Where Are We in Hunting for the Coronavirus’s Origin?

(Bloomberg) -- More than a year after Covid-19 touched off the worst pandemic in more than a century, scientists have yet to determine its origins. The closest related viruses to SARS-CoV-2 were found in bats over 1,000 miles from the central Chinese city of Wuhan, where the disease erupted in late 2019. Initially, cases were tied to a fresh food market and possibly the wildlife sold there. An investigation in early 2021 has highlighted the possibility that they acted as a vector, transferring the virus from bats to humans. More politically charged theories allege the virus accidentally escaped from a nearby research laboratory, or entered China from another country via imported frozen food. Amid all the posturing, governments and scientists agree that deciphering the creation story is key to reducing the risk of future pandemics.

1. Why don’t we know where it came from?

Where, when and how a pathogen begins spreading in humans can be difficult, if not impossible, to pinpoint. Although SARS-CoV-2 is genetically similar to coronaviruses collected from a type of bat, it may have followed a convoluted path to Wuhan, a city of 11 million people. Scientists are tracing the earliest known cases but the trail backward largely goes cold in early December 2019. Where a new disease starts spreading isn’t necessarily where it spilled over from the animal kingdom to infect the first human. HIV, for instance, is thought to have originated in chimpanzees in southeastern Cameroon, but didn’t begin spreading readily in people until the 1920s, when it reached the city of Kinshasa hundreds of miles away. Scientists reported that finding in 2014, some three decades after the AIDS pandemic was recognized.

2. Who’s looking?

The World Health Organization was asked in May 2020 to help identify the animal source of the virus and how it spread to humans. It convened a team of 17 international scientists, including one based in the U.S., and early this year they conducted a four-week joint mission with 17 researchers from China. Their findings were released in a joint report in late March. Other groups are also investigating, including an expert panel convened by the medical journal The Lancet called the Covid-19 Commission.

3. What do we know so far?

Bats were the source of two coronaviruses that caused lethal outbreaks in people during the past two decades -- severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS) -- and the flying mammals are considered the reservoir host for SARS-CoV-2 as well. (A reservoir host is an animal that harbors a pathogen but isn’t sickened by it.) After SARS-CoV-2 emerged, Shi Zhengli, who studies bat-borne coronaviruses at the Wuhan Institute of Virology, identified three closely related viruses that had been collected during the previous 15 years. The closest, about 96% identical, was isolated from a species of horseshoe bat, Rhinolophus affinis, in the southern Chinese province of Yunnan in 2013. Some researchers have linked that particular virus to a mineshaft in Mojiang county there, where six men contracted a pneumonia-like disease in 2012 that killed three of them. Although they may share a common ancestor, the two are not similar enough to indicate SARS-CoV-2 was derived from the Yunnan virus. Sampling of bats in Hubei province, which includes Wuhan, haven’t found any positive for the pandemic strain. Coronaviruses sharing genetic features with SARS-CoV-2 have been found in other bat species and pangolins, a scaly, ant-eating mammal, elsewhere in Asia, highlighting the broad distribution that may have contributed to its evolution.

4. What are the hypotheses about its emergence?

Scientists involved in the WHO-led mission identified four, which they ranked in order of likelihood:

• LIKELY-TO-VERY LIKELY: the virus spilled over via an “intermediary” host species;
• POSSIBLE-TO-LIKELY: the virus spilled over to humans directly from an animal reservoir;
• POSSIBLE: the virus was introduced via the food chain by contaminated food or packaging;
• EXTREMELY UNLIKELY: the virus emerged as a result of a laboratory-related accident.

Since no such intermediary host animal or animals have so far been found, they said more research is required, including into the potential role that the trade in animals, animal products and frozen or refrigerated foods might have played.

5. What’s known about the earliest Covid-19 cases?

The WHO mission found no evidence of widespread circulation of the virus in Wuhan before December 2019. Among the earliest cases, symptoms began on Dec. 8. That suggests infections probably occurred around the start of December or late November. It’s possible the virus was transmitted multiple times and went extinct when infected individuals didn’t transmit the virus to anyone, according to researchers at the University of California, San Diego. Eventually, the virus infected someone who passed it to several people, who also passed it on to others, possibly in a super-spreading event. The researchers studied virus genomes and the pace at which they mutated and diversified from the earliest known specimens in Wuhan. From mid-October to mid-November 2019 is the most plausible period in which the first case of a person contracting SARS-CoV-2 emerged in Hubei province, they wrote in a March 18 paper in Science.

6. What role did that food market in Wuhan play?

Researchers aren’t sure. It could have acted as a contamination source, an amplifier for human-to-human transmission, or both. Of the first 174 known cases of Covid-19, 51 or 33% had links to the Huanan seafood market. In fact, it was a cluster of pneumonia-like illness among people connected to the so-called wet market that heralded the contagion. Of Covid-19 cases linked to the market, the first person became unwell on Dec. 12, 2019. Since the first known Covid-19 case preceded that by four days, it’s possible that the virus was introduced to the market by an already infected person -- potentially a trader or a visitor not showing symptoms -- who passed it to others.

• The market had 678 stalls and more than 1,180 employees supplying seafood products as well as fresh fruit and vegetables, meat, live animals and grocery items. Testing after the market was closed (it was shut down at 1 a.m. on Jan. 1, 2020) found widespread contamination of the floor, walls, chopping boards and cleaning tools compatible with the virus being transmitted from infected people to surfaces.
• Supply chains to the market were extensive, with goods arriving from other countries and around China. Ten stall operators were selling meat from wild animals raised in captivity.
• The people running the market told the WHO-led team that all live and frozen animals that vendors had reported selling in the Huanan market were from licensed farms, and that no illegal trade in wildlife had been found. The researchers also said they weren’t able to verify reports that live mammals were sold in the market in 2019.
• Of 336 samples collected from animals that ostensibly were being legally sold, none were positive for SARS-CoV-2, but it’s possible that not enough samples were taken.

7. How credible is that?

A study published in June indicated that the information about what animals were being sold was false. Mammals susceptible to the coronavirus were being traded at the Huanan market and others around Wuhan from May 2017 to November 2019, according to the paper in Scientific Reports. The 38 species included mink, masked palm civets, raccoon dogs, weasels, badgers and bamboo rats. Both wild-caught and farmed non-domesticated species were sold -- alive, caged, stacked and in poor condition -- by 17 vendors, Xiao Xiao, from the Lab Animal Research Center at Hubei University of Chinese Medicine in Wuhan, and colleagues in China, the U.K., and Canada said. None of the vendors posted an origin certificate or quarantine certificate, “so all wildlife trade was fundamentally illegal,” they said.

8. Were there cases elsewhere?

Yes. Some early cases occurred among individuals who were linked to other markets in Wuhan and some had no market links. In addition, genetic sequencing of viral specimens collected from patients early in the pandemic showed there was some diversity already present, suggesting SARS-CoV-2 was more broadly distributed in the city.

9. Could the virus have been introduced via contaminated food?

There’s disagreement on this. Researchers in China have found that the virus can persist in conditions found in frozen food and packaging as well as cold-chain products, which are kept refrigerated. They also have linked some infections in people to imported goods, although the degree of surface contact or amount of virus required is unknown. China’s government has embraced this theory and has been testing imported food for virus traces for months; some supermarkets even have separate coolers for imported goods. The U.S. Food and Drug Administration and the U.S. Centers for Disease Control and Prevention said in February, however, that there is no credible evidence of food or food packaging associated with, or as a likely source, of transmission. Covid-19 outbreaks occurred in 2020 in meat-processing plants and some preparing ready-made meals, making it plausible that infected workers could contaminate items they’re in contact with. The WHO mission chief called the theory “worth exploring,” but pointed out that in 2019, “there were no widespread outbreaks of Covid-19 in food factories around the world.”

10. What about the lab theory?

After meetings with scientists in Wuhan, including discussions about their bio-containment and safety practices, the WHO-arranged mission found it “extremely unlikely” that SARS-CoV-2 originated in one of several labs in the city conducting research on coronaviruses, a large family that includes those that cause the common cold. Although accidents have been known to occur, sparking rare outbreaks, the scientists said there had been no reports of the virus existing before it was detected in Wuhan. Researchers who have analyzed its viral sequence have concluded that it doesn’t have the genetic signatures of a lab-engineered virus. Also labs in Wuhan tested their staff and students for evidence of SARS-CoV-2 infection and found no cases.

11. Has that been contested?

Yes. WHO Director-General Tedros Adhanom Ghebreyesus said on March 30 that he didn’t think the assessment was extensive enough and that further data and studies will be needed to reach stronger conclusions. Several countries, including the U.S., issued a joint statement the same day calling on China to be more transparent and allow greater access. The U.S. intelligence community is divided over whether its origins are natural or a lab accident, President Joe Biden said on May 26 as he ordered a new report in 90 days. The European Union has asked the WHO to present a clear timetable for follow-up work and to be regularly briefed on progress. In mid-May, a group of eminent scientists and physicians repeated calls for greater clarity about the origins. Writing in Science, Jesse Bloom, Ralph Baric, Akiko Iwasaki, Marc Lipsitch and 14 other researchers said that theories of an accidental release from a laboratory and zoonotic spillover both remain viable, though the WHO-led study didn’t give balanced consideration to the possibility of a lab accident. “Public health agencies and research laboratories alike need to open their records to the public,” they said. “Investigators should document the veracity and provenance of data from which analyses are conducted and conclusions drawn, so that analyses are reproducible by independent experts.”

12. Why wasn’t the lab investigated more?

It’s highly sensitive. Stung by criticism that it initially covered up the extent of the crisis, it took months of negotiation before a defensive China agreed to cooperate with the WHO investigation. The international team did visit the lab, although its official mandate had no mention of research specifically on Wuhan labs or any role they may have played. If a lab accident were the source, it would have huge ramifications globally, including for the regulation and practice of virology, according to Raina MacIntyre, professor of global biosecurity at the University of New South Wales in Sydney.

13. What’s considered more likely then?

There was a large network of farms supplying wildlife to the Huanan market and presumably other centers in Wuhan, including from areas where bats are known to harbor coronaviruses. Potentially, some animals were infected before being brought to market. The WHO mission said further research should involve tracing these products to their source and testing other animals there, as well as their surroundings and people living nearby. Wild animal markets were linked to the emergence of SARS in China’s Guangdong province in 2002.

14. What research has been undertaken?

To identify the earliest human cases, the team reviewed health records, mortality data, trends in retail sales of cold and cough medications and reported patterns of influenza-like illnesses and severe respiratory infections in the two months preceding the outbreak in Wuhan. Included were 76,000 cases from more than 200 medical centers. Researchers in China also tested some 4,500 patient specimens stored at hospitals in Wuhan and other parts of China for SARS-CoV-2, and analyzed blood samples for antibodies against the virus. To identify potential animal sources, 11,000 blood samples taken from livestock and poultry in 31 provinces were tested along with 1,914 samples from 35 species of wild animals. Researchers in China looked for SARS-CoV-2 in 12,000 animal swabs and 50,000 samples from 300 different species of wild animals. All were negative.

15. Did the WHO team get to see everything?

The Australian Broadcasting Corp., citing one of the international experts, reported that dozens of people were hospitalized as early as October 2019 with symptoms such as fever and coughing, but Chinese authorities refused to make available raw data on the cases because of patient privacy concerns. Chinese experts said they had found no trace of Covid-19 among the cases, but the tests were incomplete and members of the WHO-led team said more research was needed, the New York Times reported. International experts are reported to have said that, while they had access to an unprecedented amount of data, it’s uncertain whether everything available was supplied. To understand the earliest cases, scientists would benefit from full access to data, including biological samples from at least September 2019, WHO’s Tedros said, calling for studies that “include more timely and comprehensive data sharing.”

16. Are the findings credible?

It’s hard to say. Studies have been hampered by delays and geopolitics. China’s government has supported the hypothesis that SARS-CoV-2 may have entered the country in imported food, while the former Trump administration repeatedly blamed the Wuhan lab for the “China virus,” which Shi has denied. Members of the WHO-led mission described discussions in Wuhan as very tense on occasion, sometimes erupting into shouts on both sides. Meetings were also closely monitored by dozens of Chinese representatives, a large number of whom weren’t scientists or public health officials. The WHO team is still pressing Chinese officials to conduct exhaustive tests on stored blood-donation samples from Wuhan in 2019, which might indicate whether the virus was present there earlier.

17. Where to next?

In addition to further tracing of animals and products that might have been at the Huanan market, the WHO mission scientists propose:

• collecting and analyzing epidemiological, clinical, molecular and environmental data from other countries to better understand the virus’s origins, since some reports have suggested it may have been circulating outside China before December 2019;
• additional sampling of animal species that may act as a reservoir, including bat populations in China and neighboring countries;
• more research to understand if it could be transmitted from contaminated products to humans, and under which conditions that might occur;
• further analysis of cases of respiratory illness that occurred in Wuhan in October and November 2019.

The Reference Shelf

• WHO mission chief Peter Ben Embarek reflects on his China trip with Science.
• Another team member, zoologist Peter Daszak, spoke to the New York Times about the trip and comments on lessons from Covid-19 that will help prevent future pandemics.
• Wuhan coronavirus hunter Shi Zhengli answers questions on her lab’s research.
• Edward Holmes, an evolutionary biologist at the University of Sydney, gives a presentation on zoonoses and the emergence and ongoing evolution of Covid-19.
• Virologist Angela Rasmussen discusses the origins of SARS-CoV-2.
• U.S. Department of State’s Jan. 15, 2021, fact sheet on activity at the Wuhan Institute of Virology, and China’s Foreign Ministry Spokesperson Hua Chunying’s response.
• Related QuickTakes on the unanswered questions about the virus, how people catch it, its effects on children, and why the way we live now will mean more pandemics.
• Bloomberg takes a graphical look at the next generation of vaccines.

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