With the seeming wain of the MERS-CoV outbreak there is now time to reflect on the events so far. Andrea Cetra reports.
Nearly 3 years have passed since the first case of Middle East respiratory syndrome coronavirus (MERS-CoV) made headlines worldwide, when the death of a 60-year-old man in Saudi Arabia who had exhibited symptoms of acute pneumonia and renal failure was reported. Although there has been a recent decline in the number of reported cases, several unanswered questions still remain about this novel coronavirus.
“The disease is just rare”, said Christian Drosten, virologist at the University of Bonn (Bonn, Germany), who has collaborated extensively with scientists in Saudi Arabia and the Netherlands. “MERS might not have to adapt that much, and may be able to switch hosts again and again”, he said, suggesting that MERS could become more common if it becomes adapted to a human host.
Since the September, 2012, outbreak, the Command and Control Centre of the Saudi Arabian Ministry of Health has reported 726 MERS-CoV cases and 302 infection-related deaths. Today, researchers are still searching for the novel Betacoronavirus' complete profile, its zoonotic source, and its precise mechanism of transmission from animals to human beings. “Looking for the source of infection is very important to break the cycle of human infection”, stated virologist Ali Mohamed Zaki, who was based at Dr Soliman Fakeeh Hospital in Jeddah, Saudi Arabia, during the 2012 outbreak.
Young camels might have a role in the spread of MERS-CoV infection
© 2014 Martin Rietze/Science Photo Library
Although much about the virus remains a mystery, WHO has highlighted a few identifiable trends in its behaviour. According to an April, 2014, WHO Risk Assessment Report, 75% of recorded cases were secondary, occurring either in health-care workers or other hospital patients who acquired the illness from another infected individual. Several of these cases were also asymptomatic, suggesting that further research is needed into the extent of subclinical disease. Furthermore, scientists suggest that individuals with underlying medical disorders such as diabetes, renal failure, and chronic lung disease might be at greater risk of contracting MERS-CoV, although additional research is needed.
The high prevalence of diabetes in Saudi Arabia (seventh highest in the world) means residents face a substantial threat of infection. The spike in cases between April and May, 2014—when nearly 100 incidents of infection were reported—is a trend many virologists now believe might have coincided with the weaning of camel calves, during which immunosuppressive pregnant camels and their offspring are particularly prone to viral shedding. According to Marion Koopmans (Erasmus Medical Centre [EMC] and National Institute for Public Health and Environment, Netherlands), young camels might have a role to play in the spread of the infection. “They have the highest virus shedding—so it makes it more likely that they would be transmitting the infection”, Koopmans stated.
The Saudi Ministry of Health initially faced criticism for its handling of the outbreak. Top officials, including Abdullah Al-Rabeeah, Minister of Health, and Ziad Memish, Deputy Minister of Health, were removed from their posts following speculation that 113 cases and 92 deaths had gone unreported—according to the WHO's International Health Regulations of 2005 member states are required to report “events” that might result in a public health emergency. Zaki also lost his job following his discovery of the infection, when he shared samples with Dutch researchers at EMC who then patented the virus. The dispute over discovery undoubtedly raised questions about the lack of legal framework for sharing pathogens. Although the 1993 Convention on Biodiversity gives countries the “sovereign right” over “genetic resources”, it does not explicitly address the handling of pathogens. “I wanted to do something different”, Drosten said, referring to a ProMED post referencing the discovery of the “novel coronavirus” via reverse-transcription PCR that he made available after the outbreak in Jeddah on Sept 29, 2012. “When we are through with this, some people will have to say sorry to each other”, Drosten added.
However, Alimuddin Zumla (University College, London, UK) remains confident about the Ministry's current efforts. The Ministry of Health has established a new scientific advisory board led by Tariq Madani from the Faculty of Medicine at King Abdulaziz University, Jeddah, and has set up specialist health centres around the country. Madani said the Ministry is listening to guidance from international researchers and partners at the WHO, who recommend infection control measures such as washing hands after contact with animals and refraining from consumption of raw milk or camel products. The Ministry is also implementing stricter controls throughout health-care services including a new “triage system” designed to isolate patients with respiratory illness, additional funding for research, and a campaign to promote infection prevention among health-care workers. “At the national level, we are taking precautions to minimise the risk of infection based on our experience and increased understanding of the modes of transmission based on our research”, Madani said. Furthermore, in July the Ministry announced plans to do a case-control study consisting of 20 cases and 80 controls. However, as the number of reported cases diminishes, this testing becomes increasingly difficult. Madani told TLID that the study was underway and is focused on primary cases to identify the risk factors for individuals who have shown no signs of human-to-human transmission.
Efforts to trace the infection's path are ongoing as researchers continue to focus on the link between dromedary camels and transmission to human beings. In December, 2013, virologists from Qatar and the Netherlands tested 14 dromedary camels in Qatar, identifying identical strains of the virus in the camels and in two infected people living on the same farm. Although the results could not definitively identify camels as the sole animal reservoir, many scientists now believe they do play an important part in MERS-CoV transmission to human beings. “Based on the viruses we found in camels and in humans and the fact that they are more or less identical, to me suggests, that this is a potentially important host of the virus”, said Bart Haagmans, a virologist at EMC and a coauthor of the December, 2013, study. “The data on camels is convincing and I have no reason to suspect any other animal source”, Drosten added. Subsequent experiments have yielded similar results as virologists have shown an evolutionary connection between the MERS-CoV reported in camels and the severe acute respiratory syndrome-related virus found in date-eating bats, which can be traced back more than 44 years. Although evidence suggests it is unlikely for bats have an active role in transmission, Zumla believes they might serve as an intermediary host for the infection. An additional serological study published by TLID in August, 2013, reported that the virus' neutralising antibodies were present in dromedary camels from Oman, but not, however, in other livestock. Thus, the consensus among many virologists is that camels have an important part to play in transmitting the virus to human beings.
Many experts also now agree that the virus is transmitted via respiratory droplets, passed from infected patients to those within 1·5 m. “Whether the virus can also be transmitted by air is not yet known”, Madani said, adding that airborne precautions are being taken.
With just two recent MERS-CoV cases reported in August, 2014, the search for treatment or a vaccine has become somewhat more difficult in the absence of another outbreak. Instead, many virologists suggest that concentrating on localised infection control measures in places where people are in contact with camels and in hospitals where patients with respiratory illness should be identified, might prove most effective in curtailing the spread of the virus—at least until next year's camel weaning season.
Haggmans is confident that the virus is still circulating and will lead to future cases. According to Drosten, a recent study he coauthored suggests that there is a low rate of unnoticed circulation (a reproductive rate of less than 0·5) in the human population—a sign that the virus is probably introduced to humans from an external source. There is still some risk of human-to-human transmission in special situations, Drosten said.
Additional studies, Koopmans asserted, are underway in several slaughterhouses in Qatar. “What is clear is that there is a lot of movement [of camels] from different regions that may have different levels of immunity”, she added, suggesting that this mixture causes virus-free groups of camels to become infected. Still, others are committed to finding a vaccine. David Weiner (University of Pennsylvania, Philadelphia, PA, USA) is researching a DNA-based vaccine that would work even in the event of viral mutation.
Other research has identified K22 and DPP4 as novel candidate antiviral inhibitors, although it is unclear whether these findings will effect the development of antiviral drugs.
Research efforts are ongoing as many virologists suggest that finding the source of infection is key to implementing infection control measures and essential to designing a treatment or vaccine. “In my view, both need to be done”, Madani said. “We obviously need to continue research to better identify the source and modes of transmission…that work is mutually reinforcing with efforts to develop treatments and vaccines.” For now, focus is on educating the public—a relatively simple approach that might work to contain the virus in the event of a future outbreak.