Questions remain after WHO team visits Wuhan looking for answers to SARS-CoV-2
On Dec. 31, 2019, a message from the local health authority indicated that most patients with a new viral disease were epidemiologically linked to the Huanan seafood market in Wuhan, China.
Authorities closed the market a day later and began to collect environmental samples from stalls in the market. Results indicated that positive samples included a virus homologous to the one infecting patients.
China’s CDC stated on Jan. 22 that the source of the novel coronavirus was wild animals illegally sold in the Huanan market. Two days later, The Lancet published a paper indicating that 30% of the first patients had no link to the market, including one whose date of illness onset was 10 days before the earliest case linked to the market. This and additional findings led the Chinese CDC eventually to revise its initial view and state: “At the beginning, we presumed that the seafood market may have the novel coronavirus. But it now turns out that the market is one of the victims; scientific research needs time to get done.”
From the onset of the pandemic, it was assumed that the virus reservoir is, most likely, a bat. The genetically closest known coronaviruses were found in horseshoe bat samples from the Yunnan province of China: RaTG13, sharing 96.2% sequence homology with SARS-CoV-2; and RmYN02, with 93.3% homology. These viruses, sequenced by the Wuhan Institute of Virology, were regarded as distant candidate ancestors of SARS-CoV-2. During 2020, a third virus was added to this group: pangolin-CoV-GDC, identified in smuggled dead Malayan pangolins, with 91.02% homology at the whole-genome level.
The range of candidate intermediary host animals was broadened following the reporting of human-to-animal SARS-CoV-2 infections. This involved cats, ferrets, captive felids and farmed minks. During the COVID-19 epizootics in farmed minks in the Netherlands and Denmark, several animal-to-human infections were confirmed; it was concluded that virus circulation among the minks may lead to adaptive changes in the viruses that may affect receptor-binding and recognition by antibodies. This led to the termination of mink farming in both countries.
To check the potential candidature of animal species as intermediate hosts, experimental infection trials were undertaken. High susceptibility combined with capacity of horizontal transmission of the virus were demonstrated in ferrets, minks, raccoon dogs, cats, pangolins (Malay), fruit bats, North American possums, golden hamsters, three monkey species and marmosets. Rabbits and dogs were found susceptible but did not transmit. Cattle, pigs and poultry (chickens, ducks, turkeys) were found refractory to infection and did not transmit.
In July 2020, WHO, in agreement with the World Organization for Animal Health and the Food and Agriculture Organization of the United Nations, outlined terms of reference for a joint study with China to trace the animal reservoir of the virus, its route of transmission to humans and the possible role of an intermediate host. Within phase 1, short-term studies in China were expected to generate hypotheses to be recognized and assessed by a joint expert team that should lay the ground for phase 2: long-term studies.
A recently published joint report, titled “WHO-convened Global Study of Origins of SARS-CoV-2: China Part,” has become a comprehensive, science-based guiding document. During a visit earlier this year that was restricted to Wuhan, a group of investigators visited several relevant institutions and analyzed a considerable quantity of data collected in China within phase 1, allowing them to present the established knowledge while identifying lacunae.
Based on molecular sequence data, the group concluded that the outbreak may have commenced before December 2019, although likely with limited circulation. The point estimates for the time to the most recent ancestor ranged from late September to early December 2019; most estimates were between mid-November and early December.
The team analyzed data from the Huanan market, where environmental samples were collected during January 2020, addressing test results, locations of sampled stalls, their respective stocks and health histories of the vendors/clients. No correlation of contamination with the species of animal sold could be established. The Huanan market could have been COVID-19’s spillover location or — more likely — an amplifier of infection introduced by yet-unrecognized animals, or man.
The team underlined missing data required to narrow the time-space of the estimated first clinical or subclinical infections in humans.
The investigations of the market revealed long-range contacts and routes of supply of farmed wild animals, including species bred for food such as ferret badgers, bamboo rats and civets, and those bred for fur such as mink and raccoon dogs, on farms in China, Southeast Asia, and in other regions. They deserve being covered in future studies as potential intermediary hosts.
At the conclusion of the visit, the joint team rated the likelihood of four possible suggested pathways (hypotheses/scenarios) for the introduction of the virus from its reservoir:
1. Likely to very likely. “Introduction through an intermediate host, followed by zoonotic transmission”: SARS-CoV-2 transmitted from animal reservoir (bat or animal X) to animal host, followed by spread within that intermediate host, then (spillover) to humans. The passage through an intermediate host can be with or without virus adaptation.
2. Possible to likely. “Direct zoonotic transmission (also termed: spillover)”: transmission of SARS-CoV-2 (or a very closely related progenitor virus) from an animal reservoir host to human, followed by direct person-to-person transmission with or without the need for adaptation of the virus to humans. The speed of dissemination depends on chance events such as superspreading events.
3. Possible. “Introduction through the cold/food chain”: Food-chain transmission can reflect direct zoonotic transmission, or spillover through an intermediate host. It is important to distinguish between contamination of cold chain products leading to secondary outbreaks in 2020 and the potential for cold chain acting as the entry pathway for the origin of the pandemic in 2019.
4. Extremely unlikely. “Introduction through a laboratory incident”: SARS-CoV-2 introduced through a laboratory incident, reflecting an accidental infection of staff from laboratory activities involving the relevant viruses (hypothesis of deliberate release or bioengineering of SARS-CoV-2 for release, which was “ruled out by other scientists by genome analyses.”)
WHO Director-General Tedros Adhanom Ghebreyesus, PhD, MSc, responded: “As far as WHO is concerned, all hypotheses remain on the table. We have not yet found the source of the virus and must continue to follow the science and leave no stone unturned as we do.”
Notably, the report includes a hitherto unpublished piece of relevant information: “The Wuhan CDC laboratory moved on 2nd December 2019 to a new location near the Huanan market. Such moves can be disruptive for the operations of any laboratory.”
The report underlines the need for further trace-back at the wildlife farms that previously supplied the Huanan market and other Wuhan markets linked to positive cases, to include interviews and serological testing of farmers and their workers, vendors, delivery staff, cold-chain suppliers and other relevant people and their close contacts. The team concluded: “Surveys should be designed using a One Health approach in larger areas and more countries, including genomic surveys and structured serosurveys of high-risk potential reservoir hosts and their human contacts.”
- Chan JFW, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)30154-9.
- WHO. WHO-convened Global Study of Origins of SARS-CoV-2: China part. https://www.who.int/publications/i/item/who-convened-global-study-of-origins-of-sars-cov-2-china-part. Accessed April 28, 2021
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- Arnon Shimshony, DVM, is an Infectious Disease News Editorial Board Member and professor of veterinary medicine at Hebrew University’s Koret School of Veterinary Medicine.