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May 14, 2014

MERS: Getting a Handle on a Serious Zoonotic Coronavirus Infection

As a deadly virus reaches American shores, researchers seek to find out where it came from and how to stop it.

MERS: Getting a Handle on a Serious Zoonotic Coronavirus Infection

Coronaviruses are single-stranded RNA viruses that contain the largest known RNA genomes. [© fotoliaxrender - Fotolia.com]

  • A news story on Monday reported that a second patient has been admitted to an American hospital suffering from the MERS virus. The Saudi Arabian man is being treated in Orlando, Florida, while another MERS patient, an American who showed symptoms earlier this month, is in a hospital in Indiana.

    As of May 12th, the World Health Organization (WHO) said it had been informed of a total of 538 laboratory-confirmed cases in 12 countries of Middle East Respiratory Syndrome infection (MERS-CoV) that were caused, as was Severe Acute Respiratory Virus (SARS-CoV), by a coronavirus. Of 145 MERS-related deaths, 112 occurred in Saudi Arabia which has had a total of 450 cases.

    Most people confirmed to have MERS-CoV infection developed severe acute respiratory illness, with fever, cough, and shortness of breath and more than 30% of these individuals have died.

    Sporadic cases of the disease have been identified in Britain, Greece, France, Italy, Malaysia, and other countries. The U.S.-infected individual, a health worker from Indiana had worked in Saudi Arabia, is currently recovering from the disease.

    “It is understandable that some may be concerned about this situation, but this first U.S. case of MERS-CoV infection represents a very low risk to the general public,” said Anne Schuchat, M.D., assistant surgeon general and director of CDC’s National Center for Immunizations and Respiratory Diseases, in referring to the Indiana man. Federal, state, and local health officials are taking action to minimize the risk of spread of the virus. The Indiana hospital is using full precautions to avoid exposure within the hospital and among healthcare professionals and other people interacting with the patient, as recommended by CDC.

    To date, CDC has not recommended that travelers change their plans because of MERS, noting that most instances of person-to-person spread have occurred in health care workers and other close contacts such as family members and caregivers of people infected with MERS.

  • Largest Known RNA Genomes

    Coronaviruses (CoVs) are single-stranded RNA viruses that contain the largest known RNA genomes, ranging from 27 to 32 kilobases in length. As evidenced by the SARS-CoV epidemic in 2002-2003 and the recent emergence of MERS-CoV corona viruses continue to cause severe and lethal human disease.

    And although MERS-CoV is most likely of zoonotic origin, the potential animal reservoirs and mechanism(s) of transmission of MERS-CoV to humans remain unclear. The virus’ genetic similarity to bat coronaviruses suggested an origin in those flying mammals, and some recent reports have described serologic data from camels and the identification of related viruses in bats. However, scientists say more epidemiologic data linking cases to infected animals are needed to determine if a particular species is a host, a source of human infection, or both.

    To date, SARS-related CoVs were identified in Rhinolophus spp. bats in China and Europe and MERS-related CoVs in Pipistrellus bats in Europe and in Neoromicia bats in South Africa. As with SARS-CoV, it is expected that MERS-CoV might be transmitted to humans by an intermediate animal host.

    Isabella Eckerle, M.D., and colleagues at Medical Center, Institute of Virology, Germany, looking for insights into what the culprit intermediate host for MERS-CoV could be, tested the replicative capacity of the virus in cell lines derived from livestock and peridomestic small mammals on the Arabian Peninsula. Only cell lines originating from goats and camels showed efficient replication of the virus.

    These results, the authors say, provide direction in the search for the intermediate host of MERS-CoV, suggesting that ungulates such as goats and camels are possible intermediate hosts of MERS-CoV. Thus, exposure to urine and feces from these animals might constitute a source of human infection. Moreover, they add, food products derived from these animals such as meat and milk should be tested for their potential to transmit MERS-CoV. The results of the study the authors concluded, suggest that investigations into the MERS-CoV animal reservoir and intermediate host should focus on caprid (e.g., goats) and camelid hosts. And antibodies to MERS-CoV provide another clue of the camel’s culpability of as an intermediate host.

    Benjamin Meyer and teams of scientists in the Netherlands, Germany, and Dubai used serologic assays to analyze 651 dromedary camel (DC) serum samples from the United Arab Emirates; 151 of 651 samples were obtained in 2003, well before onset of the current epidemic, and 500 serum samples were obtained in 2013.

    The researchers reported that recombinant spike protein—the virus protein that is responsible for binding the virus to target cells—immunofluorescence and virus neutralization tests could clearly discriminate between MERS-CoV and bovine CoV infections. Most camels, about 87%, had anti-MERS-CoV antibodies and results included all 151 serum samples obtained in 2003. Most (389/651, 59.8%) serum samples had MERS-CoV-neutralizing antibody titers. Dromedary camels from the United Arab Emirates were infected at high rates with MERS-CoV or a closely related, probably conspecific, virus “long before the first human MERS cases” the investigators concluded.

    Abdulaziz N. Alagaili, Ph.D., of King Saud University working with colleagues at Columbia University, reported recovery of MERS-CoV from nasal swabs of DCs. Reverse transcription-PCR (RT-PCR) assays demonstrated the presence of MERS-CoV RNA in DCs at a high prevalence in Saudi Arabia. Sequence analysis of products representing three regions of the MERS-CoV genome revealed a match sequence of over approximately 3,000 nucleotides with human MERS-CoV sequences.

  • Whole-Genome Sequencing

    To determine whether this match sequence extended across larger regions of the MERS-CoV genome, Dr. Alagaili and fellow researchers used whole-genome sequencing using the Ion Torrent and Illumina platforms. Together with data indicating widespread dromedary infection in the Kingdom of Saudi Arabia, these findings support the plausibility of a role for dromedary camels, they concluded, in human infection.

    Given that it took 10 years and a couple of wrong animals, including chickens and civets, to find the likely origin of the SARS-CoV virus, the identification of camels as potential MERS-CoV happened fast. Teams led by team led by Zhengli Shi, Ph.D., from the Wuhan Institute of Virology, Chinese Academy of Sciences, and Peter Daszak, Ph.D., from Ecohealth Alliance identified SARS-like coronaviruses ( SL-CoVs) in Chinese horseshoe bats that were 95% identical to human SARS-Co., as evidenced by whole genome sequencing. These scientists isolated the first known live bat SL-CoV that replicates in human and related cells and can use human angiotensin-converting enzyme 2 (ACE2) receptor for docking and entry into human cells.

    Alarmingly, the scientists’ findings support one of their conclusions, that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs. They also highlight the importance of pathogen-discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness and to provide clear evidence that some SL-CoVs circulating in bats are capable of infecting and replicating in human cells.

    Efforts to develop vaccines protective against MERS-CoV are underway. Nature Asia reported on April 28 that Saudi Arabia's government is talking to pharmaceutical companies about developing a vaccine before another outbreak occurs. As Muslims from around the world will travel into to Saudi Arabia in July for Ramadan, and the annual Hajj pilgrimage scheduled for October, the recent surge in infections has revived fears of an epidemic.

    Last month, the University of Maryland School of Medicine and Novavax announced that an investigational vaccine candidate developed by Novavax against MERS-CoV blocked infection in lab studies. The vaccine was developed using Novavax' nanoparticle vaccine technology, and based on the spike protein responsible for viral binding to target cells. Researchers reported these findings in an article published in the April 13, 2014 issue of Vaccine.

    According to the company, vaccine strategies for emerging pathogens have been limited due to the sudden nature of the virus’ appearance and the protracted traditional vaccine development process. The Vaccine paper describes a novel method enabling rapid vaccine development against previously unknown viruses, such as MERS-CoV, which appear suddenly and cause severe human illness, explain Novavax officials. The experimental vaccines, which were tested in mice in conjunction with Novavax’ proprietary adjuvant Matrix-M™ induced neutralizing antibodies that prevent viruses from infecting cells.

    “Our protein nanoparticle vaccine technology is proving to have the potential to respond rapidly to emerging viruses such as MERS-CoV and certain potential pandemic influenza strains, addressing what are clearly urgent public health needs,” said Gale Smith, Ph.D., vp of vaccine development at Novavax. “Novavax will continue to evaluate this technology to produce highly immunogenic nanoparticles for coronavirus, influenza, and other human disease pathogens with the potential for pandemic and sustained human to human transmission.”

    But is working feverishly produce MERS vaccine a good idea? Some scientists don’t think so. “There are enormous problems with the idea of a MERS vaccine,” virologist Ian Jones, Ph.D., of the University of Reading told Reuters. “I can see that they want to say they can make it, and biochemically of course they could, but practically it doesn't make any sense.” And, he asks, “Who would you vaccinate? Would you vaccinate the whole population when only a tiny number of people seem to be susceptible?”

    Dr. Jones’ point is illustrated by the study in Lancet reporting data on a 47-patient cohort of infected Saudi individuals. Abdullah Assiri, Ph.D., and colleagues, in their paper entitled “Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study,” noted that MERS-CoV presents with a wide range of clinical manifestations and is associated with substantial mortality in admitted patients who have medical comorbidities. “It remains unclear whether persons with specific conditions are disproportionately infected with MERS-CoV or have more severe disease,” the authors said.

    Of 47 Saudi patients who were included in the study, most had fever (98%), cough (83%), and shortness of breath (72%). Many also had gastrointestinal symptoms: 26% had diarrhea, and 21% had vomiting. All but two patients (96%) had one or more chronic medical conditions, including diabetes (68%), hypertension (34%), heart disease (28%), and kidney disease (49%). Thirty-four (72%) had more than one chronic condition. Nearly half the patients in this series were part of a health-care-associated outbreak in Al-Ahsa, Saudi Arabia, a population the authors noted that would be expected to have high rates of underlying conditions. Also, the prevalence of diabetes in persons aged ~50 years in Saudi Arabia has been reported to be nearly 63%

    As Dr. Assiri and his colleagues pointed out, “Major gaps in our knowledge of the epidemiology, community prevalence, and clinical spectrum of infection and disease need urgent definition.”

    And along with this coronavirus, viruses of at least eight other families have been found to infect camels. Because camels have a close association with humans, and if they are indeed the hosts to the virus, continuous surveillance should be conducted to understand the potential for virus emergence in camels and for virus transmission to humans, scientists say. 

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