadically and 3 were part of a fam- on his return from Mecca. The patient around the cases that have occurred, ily cluster. The dates of onset for the 3 was transferred to the United Kingdom

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(UK) on 12 September where the London tested positive for nCoV. The receptor for nCoV is different from nCoV was identified through culture patient was transferred to Germany on that used by the SARS–CoV, which and PCR. Genetic sequencing indi- 24 October. The estimated number of also causes Severe Acute Respiratory cated that the virus was the same as health-care workers and family con- Syndrome [10]. It has been previously that previously found in the patient in tacts associated with the case was 85. shown that changes in the spike pro- Saudi Arabia. An investigation of health- Respiratory and serum samples were tein (S1) of the coronavirus are an care workers exposed to the patient collected from 20 of these contacts and important means by which the virus identified 4 who became symptomatic the nCoV was not detected in any of the adapts to a new host. The S1 protein after exposure, but laboratory reports respiratory samples. as the presumed binding site in nCoV were negative for all these cases when An investigation of 123 contacts was cloned and tested for binding to tested at the Health Protection Agency (120 hospital and 3 out-of-hospital con- target cells and was found to bind to (HPA) in London. tacts) of the first nCoV case identified in human cells, and in animal models. The UK Health Protection Agency Germany was conducted in November The dipeptidyl peptidase 4 (DPP4) (now known as Public Health Eng- 2012 at the Robert Koch Institute in protein, an enzyme expressed on the land) confirmed on 22 September Berlin, Germany, to evaluate human- surface of some cells, has now been 2012 infection with a novel coronavi- to-human transmission. The case was identified as a receptor to which the rus in a patient in a London hospital a patient with acute respiratory distress S1 virus protein binds in human and who had been transferred from Qa- syndrome of unknown origin and bat cells. tar 11 days previously. Following the symptom onset on 5 October who was Further studies are now going on institution of strict respiratory isola- transferred from Qatar to a specialist in the animal model related to patho- tion, infection control procedures and lung clinic in Germany. Eighty-five con- genic potential of nCoV in human enhanced surveillance as a response tacts provided blood for a serological respiratory tissues to this imported case from Qatar, 64 test and analysis was performed using a contacts (56 health-care workers and 2-stage approach with an initial immu- Sequencing studies 8 family and friends) were identified. nofluorescence assay as a screening test, The complete genome sequence of Ten days after last exposure, none of followed by recombinant immunofluo- the nCoV-EMC/2012 virus has been the 64 had developed severe disease; 13 rescence assays and an nCoV-specific published [8]. By January 2013, only of them had reported mild respiratory serum neutralisation test. None of the 2 viruses were fully sequenced: the symptoms during the 10-day follow- contacts tested positive for antibodies nCoV-EMC from Saudi Arabia and up period. The novel coronavirus was to the nCoV, indicating that no trans- the one from Qatar sequenced by the not detected in 10 of 10 symptomatic mission had occurred to contacts after HPA in London (England1_CoV). contacts tested. The health-care work- 20 days post exposure. The analysis of 3 sequenced genomic ers had a variety of exposures, includ- A cluster of severe acute respiratory fragments showed that the genetic ing some during an aerosol generating infections occurred in April 2012 in a structure of the virus isolate in Germa- procedure. Preliminary results of se- health-care setting in Zarqa, Jordan. In ny was identical to the virus isolated rological testing found no evidence of November 2012, retrospective labora- from the patient in Qatar in the UK. a serological response consistent with tory investigation of a stored specimen Methods for detecting nCoV by 2 infection among close contacts of the of bronchoalveolar lavage and a serum real-time, reverse-transcription PCR confirmed case. sample confirmed nCoV infection in 2 assays (real-time RT-PCR) were The second case from Qatar was patients, both of whom died. Addition- published in September 2012 [6]. a single male and owns a camel and ally, 11 probable cases were identified Two target regions were chosen for goat farm. He had no contact with the through a retrospective epidemiological screening, confirmation and sequenc- animals, had no history of travel, and no investigation. Ten of the 13 persons in known contact with sick people. He was this cluster were health-care workers. ing of the nCoV; the Upstream of treated in 2 hospitals in Qatar from 12 No sustained community transmission the E gene (UpE) for screening and to 24 October. Respiratory samples— was observed. ORF1b for confirmation. nasal swabs and an endotracheal tube A 700-nucleotide segment of the N (ETT) aspirate were collected from the Virological and animal gene of the virus from one of the cases investigations patient on 13 and 17 October and were in Jordan sequenced at the United negative when tested for a standard Pathogenesis of nCoV States Naval Medical Research Unit- panel of respiratory viruses in Qatar. A study conducted at the Univer- 3 (NAMRU-3) had 99% homology The ETT sample sent to the HPA in sity of Bonn found that the cellular to the EMC and London viruses.

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Development of laboratory The UK HPA tested 124 sera Experience from SARS tests for nCoV samples from family and health-care The global experience from SARS was a Tests by real-time PCR worker contacts of the imported case stark reminder of how a novel virus can The current WHO interim guidance from Qatar. The sera were screened for cause a global public health emergency, on PCR testing for nCoV states that a reactivity to coronavirus NL63 (CoV from a few sporadic cases to a world- positive PCR test should be followed gp1), OC43 (CoV gp2a), SARS (CoV wide epidemic. The SARS-CoV spread by a confirmatory test with the 1A as- gp2b) and nCoV England/1 2012 to 5 countries within a 24-hour period, say or by sequencing target sites within (CoV gp2c). No reactivity with the before international public health meas- the nucleocapsid protein region of the nCoV England 1 antigen was detected. ures were in place to identify, control genome [11]. Positive control materials When recombinant assays were tested and prevent the spread of infection. developed by the University of Bonn are for cross-reactivity with these strains The importance and challenges in the available for the upE and 1A tests. Two and bat CoV strains from groups 1, 2a, implementation of public health meas- new assays for sequencing, particularly 2b, 2c and 2d, the group 2c bat strains ures such as strict hospital infection where an insertion/deletion polymor- were reactive to the London patient control measures, case identification, phism might exist, as is the case between sera. These results were part of work and comprehensive identification and the EMC virus and the London virus, in progress, and further studies will be quarantine of contacts cannot be over- were also made available in December needed to interpret the data. Cross- emphasized. Sharing of information 2012. The assays are now available reactivity, particularly in older people at the local, national and international commercially worldwide and have been who have been exposed to different level was key to managing public and provided to some of the countries of the coronaviruses over time, can be natu- professional fear and anxiety. The les- WHO Eastern Mediterranean Region ral. Cross reactions might also occur sons learned from the SARS outbreak in where cases have occurred. The Cent- when detecting low titres that might be 2003 emphasized the need to strength- ers for Disease Control and Preven- a result of past infection combined with en international health regulations, have tion (CDC), USA, has developed two a fresh infection of a different CoV. A national plans in place to handle similar nucleocapsid assays for detection of wide range of tests are required to fully future outbreaks, maintain public health nCoV. These assays were distributed to understand these issues. epidemiological and microbiological capacity and keep ahead of the curve. Saudi Arabia and Jordan, and were used Ecological studies by NAMRU-3 to confirm the cases in Risk communication and Jordan. Ecological studies have shown that bats are natural hosts of 2b and 2c beta preparedness Serological tests coronavirus subgroups. Extensive bat The national and international public Two immunofluorescent antibody sampling has been carried out in Africa health organizations have kept the (IFA) detection assays have been de- and Europe, where a high percentage public fully apprised of the emergence veloped; one using conventional IFA of bats among the Nycteris (25%) and and investigation of the nCoV cases methods and the other a rapid method. Pipistrellus (36%) genera were found on their websites through regular bul- Confirmatory tests for positive IFA to be positive with CoV of the 2c clade. letins and updates, question and answer results are carried out through recom- The pipistrellus bats inhabit the Ara- sheets, or through publications such binant subunit assays, plaque reduction bian Peninsula but also migrate to Africa as the rapid reports in Eurosurveillance. neutralization tests, and western blot and other continents. The knowledge The WHO has 3 main communica- to rule out false positive results [6]. that insectivorous bats are natural tion channels: the Event Information Tests for sensitivity and cross-reactivity hosts for betacoronaviruses, and that Site (EIS), a password-protected rapid against other coronaviruses and other coronaviruses have been detected in a reporting system; the disease outbreak respiratory viruses with the nCoV- significant proportion of bats, does not news (DON), which is a public system; EMC found no cross-reactivity using in itself provide definitive evidence that and traditional media through its web- these confirmatory methods. Further they are the source of infection for the site and publications. The important validation studies are needed and the cases of nCoV detected in the Arabian lessons learned were mainly related IFA test is not suitable for broad popula- Peninsula. More studies are needed to to timely and adequate dissemination tion screening of asymptomatic indi- ascertain whether a virus even more of information—the more informa- viduals. Many serological samples are closely related to nCoV-EMC might tion the better—to help the affected in storage from the 9 nCoV cases and be found in other species and whether country, to help other neighbouring their contacts and these could be used other animals might be sources or car- countries, and to help the world be bet- to further validate the IFA tests. riers of the novel human coronavirus. ter prepared.

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Gap analysis and priorities for actions to improve the current knowl- in European, American and other na- future research and investigation edge gaps. tional laboratories; of novel coronavirus • encouraging cooperation in the de- A number of key knowledge gaps were velopment of virological studies; identified to better understand the evo- Conclusion and lution and public health risk associated next steps • preparing an inventory of training op- with this nCoV. The most important portunities for laboratory staff testing for nCoV; ones were the source of the virus, the The emergence of new, infectious, exposures that resulted in human infec- global threats in the past 4 decades • preparing an inventory of laboratories tion, and the mode of transmission. (e.g. AIDS, avian influenza A/H5N1 developing nCoV serological tests Those areas where more information is and SARS) has reshaped thinking at and list which laboratories are using needed to characterize the current and both national and international levels which tests; future risk posed to global health by on the nature and level of public health • preparing an inventory of countries this novel virus are: responses needed for these threats. The willing to test cases of severe acute • source of the infection and its animal International Health Regulations (2005) respiratory infection (SARI) for reservoir(s), have emphasized that all countries nCoV; • extent of geographical spread, are at risk from new infections and • liaising with the animal research therefore need to collaborate on in- • route(s) of transmission, group to strengthen collaborative formation sharing and data exchange studies and coordinate future stud- • transmissibility of infection and de- when they occur [12]. In the current ies into the reservoir of infection for gree of infectiousness, age of immediate and ongoing access nCoV; • exposure patterns, to world-wide digital information, • itemizing all collaborating resources there are high expectations globally • incubation periods, and identifying where capacity build- that everything is being done to de- • pathogenesis including age and gen- ing is required; der determinants, tect and control an emerging disease threat. Uncertainties as to how a newly • ensuring that risk assessment guide- • clinical spectrum of severe illness and discovered disease is going to evolve lines, infection control guidelines and evidence of mild infections, means that preparations have to be other documents are regularly re- • what further diagnostic tests should determined at both the national and viewed and communicated to those be developed for detection of virus, the global level. that need to know. • interpretation of test results. During the Cairo meeting, all cur- Four key areas were highlighted rent knowledge about the cases of for guiding future efforts in further- Technical working nCoV infection and about what has group members ing the global understanding and shaped priorities for future actions at knowledge of nCoV. These included the national and the international level The members of the technical work- (i) defining the geographic extent of was evaluated. After consolidating in- virus transmission, (ii) detecting any ing group include: Christian Drosten, formation on current scientific activities Walter Ian Lipkin, Ron Fouchier, escalation in incidence, (iii) improving ongoing at the global level, the delegates the case definition; and (iv) identify- Udo Buchholz, Keiji Fukuda, Jaouad identified activities that would advance ing the source of infection. A number Mahjour, Hala Esmat, Dalia Samhouri, knowledge about this infection in the of recommended actions were also Gregory Hartl, Agnus Nicoll, Richard immediate and long term. These in- proposed and future steps were identi- Pebody, Maria Zambon, Theresa Tam, clude: fied for WHO’s role. Table 1 presents Barbara Raymond, Hamad Eid Al- a summary of these priority research • preparing an inventory of current Romaihi, Said Hamed Al Dhahry and areas and the suggested recommended nCoV virological research activities Sultan Mabdalla.

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Table 1 Priority research area and recommended actions to improve global understanding and knowledge on novel coronavirus infection Priority research area Recommended actions Next steps, with support from WHO Defining the spectrum of • Develop a standardized and sensitive approach • Create a study group and framework disease severity (extent of for seroepidemiological studies to identify for designing appropriate studies using virus transmission) severely and mildly ill persons, including those standardized epidemiological methods. who may have been exposed to the virus but • Identify and prioritize groups for testing. remained well. The studies should focus on: • Develop protocols for standardized • patients with SARI; serological methods. • close contacts of cases who become • Encourage sharing of clinical samples symptomatic; between countries and laboratories. • clusters of SARI occurring in occupational • Initiate serosurveys of contacts and groups, particularly health care workers; probable cases to elucidate the full • Standardize and validate laboratory methods clinical spectrum of the disease, mindful for serological assays (IFA or ELISA) to be used of cross reaction. issues in serological for screening for more specific and conclusive studies. results. • Initiate laboratory training programmes for using standard methods. Detecting any increase or • Establish hospital baselines for pneumonia and • Develop standard surveillance tools decrease in incidence of monitor any unexplained rise in trend. for monitoring changes in rates of infection • Enhance surveillance within groups such as pneumonic illness or detection of illness case contacts, health care workers and clusters in selected population groups. of patients with severe respiratory illness. • Develop a standard protocol for guidance • Prospectively collect and test sputum on types of specimens to collect from specimens from SARI patients and their close selected population groups. contacts. • Ensure countries test single cases of unexplained severe respiratory illness and report positives to WHO.

Improving the case • Collect more data on the clinical spectrum • Contact affected countries to request data definition and natural history of nCoV to inform changes to better define key clinical features of to the case definition (implementing a 2-stage known cases. case definition of initial screening followed by • Obtain clinical information on known closer examination of cases that meet specific cases: pool all information from affected criteria can be considered). countries using a standardized extraction • Utilize protocols from the SARS epidemic to form. develop risk factor studies. • Develop a global case definition for reporting. • Continue to monitor the effectiveness of the case definition and revise when relevant. Identifying the source of • Conduct animal studies to inform sources; • Include animal studies in the framework. infection (protocols from the studies carried out for the SARS epidemic could be utilized for developing risk factor studies into nCoV infection).

ELISA = enzyme-linked immunosorbent assay; IFA = immunofluorescence assay; nCoV = novel coronavirus; SARI = severe acute respiratory infection; SARS = severe acute respiratory syndrome; WHO = World Health Organization.

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