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Investigations into the origin of COVID-19

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https://en.wikipedia.org/wiki/Investigations_into_the_origin_of_COVID-19

There are several ongoing efforts by scientists, governments, international organisations, and others to determine the origin of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. Most scientists believe that the virus is most likely of zoonotic origin in a natural setting, from bats or another closely-related mammal. [1] [2] [3] [4] [5] [6] [7] Several other explanations, as well as conspiracy theories, have been proposed about the origins of the virus. [8] [9] [10]

SARS-CoV-2 has close genetic similarity to multiple previously identified bat coronaviruses, suggesting it may have crossed over into humans from bats. [11] [12] [13] [14] [4] Research is ongoing as to whether SARS-CoV-2 came directly from bats or indirectly through any intermediate hosts. [15] [16] Initial genome sequences of the virus showed little genetic diversity, although subsequently a number of stable variants emerged (some spreading more vigorously), indicating that the spillover event introducing SARS-CoV-2 to humans is likely to have occurred in late 2019. [17] [18]

Health authorities and scientists internationally state that efforts to trace the specific geographic and taxonomic origins of SARS-CoV-2 could take years, and the results could be inconclusive. [19] Echoing the consensus among virologists, in March 2021 a joint World Health Organization (WHO) and Chinese investigation reported that the virus likely had a zoonotic origin, possibly transmitted through an intermediate host, and that a laboratory origin for the virus was "extremely unlikely". [8] [20] Scientists found the conclusions of the joint WHO-China investigation to be helpful but noted that more work would be needed. [21] In the US, the EU and other countries, some criticised what they said was the report's lack of transparency and data access. WHO director-general Tedros Adhanom said he was ready to deploy additional missions for further investigation. [22]

Scientific background

COVID-19 is caused by infection with a virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 appears to have originated in bats and was spread to humans by zoonotic transfer. [20] [23] [24] Its exact evolutionary history, the identity and provenance of its most recent ancestors, and the place, time, and mechanism of transmission of the first human infection, remain unknown. [25] [26] The biology and regional distribution of other coronaviruses in southeast Asia, including SARS-CoV, help scientists understand more about the origins of SARS-CoV-2. [27]

Taxonomically, SARS-CoV-2 is a virus of the species severe acute respiratory syndrome–related coronavirus (SARSr-CoV). [28] It is believed to have zoonotic origins and has close genetic similarity to bat coronaviruses, suggesting it emerged from a bat-borne virus. [12] [13] [14] [4] Research is ongoing as to whether SARS-CoV-2 came directly from bats or indirectly through any intermediate hosts. [15] [16] The virus shows little genetic diversity, indicating that the spillover event introducing SARS-CoV-2 to humans is likely to have occurred in late 2019. [18] Ultimately, the specific evolutionary history of SARS-CoV-2 in relation to other coronaviruses will be critical to understanding how, where and when the virus spilled over into a human population. [29]

Reservoir and origin

Transmission of SARS-CoV-1 and SARS‑CoV‑2 from mammals as biological carriers to humans

The first known infections from SARS‑CoV‑2 were discovered in Wuhan, China. [12] The original source of viral transmission to humans remains unclear, as does whether the virus became pathogenic before or after the spillover event. [18] [27] [4] Because many of the early infectees were workers at the Huanan Seafood Market, [30] [31] it has been suggested that the virus might have originated from the market. [4] [32] However, other research indicates that visitors may have introduced the virus to the market, which then facilitated rapid expansion of the infections. [18] [33] A March 2021 WHO report on a joint WHO–China study stated that human spillover via an intermediate animal host was the most likely explanation, with direct spillover from bats next most likely. Introduction through the food supply chain and the Huanan Seafood Market was considered another possible, but less likely, explanation. [34]

The mutation rate estimated from early cases of SARS-CoV-2 was of 6.54×10−4 per site per year. [34] Its viral evolution is slowed by the RNA proofreading capability of its replication machinery. [35]

Research into the natural reservoir of the virus that caused the 2002–2004 SARS outbreak has resulted in the discovery of many SARS-like bat coronaviruses, most originating in the Rhinolophus genus of horseshoe bats. Phylogenetic analysis indicates that samples taken from Rhinolophus sinicus show a resemblance of 80% to SARS‑CoV‑2. [14] [36] [37] Phylogenetic analysis also indicates that a virus from Rhinolophus affinis, collected in Yunnan province and designated RaTG13, has a 96% resemblance to SARS‑CoV‑2. [12] [38] The RaTG13 virus sequence is the closest known sequence to SARS-CoV-2. [34]

Samples taken from Rhinolophus sinicus, a species of horseshoe bats, show an 80% resemblance to SARS‑CoV‑2.

Bats are considered the most likely natural reservoir of SARS‑CoV‑2, [39] [40] but differences between the bat coronavirus and SARS‑CoV‑2 suggest that humans were infected via an intermediate host; [32] although the source of introduction into humans remains unknown. [41]

Although the role of pangolins as an intermediate host was initially posited (a study published in July 2020 suggested that pangolins are an intermediate host of SARS‑CoV‑2-like coronaviruses [42] [43]), subsequent studies have not substantiated their contribution to the spillover. [34] Evidence against this hypothesis includes the fact that pangolin virus samples are too distant to SARS-CoV-2: isolates obtained from pangolins seized in Guangdong were only 92% identical in sequence to the SARS‑CoV‑2 genome. In addition, despite similarities in a few critical amino acids, [44] pangolin virus samples exhibit poor binding to the human ACE2 receptor. [45]

Available scientific evidence and findings suggest that SARS-CoV-2 has a natural zoonotic origin. [34] Yet, its origin, which remains unknown, has become debated within the context of global geopolitical tensions. [46] [47] Early in the pandemic, conspiracy theories spread on social media claiming that the virus was a biological weapon developed by China, [48] amplified by echo chambers in the American far-right. [49] Other conspiracy theories promoted misinformation that the virus is not communicable or was created to profit from new vaccines. [50]

Some politicians and scientists have made unsubstantiated speculation that the virus may have accidentally leaked from the Wuhan Institute of Virology. [46] [51] This has led to calls in the media for further investigations into the matter. [52] [53] Many virologists who have studied coronaviruses consider the possibility very remote. [54] [50] [55] [56] The WHO–China joint study report from March 2021 stated that such an explanation is extremely unlikely. [57] [34]

Phylogenetics and taxonomy

Genomic information
SARS-CoV-2 genome.svg
Genomic organisation of isolate Wuhan-Hu-1, the earliest sequenced sample of SARS-CoV-2
NCBI genome ID 86693
Genome size29,903 bases
Year of completion2020
Genome browser ( UCSC)

SARS‑CoV‑2 belongs to the broad family of viruses known as coronaviruses. [58] It is a positive-sense single-stranded RNA (+ssRNA) virus, with a single linear RNA segment. Coronaviruses infect humans, other mammals, and avian species, including livestock and companion animals. [59] Human coronaviruses are capable of causing illnesses ranging from the common cold to more severe diseases such as Middle East respiratory syndrome (MERS, fatality rate ~34%). SARS-CoV-2 is the seventh known coronavirus to infect people, after 229E, NL63, OC43, HKU1, MERS-CoV, and the original SARS-CoV. [60]

Like the SARS-related coronavirus implicated in the 2003 SARS outbreak, SARS‑CoV‑2 is a member of the subgenus Sarbecovirus ( beta-CoV lineage B). [61] [62] Coronaviruses also undergo frequent recombination. [63] Its RNA sequence is approximately 30,000 bases in length, [64] relatively long for a coronavirus (which in turn carry the largest genomes among all RNA families) [65] Its genome consists nearly entirely of protein-coding sequences, a trait shared with other coronaviruses. [63]

A distinguishing feature of SARS‑CoV‑2 is its incorporation of a polybasic site cleaved by furin, [44] which appears to be an important element enhancing its virulence. [66] In SARS-CoV-2 the recognition site is formed by the incorporated 12 codon nucleotide sequence CCT CGG CGG GCA which corresponds to the amino acid sequence P RR A. [67] This sequence is upstream of an arginine and serine which forms the S1/S2 cleavage site ( P RR A RS) of the spike protein. [68] Although such sites are a common naturally-occurring feature of other viruses, [67] including some members of the Beta-CoV genus and other genera of coronaviruses, [69] SARS-Cov-2 is unique among members of its subgenus for such a site. [44]

Viral genetic sequence data can provide critical information about whether viruses separated by time and space are likely to be epidemiologically linked. [70] With a sufficient number of sequenced genomes, it is possible to reconstruct a phylogenetic tree of the mutation history of a family of viruses. By 12 January 2020, five genomes of SARS‑CoV‑2 had been isolated from Wuhan and reported by the Chinese Center for Disease Control and Prevention (CCDC) and other institutions; [64] [71] the number of genomes increased to 42 by 30 January 2020. [72] A phylogenetic analysis of those samples showed they were "highly related with at most seven mutations relative to a common ancestor", implying that the first human infection occurred in November or December 2019. [72] Examination of the topology of the phylogenetic tree at the start of the pandemic also found high similarities between human isolates. [73] As of 7 May 2020, 4,690 SARS‑CoV‑2 genomes sampled on six continents were publicly available. [17][ clarification needed]

On 11 February 2020, the International Committee on Taxonomy of Viruses announced that according to existing rules that compute hierarchical relationships among coronaviruses based on five conserved sequences of nucleic acids, the differences between what was then called 2019-nCoV and the virus from the 2003 SARS outbreak were insufficient to make them separate viral species. Therefore, they identified 2019-nCoV as a virus of Severe acute respiratory syndrome–related coronavirus. [74]

Proposed explanations

There are multiple proposed explanations for how SARS-CoV-2 was introduced into, and evolved adaptations suited to, the human population. There is significant evidence and agreement that the most likely original viral reservoir for SARS-CoV-2 is horseshoe bats, with the closest known viral relative being RaTG13. The evolutionary distance between SARS-CoV-2 and RaTG13 is estimated to be about 50 years (between 20 and 90 years.) [75] The earliest human cases of SARS-CoV-2 were identified in Wuhan, but the index case remains unknown. RaTG13 was sampled from bats in Yunnan, [34] located roughly 1,300 km (810 mi) away from Wuhan [76], and there are relatively few bat coronaviruses from Hubei province. [77] Each origin hypothesis attempts to explain this gap in virus evolution and location a different way. These scenarios continue to be investigated to identify the definitive origin of the virus.

Direct zoonotic transmission

The most direct pathway of introduction is direct zoonotic transmission (also known as spillover) from the reservoir species to humans. Scientists consider this to be a highly likely origin of the SARS-CoV-2 virus in humans. Human contact with bats has increased as bat habitats and human population centers encroach on one another, creating additional opportunities for spillover. Bats are a significant reservoir species for a diverse range of coronaviruses, and humans have been found with antibodies for them suggesting that this form of direct infection by bats is common. In this scenario, the direct ancestor of SARS-CoV-2 remains undiscovered in bats. [34]

Intermediate host

In addition to direct spillover, another pathway, considered highly likely by scientists, is that of transmission through an intermediate host. Specifically, this implies that a cross species transmission occurred prior to the human outbreak and that it had pathogenic results on the animal. This pathway has the potential to allow for greater adaptation to human transmission via animals with more similar protein shapes to humans, though this is not required for the scenario to occur. The evolutionary separation from bat viruses is explained in this case by the virus' presence in an unknown species with less viral surveillance than bats. The virus' ability to easily infect and adapt to additional species (including mink) provides evidence that such a route of transmission is possible. [34]

Cold/food chain

Another proposed introduction to humans is through fresh or frozen food products, referred to as the cold/food chain. Scientists do not consider this to be a likely origin of SARS-CoV-2 in humans. This scenario's source animal could be either a direct or intermediary species as described above. Many investigations centered around the Huanan Seafood Wholesale Market in Wuhan, which had an early cluster of cases. While there have been food-borne outbreaks of human viruses in the past, and evidence of re-introduction of SARS-CoV-2 into China through imported frozen foods, investigations found no conclusive evidence of viral contamination in products at the Huanan Market. [34]

Laboratory incident

A final scenario, considered unlikely by scientists, [34] is the introduction of the virus to humans through a laboratory incident. [78] The Wuhan Institute of Virology has performed research into bat coronaviruses since 2005, and identified the RaTG13 virus which is the closest known relative of SARS-CoV-2. [78] Research topics included investigations into the source of the 2002–2004 SARS outbreak and 2012 MERS outbreak, some of which involved conducting gain of function research on viruses. [79] The proximity of the laboratory to the initial outbreak has led some to speculate that it may be the entry point, [80] and politicians, media personalities and some scientists have called for further investigations into the matter. [81] Based on the available genomic evidence, bioengineering of the virus for deliberate release has been ruled out by experts, [1] [4] with remaining investigations considering the possibility of a collected natural virus inadvertently infecting laboratory staff during the course of study. [34] [82]

Investigations

Chinese government

The first investigation conducted in China was by the Wuhan Municipal Health Commission, responding to hospitals reporting cases of pneumonia of unknown etiology, resulting in the closure of the Huanan Seafood Wholesale Market on 1 January 2020 for sanitation and disinfection. [83] The market was originally suspected of being the source of the virus; however, the Chinese government and the WHO determined later that it was not. [84] [85] [20]

In April 2020, China imposed restrictions on publishing academic research on the novel coronavirus. Investigations into the origin of the virus would receive extra scrutiny and must be approved by Central Government officials. [86] [87] The restrictions do not ban research or publication, including with non-Chinese researchers; Ian Lipkin, a US scientist, has been working with a team of Chinese researchers under the auspices of the Chinese Center for Disease Control and Prevention, a Chinese government agency, to investigate the origin of the virus. Lipkin has long-standing relationships with Chinese officials, including premier Li Keqiang, because of his contributions to rapid testing for SARS in 2003. [88]

United States government

Trump administration

On 6 February 2020, the director of the White House's Office of Science and Technology Policy requested the National Academies of Sciences, Engineering, and Medicine to convene a meeting of "experts, world class geneticists, coronavirus experts, and evolutionary biologists", to "assess what data, information and samples are needed to address the unknowns, in order to understand the evolutionary origins of COVID-19 and more effectively respond to both the outbreak and any resulting information". [89] [90]

In April 2020, it was reported that the US intelligence community was investigating whether the virus came from an accidental leak from a Chinese lab. The hypothesis was one of several possibilities being pursued by the investigators. US Secretary of Defense Mark Esper said the results of the investigation were "inconclusive". [91] [92] By the end of April 2020, the Office of the Director of National Intelligence said the US intelligence community believed the coronavirus was not man-made or genetically modified. [93] [94]

US officials criticised the "terms of reference" allowing Chinese scientists to do the first phase of preliminary research. [95] On 15 January 2021, US Secretary of State Mike Pompeo said that to assist the WHO investigative team's work and ensure a transparent, thorough investigation of COVID-19's origin, the US was sharing new information and urging the WHO to press the Chinese government to address three specific issues, including the illnesses of several researchers inside the WIV in autumn 2019 "with symptoms consistent with both COVID-19 and common seasonal illnesses", the WIV's research on " RaTG13" and " gain of function", and the WIV's links to the Chinese military. [96] [97] On 18 January, the US called on China to allow the WHO's expert team to interview "care givers, former patients and lab workers" in the city of Wuhan, drawing a rebuke from the Chinese government. Australia also called for the WHO team to have access to "relevant data, information and key locations". [98]

A classified report from May 2020 by the Lawrence Livermore National Laboratory, a US government national laboratory, concluded that the hypothesis that the virus leaked from the WIV "is plausible and deserves further investigation", although the report also notes that the virus could have developed naturally, echoing the consensus of the American intelligence community, and provides no "smoking gun" towards either hypothesis. [99] [100]

Biden administration

On 13 February 2021, the White House said it has "deep concerns" about both the way the WHO's findings were communicated and the process used to reach them. Mirroring concerns raised by the Trump Administration, National Security Adviser Jake Sullivan stated it is essential that the report be independent and "free from alteration by the Chinese Government". [101] On 14 April 2021, the Director of National Intelligence Avril Haines, and other officials of the Biden Administration, said that they had not ruled out the possibility of a laboratory accident as the origin of the COVID-19 virus. [102] On 26 May 2021, President Joe Biden directed the U.S. intelligence community to produce a report within 90 days on whether the COVID-19 virus originated from a human contact with an infected animal or from an accidental lab leak, [103] stating his national security staff says there is insufficient evidence to determine either hypothesis to be more likely. [104]

On 23 May 2021, The Wall Street Journal reported that a previously undisclosed US intelligence report stated that three researchers from the Wuhan Institute of Virology became ill enough in November 2019 to seek hospital care. The report did not specify what the illness was. Officials familiar with the intelligence differed as to the strength to which it corroborates the hypothesis that the virus responsible for COVID-19 was leaked from the WIV. The WSJ report notes that it is not unusual for people in China to go to the hospital with uncomplicated influenza or common cold symptoms. [105]

Yuan Zhiming, director of the WIV's Wuhan National Biosafety Laboratory, responded in the Global Times that "Those claims are groundless. The lab has not been aware of this situation [sick researchers in autumn 2019], and I don't even know where such information came from." [106] [107] WIV virologist Shi Zhengli said in 2020 that all staff tested negative for COVID-19 antibodies. [105]

World Health Organization

In May 2020, the World Health Assembly, which governs the World Health Organization (WHO), passed a motion calling for a "comprehensive, independent and impartial" investigation into the COVID-19 pandemic. A record 137 countries, including China, co-sponsored the motion, giving overwhelming international endorsement to the investigation. [108] In mid 2020, the World Health Organization (WHO) began negotiations with the government of China on conducting an investigation into the origins of COVID-19.

In November 2020, the WHO published a two-phase study plan. The purpose of the first phase was to better understand how the virus "might have started circulating in Wuhan", and a second phase involves longer-term studies based on the findings of the first phase. [109] WHO director-general Tedros Adhanom said "We need to know the origin of this virus because it can help us to prevent future outbreaks," adding, "There is nothing to hide. We want to know the origin, and that's it." He also urged countries not to politicise the origin tracing process, saying that would only create barriers to learning the truth. [110]

Phase 1

For the first phase, the WHO formed a team of ten researchers with expertise in virology, public health and animals to conduct investigations. [111] The WHO's phase one investigation team arrived and quarantined in Wuhan, Hubei, China in January 2021. [98] [112]

Members of the investigative team included Thea Fisher, John Watson, Marion Koopmans, Dominic Dwyer, Vladimir Dedkov, Hung Nguyen-Viet, Fabian Leendertz, Peter Daszak, Farag El Moubasher, and Ken Maeda. The team also included five WHO experts led by Peter Ben Embarek, two Food and Agriculture Organization representatives, and two representatives from the World Organisation for Animal Health. [113]

The inclusion of Peter Daszak in the team stirred controversy. Daszak is the head of EcoHealth Alliance, a nonprofit that studies spillover events, and has been a longtime collaborator of over 15 years with Shi Zhengli, Wuhan Institute of Virology's director of the Center for Emerging Infectious Diseases. [114] [115] While Daszak is highly knowledgeable about Chinese laboratories and the emergence of diseases in the area, his close connection with the WIV was seen by some as a conflict of interest in the WHO's investigation. [114] [116] When a BBC News journalist asked about his relationship with the WIV, Daszak said, "We file our papers, it's all there for everyone to see." [117]

Findings

In February 2021, after conducting part of their investigation, the WHO stated that the likely origin of COVID-19 was bats, likely through another animal carrier, and that the time of transmission to humans likely was towards the end of 2019. [20]

The Chinese and the international experts who carried out the joint investigation stated that it was "extremely unlikely" that COVID-19 leaked from a lab. [20] [118] [119] [120] No evidence of a lab leak from the Wuhan Institute of Virology was found by the WHO team, with team leader Peter Ben Embarek stating that it was "very unlikely" due to the safety protocols in place. [20] During a 60 Minutes interview with Lesley Stahl, Peter Daszak, another member of the WHO team, described the investigation process to be a series of questions and answers between the WHO team and the Wuhan lab staff. Stahl made the comment that the team was "just taking their word for it", to which Daszak replied, "Well, what else can we do? There's a limit to what you can do and we went right up to that limit. We asked them tough questions. They weren't vetted in advance. And the answers they gave, we found to be believable—correct and convincing." [121]

The investigation also stated that transfer from animals to humans was unlikely to have occurred at the Huanan Seafood Market, since infections without a known epidemiological link were confirmed before the outbreak around the market. [20] In an announcement that surprised some foreign experts, the joint investigation concluded that early transmission via the cold chain of frozen products was "possible". [20]

In March 2021, the WHO published a written report with the results of the joint study. [1] The joint team stated that there are four scenarios for introduction:

  • direct zoonotic transmission to humans (spillover), assessed as "possible to likely"
  • introduction through an intermediate host followed by a spillover, assessed as "likely to very likely"
  • introduction through the (cold) food chain, assessed as "possible"
  • introduction through a laboratory incident, assessed as "extremely unlikely".

The report mentions that direct zoonotic transmission to humans has a precedent, as most current human coronaviruses originated in animals. Zoonotic transmission is also supported by the fact that RaTG13 binds to hACE2, although the fit is not optimal. [1]

The investigative team noted the requirement for further studies, noting that these would "potentially increase knowledge and understanding globally". [1]:9 WHO director-general Tedros Adhanom said he was ready to dispatch additional missions involving specialist experts. He said in a statement, "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." He also called on China to provide "more timely and comprehensive data sharing" as part of future investigations. [22]

Reactions

Tedros' call for more rigorous studies was accompanied by reactions from governments, across the EU and in a joint statement by 14 other countries (including the US), which criticised the investigation and called for more transparency and access to raw data and original samples.. [122] Some diplomats noted that Chinese officials viewed this as an attempt to politicise the study.[ citation needed] Scientists involved in the WHO report, including Liang Wannian, John Watson, and Peter Daszak, objected to the criticism, and said that the report was an example of the collaboration and dialogue required to successfully continue investigations into the matter. [123] In a letter published in Science, other scientists, including Ralph Baric, argued that the laboratory incident hypothesis had not been sufficiently investigated and remained possible, calling for greater clarity and additional data. [124] Other scientists have also criticised the study, citing major stones left unturned and the lack of access to data. [125] Doubts over the report were also echoed by some media commentators. [126] [127] [128]

The Lancet COVID-19 Commission task force

On 23 November 2020, an international task force led by Peter Daszak, president of EcoHealth Alliance, was formed as part of The Lancet COVID-19 Commission, backed by the medical journal The Lancet. [129] Daszak stated that the task force was formed to "conduct a thorough and rigorous investigation into the origins and early spread of SARS-CoV-2". The task force has twelve members with backgrounds in One Health, outbreak investigation, virology, lab biosecurity and disease ecology. [130] The task force plans to analyse scientific findings and does not plan to visit China. [129]

International politicians' calls for investigations

In April 2020, Australian foreign minister Marise Payne and Australian prime minister Scott Morrison called for an independent international inquiry into the origins of the coronavirus pandemic. [131] [132] A few days later, German chancellor Angela Merkel also pressed China for transparency about the origin of the coronavirus, following similar concerns raised by the French president Emmanuel Macron. [133] The UK also expressed support for an investigation, although both France and UK said the priority at the time was to first fight the virus. [134] [135] In May 2021, Prime Minister Justin Trudeau told reporters Canada would "support the call by the United States and others to better understand the origins of COVID-19." [136] [137]

See also

References

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