Where is ‘Animal X’? Summary of SARS-CoV2 Origins Report COVID-19 Science 30/03/2021 • Kerry Cullinan Share this:Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Facebook (Opens in new window)Click to email this to a friend (Opens in new window)Click to print (Opens in new window) WHO’s Peter Ben Embarek, head of the origins task team, at the release of the report on Tuesday. The international team assembled by the World Health Organization (WHO) to investigate the origins of SARS-CoV-2 has identified animal transmission – through an elusive ‘Animal X’ – as the most likely route of infection. The long-awaited report was released on Tuesday after the 17-person expert team, together with a 17-person team of Chinese scientists, visited Wuhan and its surroundings during January and February to examine evidence about the virus, which was first identified in 174 people in Wuhan in December 2019, and has since infected over 128 million people and caused 2.7 million deaths. WHO Director-General Dr Tedros Adhanom Ghebreyesus said that the report advances the world’s understanding in important ways, but it also raises questions that will need to be addressed by further studies. “As far as WHO is concerned, all hypotheses remain on the table,” said Dr Tedros. “This report is a very important beginning, but it is not the end. We have not yet found the source of the virus, and we must continue to follow the science and leave no stone unturned as we do.” Tedros added that no single research trip could provide all the answers, as “finding the origin of a virus takes time and we owe it to the world to find the source so we can collectively take steps to reduce the risk of this happening again”. What follows is a summary of the report’s key points, which the team described as a “work in progress”. The team examined four main scenarios for introduction: Direct zoonotic transmission from a host animal to humans Indirect zoonotic transmission, involving the virus first infecting a host animal, then adapting through an intermediate host animal, before infecting humans Introduction through the cold/ food chain, particularly frozen wild animals sold at Wuhan markets Introduction through a laboratory incident. Horsehoe bats carry viruses most similar to SARS-CoV-2 1. Direct zoonotic introduction: Finding: possible to likely. Hypothesis: Transmission of SARS-CoV-2 (or very closely-related progenitor virus) moves from an animal reservoir host to human, and is followed by direct person-to-person transmission. Arguments in favour The majority of emerging diseases originate from animal reservoirs and most of the current human coronaviruses have originated from animals. Surveys of the bat viromes conducted after the SARS epidemic in 2003 found SARSr-CoV in various bats, particularly Rhinolophus (horseshoe) bats. Viruses with a high genetic similarity to SARS-CoV-2 have been found in these bats in China, Japan, Thailand, and Cambodia. Two distinct types of SARSr-CoV were recently detected in Malayan pangolins. Minks have shown to be highly susceptible to SARS-CoV-2 and cannot be ruled out as the primary source of SARS-CoV-2. Antibodies to bat coronavirus proteins have also been found in humans with close contact with bats. Arguments against Although the closest genetic relationship to SARS-CoV-2 was a bat virus, more detailed analysis found “several decades” of evolutionary space between the viruses. Few of the identified bat virus genomes showed the ability to bind to human cells. Contact between humans and bats or pangolins is not as common as contact between humans and livestock or farmed wildlife. Despite the consumption of bats and other wild animal meat in some countries, there is no evidence for transmission of coronaviruses from such encounters. Information still needed: Detailed trace-back studies of the animal supply chain of Wuhan markets have provided some credible leads to survey potential reservoir hosts. 2. Introduction through intermediate host followed by zoonotic transmission Finding: possible to likely Hypothesis: SARS-CoV-2 is transmitted from an animal reservoir to an animal host, followed by spread within that intermediate host (“spillover host”), and then transmitted to humans. Arguments in favour Although the closest related coronaviruses have been found in bats, SARS-CoV-2 has evolved by an estimated “several decades”, which suggests a missing link. Similar viruses have also been found in pangolins, suggesting cross-species transmission from bats, but again with considerable genetic distance. Bats and pangolins have infrequent contact with humans, and an intermediary step involving an “amplifying host” has happened in a number of viruses, including influenza and MERS. SARS-CoV-2 adapts relatively rapidly in susceptible animals (such as mink). The increasing number of animals shown to be susceptible to SARS-CoV-2 includes animals that are farmed in sufficient densities to allow the potential for viral circulation. There was a large network of domesticated wild animal farms, supplying farmed wildlife to Wuhan. In high-density farms, there often are connections between farms, leading to complex transmission pathways that may be difficult to unravel. Arguments against SARS-CoV-2 has been identified in an increasing number of animal species, but genetic and epidemiological studies have suggested that these were infections from humans, rather than other animals. There is no evidence of repeated early SARS-CoV-2 strains of animal origin in humans in China. There was no genetic or serological evidence for SARS-CoV-2 in tests of a wide range of domestic animals (where large-scale screenings took place) and wild animals, where screening was more limited. Information still needed: Further surveys, including a wider geographic range. Studies of the supply chain of Wuhan markets have not found any evidence of infected animals but provided information for follow-up studies, including targeting supply chains from wild-life farms in provinces where the higher prevalence of SARSr-CoVs have been detected in bats. Animal products from outside Southeast Asia, where more distantly related SARSr-CoVs circulate, should not be disregarded. A market in Wuhan, Hubei, China 3. Introduction through the cold/ food chain Finding: Possible Hypothesis: SARS-CoV-2 is introduced or amplified through the cold/ food chain. This could involve direct zoonotic transmission, or spillover through an intermediate host. Arguments in favour The arguments are similar to those listed for zoonotic introduction, but with an emphasis on the potential for initial introduction through food animals or cold/ food chain products or the contamination of food and food containers (for instance by animal waste). Since the near-elimination of SARS-CoV-2 in China, the country has experienced some outbreaks related to imported frozen products in 2020. Screening programmes have found limited evidence for the presence of SARS-CoV-2 by nucleotide acid tests in different batches of unopened packages and containers in different cities. For example in an outbreak in Qingdao, the live virus was isolated from the outer package of imported frozen products. Foodborne outbreaks with enteric viruses are common, but contamination of food with human viruses usually comes from sewage or contaminated water for irrigation. Sewage treatment typically does not remove all infectious viruses prior to the release of wastewater in the environment. These processes have been investigated widely for non-enveloped viruses but far less for enveloped viruses in the food chain, but there is widespread evidence of SARS-CoV-2 nucleic acid in sewage. There is some evidence that the oral route could lead to infection for SARS-CoV-2 from hamster infection experiments, and the virus replicates in gut organoids. Food animal handlers had an increased prevalence of SARS-CoV-specific antibodies. Humans infected with SARS-CoV-2 shed virus through faeces and can have gastrointestinal symptoms, suggesting the involvement of the gastrointestinal tract. Humans can also be exposed to contaminated objects. Arguments against There is no conclusive evidence for foodborne transmission of SARS-CoV-2 and the probability of cold-chain contamination with the virus from a reservoir is very low. While there is some evidence of the possible reintroduction of SARS-CoV-2 through handling imported contaminated frozen products in China since the initial pandemic wave, this would have been extraordinary in 2019 where the virus was not widely circulating. Industrial food production has high levels of hygiene criteria and is regularly audited. Most viruses have been found in 2020 in low concentrations and are not amplified on cold-chain products. It is not clear what the infection route would be (possibly oral, touch, or aerosol). There was no evidence of infection in animals tested following the Wuhan outbreak. The risk of foodborne transmission of SARS-CoV-2 through pathways such as objects is very low in comparison with respiratory transmission. Information still needed: Case-control studies of outbreaks, in which the cold chain product and food supply are positive, would be useful to provide support for cold chain products and food as a transmission route. There are some preliminary reports of SARS-CoV-2 positive testing in other parts of the world before the end of 2019. There is also evidence of more distantly related SARSr-CoV in bats outside Asia. Some producers in these countries were supplying products to the markets. If there are credible links to products from other countries or regions with evidence for circulation of SARS-CoV-2 before the end of 2019, such pathways should be followed up. If there are leftover frozen products from the Huanan market from December 2019, particularly frozen animal products from farmed wildlife or linked to areas with the early circulation of SARS-CoV-2, these should be tested. 4. Introduction through a laboratory incident Finding: Extremely unlikely. Hypothesis: SARS-CoV-2 is introduced through a laboratory incident, reflecting an accidental infection of staff from laboratory activities involving the relevant viruses. We did not consider the hypothesis of deliberate release. The deliberate bioengineering of SARS-CoV-2 for release has been ruled out by other scientists following analyses of the genome. Arguments in favour Although rare, laboratory accidents do happen, and different laboratories around the world are working with bat CoVs. Humans could become infected in laboratories with limited biosafety, poor laboratory management practice, or through negligence. The closest known animal coronavirus strain (96.2%) to SARS-CoV-2 detected in bat anal swabs have been sequenced at the Wuhan Institute of Virology. The Wuhan CDC laboratory moved on 2 December 2019 to a new location near the Huanan market. Such moves can be disruptive for the operations of any laboratory. Arguments against SARS-CoV-2 from bats and pangolin are evolutionarily distant from SARS-CoV-2 in humans. There is no record of viruses closely related to SARS-CoV-2 in any laboratory before December 2019, or genomes that in combination could provide a SARS-CoV-2 genome. Prior to December 2019, there is no evidence of circulation of SARS-CoV-2 among people globally and therefore the risk of accidental culturing SARS-CoV-2 in the laboratory is extremely low. The three laboratories in Wuhan working with coronavirus diagnostics, isolation and vaccine development all had high-quality biosafety level (BSL3 or 4) facilities that were well-managed. A staff health monitoring programme showed no reports of COVID-19 compatible respiratory illness before or during December 2019, and no serological evidence of infection in workers through SARS-CoV-2-specific serology-screening. The Wuhan CDC lab which moved on 2 December 2019 reported no disruptions or incidents caused by the move. They also reported no storage nor laboratory activities on CoVs or other bat viruses preceding the outbreak. Information still needed: Regular administrative and internal review of high-level biosafety laboratories worldwide. Follow-up of new evidence supplied around possible laboratory leaks. At the end of the report, the team called for “a continued scientific and collaborative approach to be taken towards tracing the origins of COVID-19”, something that has been echoed by WHO. Image Credits: CGTN, Arend Kuester/Flickr. Share this:Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Facebook (Opens in new window)Click to email this to a friend (Opens in new window)Click to print (Opens in new window) Combat the infodemic in health information and support health policy reporting from the global South. 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