Tracking the transmission and evolution of MERS-CoV (2013)

In 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) first emerged in a patient who died of severe pneumonia in Saudi Arabia.1Zaki AM van Boheemen S Bestebroer TM Osterhaus AD Fouchier RA Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.N Engl J Med. 2012; 367: 1814-1820Crossref PubMed Scopus (4057) Google Scholar Although most cases confirmed so far in the Middle East have been sporadic with an unknown source of infection, human-to-human transmission has been reported in health-care and household settings.2Memish ZA Zumla AI Al-Hakeem RF Al-Rabeeah AA Stephens GM Family cluster of Middle East respiratory syndrome coronavirus infections.N Engl J Med. 2013; 368: 2487-2494Crossref PubMed Scopus (370) Google Scholar, 3Assiri A McGeer A Perl TM et al.Hospital outbreak of Middle East respiratory syndrome coronavirus.N Engl J Med. 2013; 369: 407-416Crossref PubMed Scopus (931) Google Scholar, 4Guery B Poissy J el Mansouf L et al.Clinical features and viral diagnosis of two cases of infection with Middle East respiratory syndrome coronavirus: a report of nosocomial transmission.Lancet. 2013; 381: 2265-2272Summary Full Text Full Text PDF PubMed Scopus (342) Google Scholar However, the source of the virus and mode of disease transmission remain unknown despite detection of a small fragment of sequence identical to the EMC/2012 MERS-CoV in a Taphozous perforatus bat captured in Saudi Arabia5Memish Z Mishra N Olival K et al.Middle East respiratory syndrome coronavirus in bats, Saudi Arabia.Emerg Infect Dis. 2013; (published online Aug 23.)https://doi.org/10.3201/eid1911.131172Crossref PubMed Scopus (512) Google Scholar and reports of cross-reactive antibodies to MERS-CoV in dromedary camels in Oman and the Canary Islands.6Reusken CB Haagmans BL Muller MA et al.Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study.Lancet Infect Dis. 2013; (published online Aug 8.)http://dx.doi.org/10.1016/S1473-3099(13)70164-6PubMed Google Scholar A hospital outbreak of MERS in the eastern province of Saudi Arabia was previously described,3Assiri A McGeer A Perl TM et al.Hospital outbreak of Middle East respiratory syndrome coronavirus.N Engl J Med. 2013; 369: 407-416Crossref PubMed Scopus (931) Google Scholar with full genome analysis of four isolates of the Al-Hasa outbreak combined with five previously identified MERS-CoV genomes. The investigators estimated that the time of most recent common ancestor (tMRCA) was August, 2011 (95% highest posterior density [HPD] November, 2009 to April, 2012), and showed that the four viruses formed a monophyletic clade. The study provided a better understanding of the transmission of MERS-CoV within family clusters2Memish ZA Zumla AI Al-Hakeem RF Al-Rabeeah AA Stephens GM Family cluster of Middle East respiratory syndrome coronavirus infections.N Engl J Med. 2013; 368: 2487-2494Crossref PubMed Scopus (370) Google Scholar, 7HPA UK Novel Coronavirus Investigation teamEvidence of person-to-person transmission within a family cluster of novel coronavirus infections, United Kingdom, February 2013.Euro Surveill. 2013; 18: 20427PubMed Google Scholar and in health-care settings.4Guery B Poissy J el Mansouf L et al.Clinical features and viral diagnosis of two cases of infection with Middle East respiratory syndrome coronavirus: a report of nosocomial transmission.Lancet. 2013; 381: 2265-2272Summary Full Text Full Text PDF PubMed Scopus (342) Google Scholar Nevertheless, the four cases selected were closely linked epidemiologically within this outbreak involving four health-care facilities.3Assiri A McGeer A Perl TM et al.Hospital outbreak of Middle East respiratory syndrome coronavirus.N Engl J Med. 2013; 369: 407-416Crossref PubMed Scopus (931) Google Scholar In The Lancet, Matthew Cotten and colleagues8Cotten M Watson SJ Kellam P et al.Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study.Lancet. 2013; (published online Sept 20.)http://dx.doi.org/10.1016/S0140-6736(13)61887-5PubMed Google Scholar further describe the geographical distribution and phylogenetic relation of MERS-CoV infections across time in Saudi Arabia. This study represents the largest number of MERS-CoV genomes described so far, with 13 complete and eight partial genomes (30–95% genome coverage) from 21 clinical MERS samples taken from the Al-Hasa outbreak and four other sites in Saudi Arabia (Riyadh, Buraidah, Bisha, and Hafr-Al-Batin). Each of the sequences was derived directly from clinical specimens of patients and thus avoided any mutations that would be introduced by tissue culture passage. The authors report three distinct MERS-CoV genotypes, whereas phylogeographic analyses suggest that the MERS-CoV zoonotic reservoir is geographically dispersed. Furthermore, genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have been caused by more than one virus introduction. The data obtained from clinical MERS samples from the Al-Hasa cluster and community outbreaks has recorded evolution of the MERS-CoV virus in this epidemic within Saudi Arabia, and the sequence variations also reveal remarkable multiple-tree clusters. The study has provided interesting data supporting circulation of MERS-CoV since the middle of 2011, with the estimated tMRCA as July, 2011 (95% HPD July, 2007 to June, 2012).8Cotten M Watson SJ Kellam P et al.Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study.Lancet. 2013; (published online Sept 20.)http://dx.doi.org/10.1016/S0140-6736(13)61887-5PubMed Google Scholar Although the human exposures that result in infection remain unknown, this study has added the novel finding of three distinct MERS-CoV genotypes in Riyadh, with at least two distinct lineages probably circulating in Riyadh in October, 2012. Disease transmission patterns in the epidemic suggest both human-to-human transmission and sporadic zoonotic events. The current genome sequence set is not adequate to discriminate definitively between single or multiple zoonotic introductions, but the description of the pair of related genomes from Riyadh and Bisha and the description of cases in east and west Saudi Arabia in both major lineages of the tree suggest many zoonotic events. Overall, this is an interesting study that extends earlier findings.2Memish ZA Zumla AI Al-Hakeem RF Al-Rabeeah AA Stephens GM Family cluster of Middle East respiratory syndrome coronavirus infections.N Engl J Med. 2013; 368: 2487-2494Crossref PubMed Scopus (370) Google Scholar, 3Assiri A McGeer A Perl TM et al.Hospital outbreak of Middle East respiratory syndrome coronavirus.N Engl J Med. 2013; 369: 407-416Crossref PubMed Scopus (931) Google Scholar Although this report provides neither direct evidence of animal transmission nor the precise mechanism of transmission, the information is useful in tracing the source and transmission of MERS-CoV.8Cotten M Watson SJ Kellam P et al.Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study.Lancet. 2013; (published online Sept 20.)http://dx.doi.org/10.1016/S0140-6736(13)61887-5PubMed Google Scholar There are some examples of the historical role and scientific value of molecular methods in tracing emerging severe acute respiratory infections. After the major outbreaks of SARS-CoV in 2003, researchers in many countries had applied molecular genome analysis to track the viral evolution and spread of the disease.9Chim SS Tsui SK Chan KC et al.Genomic characterisation of the severe acute respiratory syndrome coronavirus of Amoy Gardens outbreak in Hong Kong.Lancet. 2003; 362: 1807-1808Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 10Chiu RW Chim SS Lo YM Molecular epidemiology of SARS—from Amoy Gardens to Taiwan.N Engl J Med. 2003; 349: 1875-1876Crossref PubMed Scopus (14) Google Scholar, 11Guan Y Peiris JS Zheng B et al.Molecular epidemiology of the novel coronavirus that causes severe acute respiratory syndrome.Lancet. 2004; 363: 99-104Summary Full Text Full Text PDF PubMed Scopus (113) Google Scholar PCR has provided the scientific basis for direct examination of clinical samples for evidence of infection. Similar to MERS-CoV, sequence variations were reported in SARS-CoV obtained from different patients in this epidemic.9Chim SS Tsui SK Chan KC et al.Genomic characterisation of the severe acute respiratory syndrome coronavirus of Amoy Gardens outbreak in Hong Kong.Lancet. 2003; 362: 1807-1808Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 10Chiu RW Chim SS Lo YM Molecular epidemiology of SARS—from Amoy Gardens to Taiwan.N Engl J Med. 2003; 349: 1875-1876Crossref PubMed Scopus (14) Google Scholar, 11Guan Y Peiris JS Zheng B et al.Molecular epidemiology of the novel coronavirus that causes severe acute respiratory syndrome.Lancet. 2004; 363: 99-104Summary Full Text Full Text PDF PubMed Scopus (113) Google Scholar Cotten and colleagues8Cotten M Watson SJ Kellam P et al.Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study.Lancet. 2013; (published online Sept 20.)http://dx.doi.org/10.1016/S0140-6736(13)61887-5PubMed Google Scholar have effectively shown that sequence variations in the MERS-CoV genome can be applied as a powerful molecular method in tracing the route of transmission, when used in conjunction with standard epidemiology. Furthermore, using the publicly released full genomic sequences of SARS-CoV in 2003, various molecular detection methods based on RT-PCR were developed. Most of the diagnostic assays were initially focused on RNA extracted from nasopharyngeal aspirates, urine, and stools, but assays based on the analysis of RNA extracted from plasma and serum were later developed.12Ng EK Ng PC Hon KL et al.Serial analysis of the plasma concentration of SARS coronavirus RNA in pediatric patients with severe acute respiratory syndrome.Clin Chem. 2003; 49: 2085-2088Crossref PubMed Scopus (57) Google Scholar, 13Ng EK Hui DS Chan KC et al.Quantitative analysis and prognostic implication of SARS coronavirus RNA in the plasma and serum of patients with severe acute respiratory syndrome.Clin Chem. 2003; 49: 1976-1980Crossref PubMed Scopus (122) Google Scholar Such blood RNA assays (with one targeted at the nucleocapsid region and the other the polymerase region of the virus genome) allowed the more standardised quantitative expression of viral loads and became useful for early SARS diagnosis, with a detection rate of up to 80% during the first week of illness, when serology diagnosis of SARS was not sensitive at the early stage.12Ng EK Ng PC Hon KL et al.Serial analysis of the plasma concentration of SARS coronavirus RNA in pediatric patients with severe acute respiratory syndrome.Clin Chem. 2003; 49: 2085-2088Crossref PubMed Scopus (57) Google Scholar, 13Ng EK Hui DS Chan KC et al.Quantitative analysis and prognostic implication of SARS coronavirus RNA in the plasma and serum of patients with severe acute respiratory syndrome.Clin Chem. 2003; 49: 1976-1980Crossref PubMed Scopus (122) Google Scholar These quantitative systems, if available, might be useful for the early diagnosis of MERS-CoV and can provide viral load information that might facilitate prognostic assessments of an infected individual. With the increasing number of sporadic cases of MERS in the Middle East, more research is needed into the mode of transmission and exposures responsible for the sporadic introductions of MERS-CoV into human populations. Development of rapid and reliable diagnostic assays is also urgently needed so that health authorities can take appropriate public health measures to interrupt disease transmission and contain the virus. I declare that I have no conflicts of interest. Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic studyWe present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed. Full-Text PDF Open Access