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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 has been requested repeatedly since the outbreak of the covid-19 pandemic, and therefore, after discussion with the National Institutes of Health and the journal, it was made available to the community. Those who analyzed these sequences stated that they were very different from SARS-CoV-2.

How did this chimeric work with coronaviruses start?

Around 2012 or 2013, I heard Dr. Shi attend the 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 like to make the sequence for spike SHC014 or WIV1 available after publication.

And she was kind enough to send us this footage almost immediately – in fact, front she published. This was her main contribution to the newspaper. And when a colleague gives you the sequences ahead of time, paper co-authorship is appropriate.

This was the foundation of this collaboration. We have never provided chimeric viral sequences, clones, or viruses to WIV researchers; and Dr. Shi, or members of her research team, have never worked in our laboratory at UNC. None of my group worked in the WIV labs.

And you developed a reverse genetics method that allowed you to synthesize these viruses based on genetic sequence only?

Yes, but at the time the cost of DNA synthesis was high – about a dollar a basis. [one letter of DNA]… Thus, the synthesis of the genome of the coronavirus can cost 30 thousand dollars. And we only had a spike sequence. Synthesis of the 4,000 nucleotide spike gene alone cost $ 4,000. Thus, we have introduced the authentic SHC014 spike into a replication-competent framework: the mouse-adapted SARS strain. The virus was viable and we found that it can multiply in human cells.

So what is this function gain study? Well, the parental strain of the SARS coronavirus can replicate quite efficiently in primary human cells. The chimera could also program the infection of human cells, but no better than the parent virus. Thus, we did not get any function – rather, we kept function. Moreover, the chimera was attenuated in mice compared to the mouse-adapted parental virus, so this would be considered a loss of function.

One of the obstacles to the study of enhancement of function, including this study, is that this work has no 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 with broad anti-coronavirus activity. We identified remdesivir as the first broad-spectrum antiviral drug that worked against all known coronaviruses and published it in 2017. It was immediately put into human trials and became the first FDA-approved drug for the treatment of COVID-19 infections in the world. The second drug, named EIDD-2801, or molnupiravir, has also been shown to be effective against all known coronaviruses prior to the 2020 pandemic, and then shown to be effective against SARS-CoV-2 by March 2020.

Hence, I disagree. I would ask critics if they have identified any pre-pandemic broad-spectrum coronavirus drugs. Can they point to documents from their laboratories documenting a strategic approach to developing effective drugs against a pandemic virus that have proven effective against an unknown emerging pandemic virus?

Unfortunately, remdesivir could only be administered intravenously. We were moving towards an oral formulation, but the covid-19 pandemic broke out. I am very sorry that we did not have the oral medication early on. This is a game changer that will help people infected in developing countries as well as US citizens.

Molnupiravir is an oral drug and phase 3 studies demonstrate rapid control of viral infection. It was being considered for permission for emergency use in India.

Finally, the work also supported federal policy decisions that prioritized fundamental and applied research on coronaviruses.

And what about vaccines?

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

By early 2020, we had a wealth of data showing that, in our mouse model, these mRNA spike vaccines were indeed effective in protecting against lethal MERS-CoV infection. If it was developed against the original 2003 SARS strain, it also proved to be very effective. So I think it was not difficult for the NIH to consider mRNA vaccines as a safe and reliable platform against SARS-CoV-2 and prioritize them in moving forward.

We recently published an article showing that multiplex spiked chimeric mRNA vaccines protect mice from all known SARS-like viral infections. Global efforts to develop pansarbecoronavirus vaccines [sarbecoronavirus is the subgenus to which SARS and SARS-CoV-2 belong] will require us to create viruses like those described in the 2015 article.

So I would say that anyone who says there is no foundation for work in 2015 is simply not recognizing the infrastructure that has facilitated the development of therapeutic drugs and vaccines against covid-19 and future coronaviruses.

Work is only valuable if the benefits outweigh the risks. Are there security standards that should be applied to minimize these risks?

Sure. We do everything on BSL-3 plus. The minimum requirements in BSL-3 are an N95 mask, eye protection, gloves and a lab coat, but we actually wear Tyvek impervious suits, aprons and boots, and wear double gloves. Our staff wear hoods with PAPR. [powered air-purifying respirators] which supply HEPA filtered working air. So not only do we do all research in a biosafety cabinet, but we also do research in a negative pressure isolator, which has many redundant functions and backups, and each worker is confined in their own personal protective suit.

We also conduct emergency drills with local first responders. We are also working with a local hospital. For many laboratory infections, there is actually no known event that would trigger the infection. And people get sick, right? You should have medical follow-up plans to quickly isolate people at home, make sure they have masks, and talk to your doctor on campus regularly.

Is this all standard for other properties in the US and overseas?

No I do not think so. Different locations have different BSL-3 containment levels, standard operating procedures and protective equipment. Some of them depend on how deep your pockets are and the pathogens being studied in the institution. The N95 is much cheaper than the PAPR.

Internationally, the US cannot say what biosecurity conditions are used in China or any other sovereign country to conduct research for viruses, be it coronaviruses or Nipah, Hendra or Ebola.

The Wuhan Institute of Virology has created chimeric coronaviruses using methods similar to yours, right?

Let me be clear that we have never shipped our molecular clones or chimeric viruses to China. They developed their own molecular clone based on WIV1, which is the bat coronavirus. And into this framework, they inserted spike genes of other bats coronaviruses to find out how well the spike genes of these strains can contribute to the infection of human cells.

Would you call it function enhancement?

A committee at the NIH determines research to increase functionality. Enhancement of function regulations focus on viruses with pandemic potential and experiments to enhance the transmission or pathogenesis of SARS, MERS, and avian influenza strains in humans. WIV1 is about 10% different from SARS. Some argue that the “SARS coronavirus” by definition covers everything that belongs to the genus Sarbecoronaviruses. According to this definition, the Chinese can experiment with increasing functionality, depending on how the chimera behaves. Others argue that SARS and WIV1 are different and therefore experiments will be ruled out. Of course, the CDC considers SARS and WIV1 to be different viruses. Only the 2003 SARS coronavirus is the chosen agent. Ultimately, a committee at the NIH is the final arbiter and decides what is a feature-enhancing experiment and what is not.

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

Historically, the Chinese have done a lot of research on bat coronavirus under BSL-2 conditions. Obviously, BSL-2 safety standards differ from BSL-3, and laboratory infections are much more common in BSL-2. BSL-2 also has a lot less oversight.

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

One of the reasons I signed the letter to Science was that the WHO report did not actually discuss how the work in the WIV lab was done, or what data the expert panel reviewed to conclude that it was “very unlikely.” , an escape from the laboratory or an infection caused a pandemic.

There should be some recognition that laboratory contamination may have occurred under BSL-2 operating conditions. Some unknown viruses derived from guano or oral swabs can replicate or recombine with others, so you can create new strains with unique and unpredictable biological characteristics.

And if all this research is being conducted at BSL-2, then there are questions that need to be resolved. What are the standard operating procedures in BSL-2? What are the personnel training records? What is the history of potential radiation events in the laboratory, and how were they analyzed and resolved? What biosafety procedures are designed to prevent potential exposure events?