How medical sleuths stopped a deadly new SARS-like virus in its tracks
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Four months ago, a mucus sample arrived in Dr. Ali Mohamed Zaki’s laboratory in Saudi Arabia.
The mucus had been coughed up by a 60-year-old Saudi Arabian man with a strange case of pneumonia. He had been admitted to the Dr. Soliman Fakeeh hospital in Jeddah on June 13; soon after, his kidneys began to fail. Eleven days after being hospitalized, the man was dead.
When the patient was admitted, Zaki was working in the hospital’s virology lab, which he helped establish in 1994. He was sent samples of the patient’s sputum — mucus coughed up from his lungs.
Eventually, this spot of sputum would lead Zaki to the discovery of a virus never before seen in humans: a novel coronavirus, the same type of virus behind the SARS outbreak in 2003 that swept across 30 countries and killed approximately 800 people, including 44 Torontonians.
Zaki’s discovery — and his decision to post it online — touched off a chain of events that quickly unearthed a second patient in another country and enabled the global health community to gain an upper hand in the face of a potentially deadly new virus.
Scientists have now learned the virus’s genetic code, discovered its likely link to bats and equipped labs around the world with the means to diagnose it. Virologist buddies from the “old SARS club” have reunited, collaborating once again across borders, and teams of experts have been deployed to the Middle East to aggressively investigate the virus and its origins.
And the World Health Organization currently feels reassured enough to give its blessing for travel to Saudi Arabia, where millions of pilgrims are descending this week for the hajj, one of the world’s largest mass gatherings.
For Zaki, his discovery was fortunate, “a favour for the globe.” Yet, as of last week, it seems to have cost him his job.
But on June 13, Zaki was still faced with that basic medical question: what mysterious thing was making this patient so sick?
Zaki’s first ran a battery of tests on the sputum and blood samples. Initially, he looked for influenza, the usual suspect in a respiratory ailment. All initial results came back negative.
Zaki decided to culture the samples to see what grew. In late June, viruses began replicating in the sputum culture, but by this point, the patient was already dead.
Yet Zaki continued his sleuthing. He had a sense that this was something bigger than just one patient. So Zaki turned his mind to the possibility of a paramyxovirus, a class of virus responsible for some acute respiratory diseases. It was a path that took him to Dr. Ron Fouchier, a professor of molecular virology at the Erasmus Medical Centre in the Netherlands.
Zaki has never met Fouchier but knew his reputation as one of the world’s leading influenza researchers. He also knew Fouchier had recently developed a test for paramyxoviruses and called him.
Fouchier listened to Zaki and could not help thinking about SARS; the clinical picture just sounded so similar. Had Zaki tested for coronaviruses yet?
This was certainly going to be Zaki’s next step. He mailed the virus to Fouchier in Rotterdam. While he waited for a response, Zaki tested his virus sample to identify whether it was in the coronavirus family. It was.
Coronaviruses can infect many animals and humans and are named for their distinctive crown-like appearance under a microscope. Before 2003, there were only two coronaviruses known to infect humans and both were associated with the common cold. The discovery of SARS nine years ago changed everything and opened the world’s eyes to the coronavirus’s deadly potential and the ominous possibility that new strains were lurking undiscovered.
Zaki did not have the equipment to sequence the genome — in other words, to determine its genetic code and identify it specifically. But Fouchier did.
In 2003, Fouchier had played a major role in identifying the SARS genetic sequence, a process that took three or four weeks. Sequencing the virus’s genome allows scientists to perform their life-saving work — developing antivirals, vaccines and diagnostic tests — more easily and quickly.
This time, with advanced technologies and resources, it only took Fouchier a few days to sequence Zaki’s virus.
He found it was closely related to a coronavirus found in bats, the same animal from which SARS is believed to have sprung.
But this was not the SARS coronavirus.
“It was a new kind,” Zaki said, admitting that at this point he began to worry about his own exposure to the virus. “I became afraid it could (spread) like SARS and I listed it on ProMed.”
ProMed is an infectious disease reporting website that had been used during the SARS outbreak. Designed to quickly disseminate information, every message is vetted by a panel of experts before being posted online and sent to more than 60,000 subscribers worldwide.
Zaki’s email, which described his and Fouchier’s findings in three short paragraphs, went online on Sept. 20.
“NOVEL CORONAVIRUS — SAUDI ARABIA,” the summary read in capital letters. “HUMAN ISOLATE.”
Zaki’s inbox was immediately flooded. Some congratulated him on his discovery but most were anxious queries.
“The coronavirus is really not like any other virus,” said Dr. Christian Drosten, who runs the virology department at the University of Bonn in Germany. “This is not a thing that you see every day, popping up new.”
“If it’s a new coronavirus that has never been seen before in humans — that is ringing the bell.”
The ringing of this bell was heard in every corner of the globe. Most importantly, it reached a north London lab in England, where doctors and scientists were scratching their heads over a puzzling case.
On Sept. 12, eight days before Zaki’s email went live on ProMed, a 49-year-old Qatari man with “atypical pneumonia” was airlifted to a London hospital. The patient had fallen sick in Qatar but had visited Saudi Arabia in August.
Within days, the United Kingdom’s public health organization, the Health Protection Agency (HPA), was notified of the case.
Initially, as had Zaki, they figured this could be influenza. The HPA began conducting tests on Sept. 20, the same day Zaki’s ProMed email went online.
That same night, two HPA employees working on this case — a clinician and a scientist — independently noticed Zaki’s post.
“They both had a sort of light-bulb moment,” said Maria Zambon, the HPA’s director of reference microbiology. “Should we test for this new virus?”
The next day, Friday, Sept. 21, the HPA clinicians tested for coronaviruses. Positive.
But they needed to figure out which coronavirus. The team quickly began sequencing a tiny snippet of the virus’s RNA, working through the night.
Early Saturday morning, Zambon decided to contact Dr. Albert Osterhaus, a long-time colleague with whom she had worked during the SARS outbreak.
Osterhaus is a flu expert and one of the world’s leading virologists, but that is not why Zambon contacted him exactly. Osterhaus works at the same Rotterdam laboratory as Fouchier, the doctor contacted by Zaki who now had a sample of the new coronavirus.
Zambon emailed Osterhaus and asked him to call her. About 20 minutes later, her phone rang.
“So, that tells you two things. One, that he reads his emails at 7 o’clock in the morning,” Zambon said, chuckling. “And secondly, that he takes messages from me quite seriously.”
Osterhaus hung up the phone with Zambon and called Fouchier, who was actually in Canada at the time, attending a flu conference in Bromont, Que., with post-doctoral students.
“That is the moment where you’re really shocked,” Fouchier said. “Once you hear about a second case you think, ‘Whoa. We’re not going to get another SARS.”
By 2 p.m. London time, Zambon’s team had a genetic sequence for the virus from the Qatari patient. It was indeed a new coronavirus. But was it the same that had strickened the Saudi patient? She sent the sequence to Fouchier.
As Fouchier’s post-doctoral students spoke at the conference, he hovered over his laptop at the back of his room, analyzing the two viruses. He remembers a crowd gathering around him as the sequences began to align.
“We were with quite a lot of people in Canada. They were all sitting very excited up on my table as we were analyzing the sequences,” he recalled.
At about 4 p.m. London time, Fouchier reported his result: a 99.5 per cent match. It was the same virus.
And with that revelation, the situation took on a new level of urgency.
“There was this kind of concern that you may be looking at the tip of an iceberg,” Zambon said.
That night, Zambon had a meeting with the HPA’s incident control team. Fouchier also participated via teleconference, calling from a bus taking him to the Montreal airport, where he caught his flight back to Rotterdam.
The HPA declared a Level 3 incident, indicating a public health event with potential national impact and the news began to make its way around the world (the HPA has five levels of alert for public health threats, with 5 being the most serious).
The World Health Organization was also notified.
“At that point, the machinery started,” said Dr. Maurizio Barbeschi, with the WHO’s global capacity, alert and response department.
One of the cogs in the machine was Drosten, the energetic 40-year-old University of Bonn virologist. Drosten had shot to international recognition in 2003 when he worked furiously (and mostly without sleep) to develop the first diagnostic test for SARS just 11 days after the WHO had issued a global alert, thus beating several other high-performance labs racing toward the same goal.
Drosten, by this point, was well aware of the new coronavirus; about a week before Zambon was emailing Osterhaus about the Qatari patient, Fouchier and Drosten were discussing the virus from the Saudi.
Fouchier knew that Drosten, a friend and colleague, had done a lot of work with bat coronaviruses. They are also both members of EMPERIE, a European Commission-funded project co-ordinated by Osterhaus and created post-SARS to establish a network of experts and medical labs capable of mobilizing quickly in the face of a new virus.
The new coronavirus was reuniting scientists who were in the trenches together during SARS. “This is the old SARS club,” Drosten commented to Nature earlier this month.
Two days after the second confirmed case was announced, Fouchier sent Drosten the virus so he could begin developing a diagnostic test. If this virus were to spread, labs around the world would need tools for diagnosing it.
Drosten’s capacity has also been hugely improved since SARS. In 2003, it took him about five days to develop a diagnostic test; this time, it took just over two.
Drosten actually developed three diagnostic tests and shipped them to Zambon, who tested them on the Qatari patient to confirm which ones worked (two did, one failed).
On Sept. 27, the team published a paper — a detailed description of how they developed a diagnostic test for identifying the new coronavirus — in Eurosurveillance, a scientific journal that emphasizes the rapid publication of papers on ongoing outbreaks.
“We sent the paper in the morning. I wrote it overnight and it was reviewed during the day by two proper reviewers and it was out at midnight,” Drosten said. “We published a complete scientific paper — I think about 2,800 words or something — showing all of this validation data.”
For Zambon, she believes this “must be a world record” of some sort (she notes, however, that the team barely slept that week).
“That’s e-publishing,” Drosten said. “This speeds up everything.”
In their paper, the team included information on how laboratories can order materials for diagnosing the virus. Shipments have now been made to approximately 150 labs around the world, according to Drosten.
On Oct. 4, exactly two weeks after Zaki’s ProMed post, public health officials in the United Kingdom had tracked down 64 people who had come into contact with the Qatari patient. Their finding likely unleashed sighs of relief: nobody had developed serious symptoms.
The novel coronavirus, it would seem, is not easily transmitted between humans. There have been multiple reports of suspected new cases in recent weeks, everywhere from Hong Kong to Denmark, but none has ultimately tested positive for the novel coronavirus. As for the Qatari patient, he is still alive.
Investigations continue at a furious pace, both in laboratories and on the ground in Qatar and Saudi Arabia, where international experts have descended in recent weeks. They are searching for more signs of the virus, both in humans (have other people been exposed?) and the environment (could bats have passed the virus to other animals, who are now transmitting it to humans?). Fouchier and Osterhaus are also working to prove the novel coronavirus ultimately killed the Saudi Arabian victim, who also had bacterial infections that could have caused the respiratory disease.
For Drosten, the discovery of this new coronavirus reinforces that mysterious viruses lurk undetected in animal reservoirs, waiting to spill over into human populations.
“You don’t hear about them for years and then suddenly they pop up,” Drosten said. “Chances are there’s close human-animal contact and there’s been a jump.”
As for Zaki, he will also continue work on the novel coronavirus. But not in Saudi Arabia.
This is not the first time Zaki had discovered a new virus in Saudi Arabia and, in 1994, he was the first scientist to isolate dengue fever in the country. He found another virus, a tick-borne virus that killed two young butchers, in 1995.
But this time around, Zaki said his discovery has made the Saudi Arabian ministry of health “very angry.”
“They were very aggressive with me. They sent a team to investigate me,” he said. “And now they force the hospital administration to force me to resign.”
A spokesperson for the hospital, however, said in an email that Dr. Zaki is still employed there. She did not respond to follow-up questions seeking clarification.
Zaki is back in his homeland, Egypt. He said he will now help the Egyptian government test sick people returning from the hajj, the annual Islamic pilgrimage to the holy city of Mecca in Saudi Arabia, which begins Thursday.
The hajj attracts millions of pilgrims every year. In other words, Mecca will soon become the perfect breeding ground for a virus looking to cause maximum damage. But so far, this virus is not easily transmitted and the WHO has not recommended any travel restrictions to Saudi Arabia. But rest assured, they will be monitoring the situation closely.
With this new coronavirus, the world has been much more prepared than in 2003. But sheer luck has also been on our side.
With SARS, it was the outbreak that came first. The virus was only discovered later.
“Now, it’s really the reverse situation,” Drosten said. “We already have the virus and we’re waiting for an epidemic to show up or not show up. It’s a much better scenario.”
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