Once again, the ‘lab leak’ theory of COVID’s origin has returned to the headlines. On Sunday, the Wall Street Journal revealed that a US Department of Energy report had determined that the origin of COVID was ” most likely” an accidental release from a laboratory, according to those who had read the report, though the assessment was with “low confidence”.
Ambassador Nicholas Burns told a US Chamber of Commerce event on Monday that China needs to “be more honest about what happened three years ago in Wuhan with the origin of the Covid-19 crisis”.
China’s foreign ministry countered that COVID’s origin “was about science and should not be politicised”.
The FBI assigned “moderate confidence” to a laboratory origin for the virus, while four other US agencies assigned a “low confidence” to a natural origin. Two others, including the CIA, remained undecided. An update on their views has been provided, apparently due to new information, but has not been made public.
To many scientists, the origin of SARS-CoV-2 has been settled as it has been traced to outbreaks in the Wuhan meat market two weeks before its first detection. A literature analysis published in PNAS concluded that the evidence overwhelmingly favoured a natural origin.
Many other scientists are not convinced by the zoonotic hypothesis. Virologist Jesse Bloom, at the Fred Hutchinson Cancer Center, said the PNAS review’s literature analysis was a good idea – but the zoonosis proponents haven’t provided much new data. “What we’ve seen is mostly reanalysis and reinterpretation of existing evidence.”
The PNAS review started out as a Lancet commission led by Jeffrey Sachs, who disbanded the task force due to a number of members with vested interests against the lab leak hypothesis. Their aim was to gather lessons learnt from the pandemic. The Lancet eventually published its own review, which concluded that there was equal probability for a laboratory or natural origin.
Even so, a continued lack of cooperation from China with international investigators has made it virtually impossible to definitively pinpoint the virus’s emergence. Ultimately, the lesson of past pandemics is that outbreaks can result from either zoonotic origins or from laboratory accidents, both of which are factors which need to be safeguarded against by humans.
The source of the COVID pandemic likely is down to live animals sold at the Huanan Seafood Wholesale Market, according to an international team of researchers.
The researchers traced the start of the pandemic to the market in Wuhan, China, where animals susceptible to the virus were sold live immediately before the pandemic began. Their findings were published in a pair of papers in the journal Science.
The publications all but rule out other explanations for the start of the pandemic, such as the ‘lab leak’ hypothesis. The authors further conclude that the first spread to humans from animals likely occurred in two separate transmission events in the Huanan market in late November 2019.
The first study looked at the locations of the first known COVID cases, as well as swab samples taken various places in the market. The second study examined genomic sequences of SARS-CoV-2 from samples collected from COVID patients during the first weeks of the pandemic in China.
The first paper, led by University of Arizona virus evolution expert Michael Worobey and Professor Kristian Andersen, was able to determine the locations of almost all of the 174 COVID cases identified by the World Health Organization in December 2019, 155 of which were in Wuhan.
A ‘bullseye’ on the market
Analyses showed that these cases were clustered tightly around the Huanan market, whereas later cases were dispersed widely throughout Wuhan. A striking percentage of early COVID patients had not visited there but turned out to live near the market. This suggests that vendors got infected first and set off a chain of infections among community members in the surrounding area, said Worobey.
“In a city covering more than 3000 square miles, the area with the highest probability of containing the home of someone who had one of the earliest COVID cases in the world was an area of a few city blocks, with the Huanan market smack dab inside it,” said Worobey.
This conclusion was supported by another finding: When the authors looked at the geographical distribution of later COVID cases, from January and February 2020, they found a “polar opposite” pattern, Worobey said. While the cases from December 2019 mapped “like a bullseye” on the market, the later cases coincided with areas of the highest population density in Wuhan.
“This tells us the virus was not circulating cryptically,” Worobey said. “It really originated at that market and spread out from there.”
Worobey and collaborators also addressed the question of whether health authorities found cases around the market simply because that is where they looked.
To rule out bias even more, from the market outwards the team removed cases ran the stats again. They found that even when two-thirds of cases were removed, the findings remained the same.
“Even in that scenario, with the majority of cases, removed, we found that the remaining ones lived closer to the market than what would be expected if there was no geographical correlation between these earliest COVID cases and the market,” Worobey said.
The study also looked at swab samples taken from market surfaces like floors and cages after Huanan market was closed. SARS-CoV-2-positive samples were significantly associated with stalls selling live wildlife.
The researchers determined that mammals now known to be susceptible to SARS-CoV-2, including red foxes, hog badgers and raccoon dogs, were sold live at the Huanan market in the weeks preceding the first recorded COVID cases. The scientists developed a detailed map of the market and showed that SARS-CoV-2-positive samples reported by Chinese researchers in early 2020 showed a clear association with the western portion of the market, where live or freshly butchered animals were sold in late 2019.
“Upstream events are still obscure, but our analyses of available evidence clearly suggest that the pandemic arose from initial human infections from animals for sale at the Huanan Seafood Wholesale Market in late November 2019,” said Prof Andersen at Scripps Research, co-senior author of both studies.
Virus likely jumped from animals to humans more than once
The second study, was an analysis of SARS-CoV-2 genomic data from early cases.
The researchers combined epidemic modeling with analyses of the virus’s early evolution based on the earliest sampled genomes. They determined that the pandemic, which initially involved two subtly distinct lineages of SARS-CoV-2, likely arose from at least two separate infections of humans from animals at the Huanan market in November 2019 and perhaps in December 2019. The analyses also suggested that, in this period, there were many other animal-to-human transmissions of the virus at the market that failed to manifest in recorded COVID-19 cases.
Using molecular clock analysis, which relies on the natural pace with which genetic mutations occur over time, researchers established a framework for the evolution of the SARS-CoV-2 virus lineages. They found that a scenario of a singular introduction of the virus into humans rather than multiple introductions would not align with molecular clock data. Earlier studies had suggested that one lineage of the virus – named A and closely related to viral relatives in bats – gave rise to a second lineage, named B. The more likely scenario in which the two lineages jumped from animals into humans on separate occasions, both at the Huanan market, Worobey said.
“Otherwise, lineage A would have had to have been evolving in slow motion compared to the lineage B virus, which just doesn’t make biological sense,” said Worobey.
The two studies provide evidence that COVID originated via jumps from animals to humans at the Huanan market, likely following transmission to those animals from coronavirus-carrying bats in the wild or on farms in China. Moving forward, the researchers say scientists and public officials should seek better understanding of the wildlife trade in China and elsewhere and promote more comprehensive testing of live animals sold in markets to lower the risk of future pandemics.
SARS-CoV-2 virus. Source: Fusion Medical Animation on Unsplash
In an unexpected turn of events, the US National Institutes of Health (NIH) has acknowledged that it funded research into enhancing coronavirus infectivity, Vanity Fair reported.
The agency had last week sent a letter to the US House Committee on Energy and Commerce stating that its grant recipient, EcoHealth Alliance, enhanced a bat coronavirus to become potentially more infectious to humans. This was an “unexpected result” of the research, done in collaboration with Wuhan Institute of Virology.
The NIH letter also noted that EcoHealth Alliance violated terms of its grant conditions, which had stipulated that it was supposed to report to the agency if its work boosted viral growth by a factor of 10.
EcoHealth Alliance was supposed to submit a progress report at the end of the grant period in 2019 but it didn’t arrive at the NIH until August 2021, according to Vanity Fair. However, in a statement to Vanity Fair, EcoHealth Alliance said that it had reported the relevant information “as soon as we were made aware, in our four year report in April 2018.”
In that missing progress report (dated August 2021), lab mice infected with the enhanced virus became more ill than those infected with a wild one, reported Vanity Fair.
The Vanity Fair report also reveals a rather concerning detail contained in a leaked EcoHealth Alliance grant proposal submitted to the Defense Advanced Research Projects Agency in 2018. EcoHealth Alliance and the Wuhan Institute of virology proposed to engineer a furin cleavage site for the coronavirus to more easily enter humans cells. This matches a distinctive segment of SARS-CoV-2’s genetic code.
“If I applied for funding to paint Central Park purple and was denied, but then a year later we woke up to find Central Park painted purple, I’d be a prime suspect,” Jamie Metzl, a member of the WHO advisory committee on human genome editing, told Vanity Fair.
In its letter to US Congress, the NIH emphasised that the virus EcoHealth Alliance was studying could not have sparked the pandemic, as there was a vast genetic difference between it and SARS-CoV-2. NIH Director Francis Collins, MD, PhD, also issued a statement addressing the concerns raised by the letter, noting that such claims were “demonstrably false.”
“The scientific evidence to date indicates that the virus is likely the result of viral evolution in nature, potentially jumping directly to humans or through an unidentified intermediary animal host,” Dr Collins said in the statement.
Gilles Demaneuf, a data scientist in New Zealand, told Vanity Fair, “I cannot be sure that [COVID originated from] a research-related accident or infection from a sampling trip. But I am 100% sure there was a massive cover-up.”
In response to these criticisms of poor oversight and bad scientific judgment, the NIH has “circled its wagons”, Vanity Fair observed.
COVID heat map. Photo by Giacomo Carra on Unsplash
A recent article by The Telegraph revealed documents on grant applications by US and Wuhan scientists to conduct coronavirus research in 2018. However, it is important to note that these grants were not funded, and are not direct evidence of a ‘lab leak’ or research-related origin for the coronavirus.
The documents, obtained by a scientist-activist group calling itself DRASTICand confirmed as authentic by a member of the Trump administration, detail grant requests for antigen-bearing nanoparticles and aerosols to be released into bat caves to immunise bat populations. Note that “coronavirus particles” as The Telegraph describes them would be immunising nanoparticles which could describe coronavirus vaccines. Another proposal involved adding “human-specific cleavage sites” to bat coronaviruses to facilitate entry into human cells. The Defense Advanced Research Projects Agency (DARPA) however, refused to fund the work, saying it would have “put local communities at risk.”
What is perhaps more concerning were details of an effort for gain of function research in MERS-CoV, which has a 30% fatality rate, something which an anonymous World Health Organization COVID researcher suggests could have resulted in a pandemic that was “nearly apocalyptic.”
Scientists, however, urge continued impartiality and examining all possibilities, even controversial ones. In an article published on Friday, 24 September in The Lancet, authors point out that there is neither solid evidence for either a natural origin or a for a research origin. In the nineteen months since the beginning of the pandemic, no natural origin has been found despite extensive searching, and independent international researchers do not have access to the investigation sites in China, raw data or samples. However, it took several years for the natural origins of SARS-CoV-1 to be discovered.
They also point out that a research origin for the virus cannot be excluded. Optimisation of the receptor binding domain for human ACE2 could occur through selection or cell cultures, without requiring knowledge of it in advance. Although certain genetic engineering techniques leave signatures in the genome, so-called ‘seamless’ techniques exist.
“On the basis of the current scientific literature, complemented by our own analyses of coronavirus genomes and proteins, we hold that there is currently no compelling evidence to choose between a natural origin (ie, a virus that has evolved and been transmitted to humans solely via contact with wild or farmed animals) and a research-related origin (which might have occurred at sampling sites, during transportation or within the laboratory, and might have involved natural, selected, or engineered viruses).”
An article in Science explores the evidence for the animal origin of COVID, which was first detected in December 2019, but inferred to be present in Hubei province, China, for about a month beforehand.
The current COVID epidemic can be better understood by examining the severe acute respiratory syndrome coronavirus (SARS-CoV) outbreak which began in 2002. Investigations later found that horseshoe bats (Rhinolophus) in China harboured related coronaviruses. It was inferred that a sarbecovirus circulating in horseshoe bats seeded the progenitor of SARS-CoV in an intermediate animal host, most probably civet cats Although other possible intermediate hosts for SARS-CoV were identified, it is a population of civet cats within markets that appear to have acted as the conduits of transmission to humans from the horseshoe bat reservoir of SARS-CoV. Presumably a captive civet cat initially became infected by direct contact with bats or was infected before capture.
SARS-CoV-2 first emerged in Wuhan city, over 1500 km from the closest known naturally occurring sarbecovirus collected from horseshoe bats in Yunnan province. Coronaviruses genetically close to SARS-CoV-2 are circulating in horseshoe bats with wide geographic ranges indicate that the singular focus on Yunnan is misplaced. Confirming this assertion, the evolutionarily closest bat sarbecoviruses are estimated to share a common ancestor with SARS-CoV-2 at least 40 years ago, showing that these Yunnan-collected viruses are highly divergent from the SARS-CoV-2 progenitor.
Though the virus may have jumped to humans from direct horseshoe bat–to–human contact, a known risk for SARSr-CoVs, the first detected SARS-CoV-2 cases in December 2019 are associated with Wuhan wet markets. This is consistent with multiple animal-market–associated spillover events in November and December (9). It is currently not possible to be certain of the animal source of SARS-CoV-2, but it is notable that live animals, including civet cats, foxes, minks, and raccoon dogs, all susceptible to sarbecoviruses, were for sale in Wuhan markets, including the Huanan market (identified as an epicenter of the outbreak in Wuhan) throughout 2019.
Together, this suggests a central role for SARSr-CoV–susceptible live intermediate host animals as the primary source of the SARS-CoV-2 progenitor that humans were exposed to, as was the case with the origin of SARS.
Spillover events are not so rare, indicated by evidence of SARSr-CoV–specific antibodies in people living in rural areas, and even higher rates recorded in people living near bat caves. When exposed a densely packed human population, such as in Wuhan city, these spillover events have a much higher chance of resulting in substantial onward spread
Interestingly, the proximity of humans to wildlife may have been increased by demand for alternative meat sources caused by reduced availability of pork in 2019. This was caused by the African swine fever virus (ASFV) pandemic, which led to ∼150 million pigs being culled in China, resulting in a pork supply reduction of ∼11.5 million tonnes in 2019, and from which the country is still recovering. Increased use of cold-chain logistics in the wake of the ASFV pandemic means that frozen animal carcasses carrying SARS-CoV-2 may have been brought from much farther afield.
Once crossed over, SARS-CoV-2 readily established itself in humans by being a generalist, as opposed to being specialised for humans. Ironically, since humans are now the largest reservoir of the virus, animals in contact with humans are at risk of virus spillover. The article authors closed by stressing the need for much greater viral surveillance to spot emerging threats, as current coverage is extremely spotty.
