EXPERT REACTION: The origins of COVID-19 (*preprint)

Prof Holmes and colleagues (among which are world leaders in viral molecular epidemiology) have outlined the evidence for and against the natural versus laboratory origins of SARS-CoV-2.

Prior to commenting further, I have no conflicts of interest with the listed authors. I have an interest in viral molecular epidemiology, but my core expertise is working with live viruses and their interface with host cells. The latter is especially focused on the role of viral glycoproteins.

On a separate note before commenting further, science is a deliberately slow business for a reason. It takes time to methodologically build up conclusions to support hypotheses. Whilst social media is great, it does not fit with this careful and stringent philosophy. In addition, it can and is populated with people working under pseudonyms where we have people with significant conflicts that are unknown and those commenting on the science do not have any background knowledge or experience of viruses (certainly not to the extent of any of the listed authors on this article). 

The work outlines the history of the appearance of related viruses from animal reservoirs. What have we learned from our past? History is the best place to start.

Eg. 'It displays clear similarities to SARS-CoV that spilled over into humans in Foshan, Guangdong province, China in November 2002, and again in Guangzhou, Guangdong province in 2003. Both these SARS-CoV emergence events were associated with markets selling live animals and involved species, particularly civets and raccoon dogs, that were also sold live in Wuhan markets in 2019 and are known to be susceptible to SARS-CoV-2 infection. Animal traders working in 2003, without a SARS diagnosis, were documented to have high levels of IgG to SARS-CoV (13% overall and >50% for traders specializing in civets).'

It also outlines the detective work taken to establish the link of SARS-CoV-1 to the animal reservoirs. Of note, there were active collaborative investigations looking not only at the animals but also the people closely associated with them. Our immune systems and those in animals give us traces of events in the past. Antibodies in someone’s blood towards a virus gives us the evidence their bodies have seen the virus prior. The work outlined before and listed by the authors needs to take a similar track for SARS-CoV-2. The detective work needs to continue.

The work presents the appearance of the virus over time. The data support the clear link to the Wuhan market, as is now well known. It states that animal carcasses were tested in the market but these were unrepresentative of the live animal species sold within the market. An inventory of the market animals is provided by links to reference 5, where a study was ongoing prior to 2019 to look at animal sales in the market. Drawing from the history of SARS-CoV-1, testing of animals needs to continue and encompass that outlined in the inventory (especially in animals like Civets and Raccoon dogs). Of note there was a signal for SARS-CoV-2 in the market at the western section that traded in wildlife and domestic animal products. This is outlined in the WHO report in reference 10.

The discussion then moves to the “lab leak” discussions. It states clearly in the conclusions that it cannot completely be dismissed. Rather the discussion in this manuscript focuses on the lack of evidence for this to be the case. This is based on:

1- Lack of epidemiological evidence that it started within the laboratory. The key source would be an infected worker that may have taken it home after being infected in the lab. Yet this is not documented in any early index cases and to date, laboratory workers like Shi Zhengli do not have antibodies that would highlight a previous exposure event. Investigation, one would assume, would be ongoing.

2- Lack of evidence the virus was engineered to be a good fit with humans. This I agree with. Although the virus could infect humans, it certainly does a better job now with the contemporary variants like Delta. In 2020, it changed to be better suited to humans. It did this via the pandemic and rampant global spread. 

3- Lack of signature motifs that tell us it is from a lab. Viruses do not need to be engineered to be in a lab. Many are “grown” from samples. They could have been grown from animal samples. Many virologists use Vero cells that are kidney cells from a monkey. If viruses are grown for too long within those cells, the virus changes in key areas to “adapt” to that setting. There are no signature changes that suggest this. It could have been grown in an animal. Yes, but SARS-CoV-2 doesn't infect rodents like mice very well. Mice can be engineered to be infected by enabling them to express the receptor human ACE2. If the latter was the case, would not the virus be better suited to humans? One could argue though, that it had made that step in this animal model and was why the pandemic started in the first place, only to become fitter in humans over time. The issue here again is the lack of evidence. It would need to have been transmitted to a lab worker to then move it from the lab into the community. There is not epidemiological evidence for this as listed above. 

4-They do state the evidence for lab breaches that did occur in the past for SARS-CoV-1. A bit of history like that outlined above for zoonotic animal transfer is always the best start. Working through how the epidemiology presented in the lab breach cases would present how the observations would look in this case vs the current lack of evidence for the SARS-CoV-2 case. Yet as outlined by the authors, there is presently no evidence to support the lab breach to date.

It is a well written thoughtful piece. It adds to the debate and updates the evidence based on what we know of the contemporary viral variants. Its authors have a significant track record in this area. They don't rule out a lab leak, rather they state the present evidence in front of us does not support this theory.

The 'slow and careful business' of science will continue. More evidence will be uncovered over time, The detective work will continue. It's important we keep that in mind. We are always learning.

Our careful and critical analysis of the currently available data provided no evidence for the idea that SARS-CoV-2 originated in a laboratory.