The SARS-CoV-2 pandemic most likely arose from horseshoe bats in caves in South China, transferring into humans from an unknown intermediate animal source, according to a World Health Organization (WHO) report and other research papers cited in this article. The WHO report raises four distinct scenarios and rules out none of them.

 

An international WHO team, joined by Chinese scientists, spent one month in China trying to find the origin of a pandemic coronavirus that arose in Wuhan in late 2019 and now is approaching 3 million deaths globally.

The joint international team examined four scenarios for the introduction of SARS-CoV-2 and assessed the likelihood of each as follows:

  • direct zoonotic transmission to humans (spillover): possible to likely;
  • introduction through an intermediate host followed by spillover: likely to very likely;
  • introduction through the (cold) food chain: possible;
  • introduction through a laboratory incident: extremely unlikely.1

The intermediate host scenario — a missing link animal between bat and human — is considered the most likely, in part because this was the case in the original 2002-2003 severe acute respiratory syndrome (SARS) outbreak (civet cats) and the 2012 emergence of Middle East respiratory syndrome (MERS) coronavirus (camels).

“Evidence from surveys and targeted studies so far have shown that the coronaviruses most highly related to SARS-CoV-2 are found in bats and pangolins, suggesting that these mammals may be the reservoir of the virus that causes COVID-19,” the WHO report stated.

“However, neither of the viruses identified so far from these mammalian species is sufficiently similar to SARS-CoV-2 to serve as its direct progenitor. In addition to these findings, the high susceptibility of mink and cats to SARS-CoV-2 suggests that additional species of animals may act as a potential reservoir. More than 80,000 wildlife, livestock, and poultry samples were collected from 31 provinces in China and no positive result was identified,” the report continued.

If the reservoir animal can be identified, the goal is to prevent both reinfection with the virus in animals and humans and to stop the establishment of new zoonotic reservoirs.

Plot Thickens in Lab Scenario

The most controversial of the four theories put forward in the WHO report was the “extremely unlikely” escape of the virus from a research lab in Wuhan.

“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,” the WHO reported. “The three laboratories in Wuhan working with either CoVs diagnostics and/or CoVs isolation and vaccine development all had high-quality biosafety level (BSL-3 or BSL-4) facilities that were well-managed, with a staff health monitoring program with no reporting of COVID-19-compatible respiratory illness during the weeks/months prior to December 2019, and no serological evidence of infection in workers.”

With the investigators largely dismissing the lab escape scenario — which some consider a politicized conspiracy theory — it was all the more surprising when WHO Director Tedros Ghebreyesus, PhD, took a critical view of the findings after the report was released.

“The team visited several laboratories in Wuhan and considered the possibility that the virus entered the human population as a result of a laboratory incident,” he said in a press conference. “However, I do not believe that this assessment was extensive enough. Further data and studies will be needed to reach more robust conclusions. Although the team has concluded that a laboratory leak is the least likely hypothesis, this requires further investigation, potentially with additional missions involving specialist experts, which I am ready to deploy.”

These strong words came only days after another bombshell — the provocative assertion by Robert Redfield, MD, the immediate past director of the Centers for Disease Control and Prevention (CDC), that a lab escape is the most likely explanation.

“If I was to guess, this virus probably started to transmit somewhere in September or October [of 2019] in Wuhan,” Redfield said in a broadcast interview. “That is my opinion. I am allowed to have opinions now. I am of the point of view that I still think the most likely etiology of this pathogen was from a laboratory escape. Other people don’t believe that. That’s fine, science will eventually figure it out. It’s not unusual for respiratory pathogens being worked on in a laboratory to infect a lab worker.”

The Wuhan Institute of Virology has extensively studied coronaviruses, identifying the progenitor of the original 2002-2003 SARS as horseshoe bats in caves in Southern China.2 The Wuhan lab also sequenced the genome of the SARS-CoV-2 from the some of the early unexplained cases of pneumonia in the city, posting the data in early 2020 so other scientists could work on treatments and vaccines.

Virus Appears of Natural Origin

It should be emphasized that China has denied any lab incident or undisclosed work with the SARS-CoV-2 virus. Renowned Chinese virologist Shi Zhengli, a veteran researcher at the lab, said she could not sleep until she checked every stored viral specimen to confirm SARS-CoV-2 was not among the isolates.3 In addition, several molecular virologists have said SARS-CoV-2 has distinctive signs of natural origin, in stark contrast to a virus engineered or altered in a lab.4,5

“[I am] not implying any intentionality,” Redfield said, although he added that the goal of a laboratorian working on a rare virus would be to “grow” more of it to study.

“I am a virologist — I spent my life in virology,” he said. “I do not believe that this virus suddenly came from a bat to a human and then at that moment became one of the most infectious viruses in humanity for human-to-human transmission. Normally, when a pathogen goes from a zoonoses to a human it takes a while for it to figure out how to become more efficient in human-to-human transmission. I just don’t think this makes biological sense.”

Calling the comments “unfortunate,” a nationally renowned medical epidemiologist and CDC advisor disagreed, fact-checking Redfield on the point that zoonotic viruses take time to become adept at transmitting between humans.

“He provided no critical rationale for [the lab origin theory] other than his notion that viruses newly introduced into the human population cannot spread readily,” says William Schaffner, MD, of Vanderbilt University School of Medicine. “Well, that certainly happens with pandemic influenza. Why is it so strange that this could have happened with coronavirus?”

Indeed, after the 2009 H1N1 influenza A strain accomplished an antigenic “shift” signaling a pandemic, there was no vaccine and vast susceptibility in the human population. More than a million people were infected around the world, although, fortunately, it was a relatively mild flu.

“Furthermore, we have two other coronaviruses that have jumped species — SARS and MERS,” Schaffner says. “They didn’t spread the same. They have different mutations that confer upon them different characteristics.”

That said, Schaffner notes that the lab theory should remain part of the “differential diagnosis,” in part because the WHO team was widely perceived to be constrained in their investigation by the Chinese.

“They were not provided totally open access to all of the information that a really thorough investigative committee would like to have,” Schaffner says. “We do have limitations there. I don’t think the lab question has been definitively answered, unfortunately.”

Lab Incidents Include CDC

For the record, there have been several international lab escapes and near misses over the years, including one in 2003 of the original SARS from a lab in Singapore. Inappropriate laboratory procedures and cross-contamination with West Nile virus and SARS coronavirus samples led to the infection and hospitalization of a lab worker, investigators concluded.6 There was no evidence of secondary transmission to the lab worker’s contacts and caregivers.

The CDC has fared little better, having an embarrassing series of lab accidents and incidents less than a decade ago that eroded public confidence in the agency’s ability to contain pathogens. Consider these words from former CDC director Tom Frieden, MD, in a 2014 press conference after the lab incidents:

“First, we had the potential exposure to anthrax at CDC’s laboratory,” he said.7 “Second, earlier this week, we learned about an incident in CDC’s influenza laboratory. And third, we had the discovery of vials labeled as smallpox in a storage room on the NIH campus. These events should never have happened. Together, these events, I’m sure, have many people asking and questioning government labs.”

The assurances of various Chinese scientists and government officials that no lab incident occurred are met with skepticism by Daniel Lucey, MD, MPH, FIDSA, a pandemic investigator for more than 20 years as a member of the Infectious Disease Society of America.

“We have the word of various researchers, government and lab officials, but that’s it — that’s the level of certainty and knowledge,” he says. “An appropriate investigation could be done, but even then, it is 15-17 months later depending on when the outbreak might have started. How could even a forensic investigation determine that, given this much time? There are limits to what might be found, but I think it is worth doing.”

The outbreak likely began earlier than the Dec. 8, 2019, date reported by the WHO investigation, he argues, noting that after that date, 174 patients were identified in Wuhan by Dec. 31, 2019.

“To me, it’s just not plausible that there were none before Dec. 8,” Lucey says. “That doesn’t help us because we need to know about the earlier cases, even if there is just one, two, or four. They are the clue — they are the signposts. How did they get infected, where did they travel, what animals were they exposed to and what other people were they around?”

Again, the WHO report proposes an intermediate animal between bat and man as the most likely explanation for the emergence of SARS-CoV-2.

“What have we learned from the animal investigations?” says Lucey, an infectious disease adjunct professor at Georgetown Medical Center. “The bottom-line fact is, after 15-16 months, no animal has been found infected with this virus that might have been the origin of the outbreak. None.”

The WHO report recommends testing farmed animals and farmers in South China where the suspect bats live in caves.

“Honestly, for me, it is not plausible that China did not immediately recognize this possibility of farmed animals from the South where there are bats with coronaviruses,” says Lucey. “China probably recognized this hypothesis way back at the end of December of 2019, and certainly the first week or two of January 2020. I don’t know why they didn’t disclose that they did it and they didn’t disclose any data. I can only speculate — why would China not have done such an investigation?”

‘Silence of the Mink’

Another piece of missing information is particularly troublesome to Lucey, something he dubs “the silence of the mink.” A global leader in the fur industry, China has large mink farms in the provinces far north of Wuhan. There was no listing in the report of testing data from these farmed mink, although 91 mink were negative in testing of livestock, domesticated animals, and captive wildlife in Wuhan and surrounding areas

“There are farms in Denmark and other places where humans infected the minks and then they infected other humans,” he says. “It was humans [who] infected the mink in the Netherlands and nine countries in Europe and three states in U.S. So that is a theoretical concern.”

Indeed, the WHO report concludes at one point that “direct spillover from bats to humans may have occurred, or as with MERS-CoV and likely SARS-CoV, transmission to humans may have involved an intermediate host. Candidate intermediate host species may include mink, pangolins, rabbits, raccoon dogs, and domesticated cats that can be infected by SARS-CoV-2.”

Although the WHO report refers to minks as possible reservoirs several times, there are no data reflecting testing at the large mink farms Lucey is referring to. In a rather oddly worded sentence, the WHO report states, “Screening of farmed wildlife was limited, but did not provide conclusive evidence for the existence of circulation.”

With no reports of widespread testing of mink farms, Lucey suspects that this is something that China has done but reported no data.

“I looked into the mink farms in provinces all north of Hubei province,” he says. “There are large mink farms, but that is a big silence in this report unless I missed it. It’s never been discussed in press conferences. What are the results of mink testing on these farms in China? It is not believable to me that China did not test the mink. Of course, they thought of it — of course they tested their mink.”

Lucey’s contention that China likely has tested their mink farms is further borne out by a study published by Chinese researchers. The authors, who included researchers from elite Peking University, concluded, “by comparing the infectivity patterns of all viruses hosted on vertebrates, we found mink viruses show a closer infectivity pattern to 2019-nCoV. These consequences of infectivity pattern analysis illustrate that bat and mink may be two candidate reservoirs of 2019-nCoV.”8

There have been massive culls of mink in countries such as the Netherlands and Denmark after SARS-CoV-2 has been detected on farms, just as China killed their civet cats in the 2002-2003 SARS outbreak. Without definitive evidence, critics theorize that China may be protecting its multibillion-dollar mink and fur industry.9 Although the stakes are immeasurably higher with SARS-CoV-2, it is well to remember that Saudi Arabia still hasn’t culled its iconic camels — the known intermediate reservoir for the less transmissible but still deadly MERS coronavirus.

REFERENCES

  1. World Health Organization. Origins of the SARS-CoV-2 virus. March 30, 2021. https://www.who.int/health-topics/coronavirus/origins-of-the-virus
  2. Hu B, Zeng L-P, Yang X-L, et al. Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. PLoS Pathog 2017;13:e1006698.
  3. Qiu, J. How China’s ‘bat woman’ hunted down viruses from SARS to the new coronavirus. Scientific American. June 1, 2020. https://www.scientificamerican.com/article/how-chinas-bat-woman-hunted-down-viruses-from-sars-to-the-new-coronavirus1/
  4. Lytras S, Hughes J, Xia W, et al. Exploring the natural origins of SARS-CoV-2. bioRxiv 2021; Jan 30. [Preprint]. doi: https://doi.org/10.1101/2021.01.22.427830
  5. Boni MF, Lemey P, Jiang X, et al. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Nat Microbiol 2020;5:1408-1417.
  6. National Archives of Singapore. Biosafety and SARS Incident in Singapore September 2003: Report of the Review Panel on New SARS Case and Biosafety. https://www.nas.gov.sg/archivesonline/data/pdfdoc/20030923-MOH.pdf
  7. Centers for Disease Control and Prevention. CDC press conference on laboratory quality and safety after recent lab incidents. July 11, 2014. https://www.cdc.gov/media/releases/2014/t0711-lab-safety.html
  8. Guo Q, Mo L, Wang C, et al. Host and infectivity prediction of Wuhan 2019 novel coronavirus using deep learning algorithm. bioRxiv 2020; Aug 23. [Preprint]. doi: https://doi.org/10.1101/2020.01.21.914044
  9. Faure Y, Sciama Y. Mounting evidence suggests mink farms in China could be the cradle of Covid-19. Reporterre. Jan. 14, 2021. https://reporterre.net/Mounting-evidence-suggests-mink-farms-in-China-could-be-the-cradle-of-Covid-19-22020