A new analysis of genetic history confirms the long-held suspicion that Middle East respiratory syndrome virus, which alarmed global health leaders in 2012 when it spilled over from camels to cause an often fatal illness in people, does not spread easily between humans.
At least not yet.
In a paper published today in the journal eLife, Fred Hutchinson Cancer Research Center’s Drs. Gytis Dudas and Trevor Bedford modeled phylogenetic trees, or genetic histories, of all available MERS genome sequences — 100 from camels and 174 from humans.
“The genomic data confirms that the MERS virus is not at the moment spreading readily from person to person,” said Bedford, an evolutionary biologist, and the paper’s senior author. “Almost all of the cases in the Arabian Peninsula are short chains that spill over from camels, infect a few people and then die out. That had been suspected, but not quantified.”
The new analysis compared evolutionary changes in the camel and human genetic sequences to show that the virus jumped from camels to humans hundreds of times since 2012, with the 2,000-plus human cases recorded since resulting mostly from repeated spillovers rather than person-to-person spread.
“Andrew [co-author Andrew Rambaut, a professor at the University of Edinburgh’s Institute of Evolutionary Biology] had championed this idea for some time, and it had been accepted by most that it was not one introduction from camels into humans back in 2012,” Bedford said. “Our analysis placed it at somewhere between 300 and 800 introductions with each introduction being responsible for an average of three or four cases.”
Like other RNA viruses, MERS mutates rapidly, so researchers are able to use genomic sequences to track evolutionary changes over a span of months rather than, say, the million years it would take in humans or other large animals, said Dudas, a Mahan Postdoctoral Fellow at Fred Hutch and the paper’s lead author.
“Mutations that accumulate over time are unique markers, and the patterns of shared ancestry between individual strains can be very informative,” he said. “You can use those data to reconstruct the pathogen’s perspective of an outbreak.”
To build phylogenetic trees, Dudas used data from almost 300 genomic sequences along with when and from which host each sequence was collected. Many of the sequences came from public sources, such as GenBank, but a handful of them were openly shared by the team’s collaborators from Saudi Arabia and the United Kingdom.
The model showed that only mutations that arose during camel infection persisted in the viral population, indicating that camels are the host in which conditions are amenable for MERS to spread and sustain transmission.
“Once a virus entered humans — it could be a single case, it could be small family clusters or limited community-transmission chains, it could be sizeable hospital outbreaks — ultimately, those transmission chains died out,” Dudas said. “MERS is sustained in camels, and humans are a dead-end host.”
Although the data confirm that the MERS virus is poor at spreading among people, the paper points out that continued introductions of the virus from camels to humans remains alarming.
“Whenever we see a scenario like MERS where you have constant spillover from [an animal] reservoir into humans, that’s asking for trouble,” Dudas said. “You might get a variant that by pure luck happens to be good at transmitting between humans and gets naturally selected for better transmission.”
Public health officials had reason to fear such a scenario when MERS emerged in 2012. MERS is part of a large family of viruses called coronaviruses that cause, among other human diseases, common colds. What alarmed the global health community was that MERS resembled a more serious illness caused by another coronavirus relative: severe acute respiratory syndrome, or SARS.
SARS emerged in southeast China in late 2002 — possibly spilling over from bats to civet cats before spreading efficiently among humans. The following year it swept the globe to more than two dozen countries in Asia, Europe, North America and South America, sickening 8,089 people and killing 774 of them before the 2003 outbreak was contained. (No new cases have been reported since.)
MERS has caused 740 deaths in 2,123 laboratory-confirmed cases of infection reported to the World Health Organization since the first case was identified in Saudi Arabia. An outbreak in multiple hospitals in South Korea in 2015 — the largest outbreak outside the Middle East with 186 laboratory-confirmed infections and 36 deaths — raised more alarms.
But MERS, despite its high mortality rate, has not behaved as SARS did. About 80 percent of human cases have been in Saudi Arabia, according to WHO. Epidemiologists traced human MERS cases to contact with infected camels or with people who had such contact. (The exact routes of transmission are unknown.) Cases identified in 26 other countries, including the South Korean hospital outbreaks, were traced to people who were infected while traveling in the Middle East.
All the signs on the ground pointed to the virus not spreading easily among people. But earlier attempts to model the genetic history of MERS showed the opposite. The problem, said Dudas, was that they did not correct for biases in the existing data, which include almost twice as many viral sequences from humans as from camels.
“Unlike previous attempts at reconstructing hosts of MERS coronavirus lineages, we chose a method that can quantify differences in viral population sizes between camels and humans,” he said. “If you imagine that you are led into a dark room and you’re allowed to make sound, chances are you would be able to tell something about the size of the room from the way the sound echoes. If you were led into two [dark] rooms of different sizes, you could probably tell that one room is smaller than the other simply from the way it echoes. For us, we’re able to tell which host the virus is in by looking at genetic relatedness of sampled viruses.”
Understanding how a new virus spreads — whether 10 new cases arise from a single introduction, for example, or 10 separate introductions — is key to getting the public health response right. The analysis published today, according to Bedford, confirms that the global health community’s focus on developing a vaccine for camels is a smart approach.
“Because the human cases are part of small sporadic chains, you’d have to vaccinate a whole bunch of people who will never be at risk,” said Bedford. “It may make sense to roll out a vaccine specifically for livestock handlers, but even there you’d probably get a very small result — most of them aren’t going to get MERS. But almost all camels are getting MERS and transmitting it forward, so by vaccinating camels, you should be able to abate the overall epidemic and bring the virus down.”
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Mary Engel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.