Has research into gaining function created covid-19? We asked Ralph Baric.

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[Baric is referring to a 2015 collaboration with Zhengli Shi of the Wuhan Institute of Virology, or WIV, in China, which created a so-called chimera by combining the “spike” gene from a new bat virus with the backbone of a second virus. The spike gene determines how well a virus attaches to human cells. A detailed discussion of the research to test novel spike genes appears here.]

However, the sequence was repeatedly requested after the outbreak of the covid-19 pandemic, so it was provided to the community after talks with the NIH and the magazine. Those who analyzed these sequences stated that it is very different from SARS-CoV-2.

How did this chimeric work on coronaviruses begin?

Around 2012 or 2013, I heard Dr. Shi attend a meeting. [Shi’s team had recently discovered two new coronaviruses in a bat cave, which they named SHC014 and WIV1.] We talked after the meeting. I asked her if she would be willing to make the sequences of either SHC014 or WIV1 spike available after she posted.

And she was kind enough to send us those sequences almost immediately – in fact, before she announced. That was her main contribution to the newspaper. And when a colleague gives you sequences beforehand, co-authorship on paper is appropriate.

That was the basis of that collaboration. We have never given a chimeric sequence of viruses, clones, or viruses to WIV researchers; and others. Shi, or members of her research team, have never worked in our laboratory at UNC. No one in my group worked in WIV labs.

And you developed a reverse genetics technique that allowed you to synthesize those viruses only from a genetic sequence?

Yes, but at the time, the cost of DNA synthesis was expensive – about a dollar per base [one letter of DNA]. Thus, synthesizing the coronavirus genome could cost $ 30,000. And we only had a sequence of spikes. The synthesis of only 4,000 nucleotide spike genes cost $ 4,000. So we introduced an authentic SHC014 spike into a backbone that is competent for replication: a SARS strain adapted to a mouse. The virus was viable and we found that it could replicate in human cells.

So is this research getting to function? Well, the parental strain of SARS coronavirus could replicate quite efficiently in primary human cells. A chimera could also program an infection of human cells, but no better than a parent virus. So we didn’t get any function – rather, we did retained function. Moreover, the chimera in mice is attenuated relative to the parent virus adapted to the mouse, so this would be considered a loss of function.

One of the blows to the research of obtaining a function – including this research – is that the work has little practical value. Would you agree?

Well, by 2016, using chimeras and reverse genetics, we had identified enough high-risk SARS-like coronaviruses to be able to test and identify drugs that have broad activity against coronavirus. We identified remdesivir as the first broad-based antiviral drug to work against all known coronaviruses and released it in 2017. It immediately entered human trials and became the first drug approved by the FDA for the global treatment of covid-19 infections. Another drug, called EIDD-2801, or molnupiravir, was shown to be effective against all known coronaviruses before the 2020 pandemic, and then shown to work against SARS-CoV-2 until March 2020.

Accordingly, I do not agree. I would ask critics if they had identified any drug with a broad spectrum of coronavirus activity before the pandemic. Can I point to work from my labs documenting a strategic approach to developing effective pan-coronavirus drugs that have been shown to be effective against an unknown emerging pandemic virus?

Unfortunately, remdesivir could only be given by intravenous injection. We moved toward an oral formulation, but a covid-19 pandemic ensued. I really wish we had oral medicine early. It’s a game change that would help people infected in developing countries as well as U.S. citizens.

Molnupiravir is an oral drug, and phase 3 studies show rapid control of viral infection. It is considered an emergency use permit in India.

Finally, the paper also supported federal policy decisions that provided basic and applied research on coronaviruses.

What about vaccines?

From approximately 2018 to 2019, the NIH Vaccine Research Center contacted us to begin testing a vaccine based on the RNA messenger against MERS-CoV [a coronavirus that sometimes spreads from camels to humans]. MERS-CoV has been a constant problem since 2012, with a mortality rate of 35%, so it has a real potential for global health hazards.

By early 2020, we had a huge amount of data showing that in the mouse model we developed, these mRNA vaccines with spikes were indeed effective in protecting against the deadly MERS-CoV infection. If it was designed against the original SARS strain from 2003, it was also very effective. So I don’t think the NIH is at all wise to consider mRNA-based vaccines a safe and robust platform against SARS-CoV-2 and give them high priority in moving forward.

We recently published a paper showing that multiplexed, chimeric helical mRNA vaccines protect against all known SARS-like viral infections in mice. Global efforts to develop pan-sarbecoronavirus vaccines [sarbecoronavirus is the subgenus to which SARS and SARS-CoV-2 belong] they will ask us for viruses like the ones described in the 2015 paper.

I would therefore argue that whoever says there was no justification for doing the job in 2015 simply does not recognize the infrastructure that contributed to the therapy and vaccines for covid-19 and future coronaviruses.

Work has value only if the benefits outweigh the risks. Are there safety standards that need to be applied to mitigate these risks?

Certainly. We do everything on BSL-3 plus. The minimum requirements for the BSL-3 would be an N95 mask, eye protection, gloves and a lab coat, but we actually wear Tyvek waterproof suits, aprons and boots and we are in double gloves. Our staff wears hoods with PAPRs [powered air-purifying respirators] which bring HEPA filtered air to the worker. So not only do we do all the research in the biosafety cabinet, but we also do the research in a negative pressure detention facility, which has a lot of redundant features and backups, and each worker is housed in their own private personal detention chamber.

Another thing we do is conduct emergency exercises with local emergency services. We also work with a local hospital. In many laboratory infections, there is actually no known event that would cause that infection to occur. And people get sick, right? You need to have medical supervision plans in place to quarantine people quickly, to make sure they have masks, and to communicate regularly with a doctor on campus.

Is all this a standard for other facilities in the US and internationally?

No, I don’t think so. There are different BSL-3 retention levels, standard operating procedures, and protective equipment in different locations. Some of it depends on how deep your pockets are and the pathogens being studied at that facility. The N95 is much cheaper than the PAPR.

Internationally, the United States has no questions about which biosafety conditions are used in China or any other sovereign country to conduct virus research, be it coronaviruses or Nipah, Hendra or Ebola.

The Wuhan Institute of Virology worked chimeric coronaviruses, using techniques similar to yours, right?

I make it clear that we have never sent any of our molecular clones or any chimeric virus to China. They developed their own molecular clone, based on WIV1, which is the bat coronavirus. They also mixed the spike genes of other bat coronaviruses into that spine, in order to learn how well the spike genes of these strains can promote infection in human cells.

Would you call it a function gain?

The NIH board makes decisions about researching function gains. The rules of gain function focused on pandemic potential viruses and experiments aimed at improving the transmission or pathogenesis of SARS, MERS, and avian influenza strains in humans. WIV1 is approximately 10% different from SARS. Some claim that “SARS coronavirus” by definition covers anything of the genus sarbecoronavirus. According to this definition, the Chinese can do experiments with gaining function, depending on how the chimera behaves. Others argue that SARS and WIV1 are different and as such experiments would be excluded. Certainly, the CDC considers SARS and WIV1 to be different viruses. Only the 2003 SARS coronavirus is the selected agent. Ultimately, the board at NIH is the final arbiter and decides what is or is not an experiment in obtaining office.

Aside from the definitions, we know they did the job under BSL-2 conditions, which is a much lower level of security than your BSL-3 plus.

Historically, the Chinese have conducted much of their research on bat coronavirus under BSL-2 conditions. It is obvious that the safety standards of BSL-2 differ from BSL-3, and laboratory-acquired infections occur much more frequently with BSL-2. There is also much less control over BSL-2.

This year, a joint commission of the World Health Organization and China said it was highly unlikely that the laboratory accident caused SARS-CoV-2. But later you signed a letter with other scientists asking for a thorough investigation of all possible causes. Why?

One of the reasons I signed the letter to Science was that the WHO report did not actually discuss how the WIV lab was working, nor what data the review panel reviewed to conclude that a laboratory escape or infection was “very unlikely.” they were the cause of the pandemic.

There must be some recognition that the laboratory infection could have occurred under the operating conditions of BSL-2. Some unknown viruses associated with guano or oral swabs can replicate or recombine with others, so you can get new strains with unique and unpredictable biological characteristics.

And if all this research is being done on BSL-2, then there are issues that need to be addressed. What are the standard operating procedures in BSL-2? What are the staff training records? What is the history of potential laboratory exposure events and how are they reviewed and resolved? What biosecurity procedures are designed to prevent potential exposure events?



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