LONDON – The World Health Organization’s (WHO) mission to Wuhan has rejected accidental laboratory escape as the source of the SARS-CoV-2 pandemic, but failed to uncover satisfactory evidence of its exact origin.

The chair of the WHO investigation into the source of the virus, Peter Ben Embarek, said the most probable hypothesis is that rather than a direct zoonotic spillover from horseshoe bats, the most likely route was through an intermediary animal species.

“Our initial findings suggest that the introduction through an intermediary host species is the most likely pathway; [confirming] that will require more studies,” Embarek told attendees of a press briefing held in Wuhan at the conclusion of his group’s four-week field trip to China.

Intermediary species could have been live animals, or frozen wild animals, seafood or meat products that were on sale in Huanan seafood market, where the first cluster of COVID-19 cases was reported. Embarek noted some of the frozen products were imported into China, and said the possibility of cold chain transmission also requires further study.

After starting one hour and 20 minutes late, the briefing went on for almost three hours, going into exhaustive details of the epidemiological, molecular biology and environmental and animal research the WHO group of 17 experts has weighed up with its Chinese counterparts.

Despite that, there seems little to show other than a list of recommendations for more research, as Embarek, WHO’s food safety and animal diseases expert, acknowledged. “Did we change dramatically the picture we had beforehand? I don’t think so,” he said. “Did we improve our understanding? Did we add details to the story? Absolutely.”

The only aspect not requiring more investigation is accidental release from the Wuhan Institute of Virology, where research into the origins of coronaviruses is taking place. “The lab hypothesis is extremely unlikely to explain the introduction of the virus. It is not a hypothesis that needs further studies,” Embarek said.

The WHO group visited the institute, where there was “quite substantial interaction” and “long, frank, open discussion” with management and staff, said Embarek. They are the people best placed to be able to discount the possibility of laboratory escape, and their full account will be minuted in the WHO report of the mission, he said.

Source tracing

Following an expert mission to China in February 2020, the WHO made its request to carry out research to identify the zoonotic source of SARS-CoV-2, including possible intermediate hosts, in May 2020. The objective was to find and reduce viral reservoirs, and cut the risk of further transmission.

The terms of reference, agreed in July, stated origin tracing should be at a global level, not limited to a single geography. The overall aim was to “improve the response to SARS-CoV-2 and zoonotic diseases of any origin,” said Liang Wannian, head of the China expert panel on COVID-19 response.

In the search for animal hosts, viral sequences with high homology to SARS-CoV-2 have been found in some species, “but the reservoir hosts remain to be identified,” Liang said. Coronavirus sequences from bats and pangolins, suggested as possible sources, are not similar enough to be progenitors of the virus.

Spillovers may have occurred repeatedly, with initial spillovers going undetected, but the virus has become increasingly optimized to infect humans, Liang said, and noted there have been some reports from outside China indicating SARS-CoV-2 could have infected human hosts before the first case was reported in Wuhan. “There is the possibility of missed circulation in other regions,” he said.

As part of source tracing, the researchers looked at records of flu and other respiratory diseases in Wuhan in the month before the outbreak of COVID-19, but found no earlier evidence of the infection. Trawling through records of pharmacies in the city did not show any increase in sales of cold remedies.

Similarly, blood and other patient samples stored at various hospitals in the second half of 2019 did not show any traces of SARS-CoV-2 antibodies. A review of mortality data for the same six months did not point to any causes of death that could be attributed to SARS-CoV-2. “It is considered unlikely there was any substantial transmission in Wuhan in the two months before the outbreak,” said Liang.

Embarek agreed. “We did not find evidence of any cases in Wuhan or elsewhere [in China] before December 2019,” he said.

Not the whole story

However, some stones remained unturned. Further samples have been identified, for example in blood banks, that will be investigated, while samples that already have been tested could be subjected to further analyses, Embarek said.

It also has not been possible to detect how SARS-CoV-2 was introduced to Huanan seafood market. “We know it was spread through the market throughout December [2019], but we don’t know how it got there. We have a picture of where the cases worked in the market and we have got genetic sequences for some of them,” Embarek said. “The market probably was a setting where spread could happen easily, but it’s not the whole story; it was spread among individuals linked to other markets and with no links to markets.”

One thread of further research will be to investigate farms and other places of origin of frozen and refrigerated products sold at Huanan market. “Could a frozen wild animal be the vehicle for introducing the virus to a market, where conditions are good for viral replication?” Embarek asked. There will be an effort to see if there are any products from December 2019 that could be analyzed.

Liang said tens of thousands of tests on animals in China, looking for evidence of SARS-CoV-2, have all drawn a blank. Sampling of animals elsewhere should now take place to try and identify the intermediary host, he said.