Was NIH-funded work on MERS virus in China too risky? Science examines the controversy

Questions related to the frustrating search for the origin of the COVID-19 pandemic keep creating commotion. Last week, the U.S. National Institutes of Health (NIH) placed one of its grantees, and itself, in the hot seat when it told Congress in a letter that the EcoHealth Alliance in New York City had failed to promptly report potentially worrisome results from a virology experiment done by a collaborator in China. In a progress report for one of its grants, EcoHealth had mentioned an altered bat coronavirus made mice sicker than expected, a discovery it should have notified the agency of immediately, NIH asserted in a letter to Congress.

EcoHealth, which has directed some of its NIH money to researchers at the Wuhan Institute of Virology (WIV), was already under attack. Some scientists, politicians, and journalists espouse the idea that the ongoing pandemic was likely sparked by a virus that escaped from WIV.

There is no concrete evidence for that. But to detractors of NIH and EcoHealth, the letter and the progress report show NIH supported what’s often called gain-of-function (GOF) virus research in China, the type of studies that can make pathogens more dangerous to humans and that some think may have spawned SARS-CoV-2. (“In Major Shift, NIH Admits Funding Risky Virus Research in Wuhan,” Vanity Fair declared, for example.)

NIH has consistently denied that it has funded risky GOF research in China, and still does. EcoHealth’s work didn’t meet the bar, the agency says, because the more pathogenic bat coronavirus was created from one not known to infect humans. Still, NIH demanded that EcoHealth provide by this week any unpublished data beyond its last progress report, which covered year five of the grant.

Peter Daszak, EcoHealth’s founder and president, tells ScienceInsider the group has submitted a response and defends its efforts as transparent and legitimate. Echoing what an EcoHealth spokesperson said last week, Daszak also challenges NIH’s claim that EcoHealth has violated any grant conditions with the mouse results, saying it notified them of the data and NIH failed to request follow-up action. “This is spelled out in detail in a letter we sent to NIH yesterday, with detailed documentary evidence, strongly refuting that we were out of compliance with our reporting requirements,” he wrote to ScienceInsider today.

But to some scientists, another part of EcoHealth’s year five grant progress report was also troubling: results from studies that manipulated a different coronavirus, the one that causes Middle East respiratory syndrome (MERS). That virus, MERS-CoV, which originated in bats before spreading to camels and then people, is lethal in roughly 35% of diagnosed human cases.

Concerns about risky studies with MERS-CoV, SARS-CoV—the virus that caused the 2003 severe acute respiratory syndrome (SARS) outbreak—and H5N1 avian influenza led to a 2017 U.S. policy requiring a special review to weigh potential benefits and risks for certain work with specific pathogens. Some virologists and biosecurity experts say EcoHealth’s studies with MERS-CoV should have warranted that type of review, and expressed dismay that EcoHealth backed such work in China.

But NIH says EcoHealth’s MERS-CoV experiments didn’t fit the Department of Health and Human Services’s (HHS’s) definition of research requiring special review because “the research was not reasonably anticipated to result in an ePPP,” or an enhanced pathogen of pandemic potential. (NIH has recently asked media to avoid the term “gain of function,” saying it is confusing for the public—it even scrubbed the term from a web page URL and header in favor of ePPP last week, a move that was quickly spotted.)

The letter has reignited the debate about the benefits and risks of engineering pathogens that could spark a pandemic. A recent draft directive from a Senate appropriations committee may force NIH and the virology community to revisit that contentious topic in depth.

Here’s a closer look at the issues, including Daszak’s defense of EcoHealth’s work with MERS-CoV.

Q: What experiments were done with the MERS virus and why?

A: EcoHealth and WIV researchers had collected novel bat viruses dubbed HKU4 in several provinces in southern China, found they were closely related to the MERS virus, and wanted to study their ability to transmit and cause disease in other species, to see whether they posed a pandemic risk. Some of their work focused on the spike surface protein that coronaviruses use to infect cells, specifically a portion called the receptor-binding domain (RBD).

Researchers frequently can genetically sequence coronaviruses found when sampling bats in the wild, but they rarely can grow those viruses in culture. So they create chimeric viruses with ones that do grow in culture, which in this case was MERS-CoV.

Specifically, the scientists isolated the genetic code for the RBD from various HKU4 strains and swapped it into the genetic “backbone” of the MERS virus, a June 2018–May 2019 progress report states. The researchers showed these chimeric viruses could infect human tissues, and that they replicated well in cells that had a receptor named DPP4 that MERS-CoV uses to enter human cells. “The results suggest potential risk of the bat HKU4r-CoVs for cross-species infection in humans,” the report concludes.

Q: Are such studies justified and necessary?

A: That’s where scientists disagree. To put RBDs from some of the novel HKU4 viruses into MERS-CoV, already a lethal human pathogen, is “sort of crazy” and “unjustified,” says University of Montana, Missoula, virologist Jack Nunberg.

Tulane University virologist Robert Garry has a more charitable take. “They are trying to determine if the HKU4 viruses have pathogenic potential,” or whether these viruses could jump to humans if they acquire certain mutations, he says. “That’s legitimate.” Another lab that has collaborated with WIV, Ralph Baric’s group at the University of North Carolina, Chapel Hill, has done similar, albeit controversial chimeric virus studies with SARS-CoV, the virus that caused the global SARS outbreak of 2003. “I don’t think [this Wuhan work] is that different,” says virologist Stephen Goldstein, a postdoc at the University of Utah.

Another reason to modify MERS-CoV and SARS-CoV is to be able to infect mice with these viruses, which makes other types of studies possible, Goldstein notes. For example, Baric has developed a mouse model to test drugs and vaccines against viruses related to MERS-CoV.

Yet the EcoHealth studies may not have been necessary because Baric’s lab had already done studies with HKU4 “pseudoviruses,” which are designed to bind and enter cells but can’t replicate, Garry says. Virologist Stanley Perlman of the University of Iowa says he’s not convinced the chimeric viruses tell scientists anything more about pathogenicity than pseudoviruses. “I think that this is not the best way to answer the question,” Perlman says.

But Daszak argues that the chimeric viruses added crucial information beyond infectivity. “Pseudoviruses will demonstrate capacity to bind cells, recombinant viruses allow measures of things like viral genome copy per gram–clues as to the potential importance of these viruses for public health,” he wrote in an email to ScienceInsider.

Q: The MERS-CoV studies are modifying a dangerous human virus. So why didn’t the work qualify as ePPP (or GOF, the term NIH now wants to abandon), which would have triggered an extra layer of review?

A: NIH says the work did not qualify as ePPP because the researchers did not anticipate that the modified MERS viruses would be more infectious to people than the original virus. Virologist Michael Imperiale of the University of Michigan, Ann Arbor, says that makes sense. “MERS-CoV already infects humans,” he says; if the same virus but with a bit of bat virus RNA stitched in does the same, that isn’t GOF research, Imperiale says.

Garry does not see a problem either. “The odds of combining any random bat virus with MERS-CoV and getting a more pathogenic virus than MERS-CoV is vanishingly small,” he says. And it did not happen: In the EcoHealth-backed cell experiments, one chimeric virus replicated equally as well as MERS-CoV in cells expressing DPP4, and three others did not grow as well.

Q: Why did EcoHealth deny it was doing MERS-CoV studies?

A: EcoHealth did not keep the MERS-CoV studies secret from NIH. It included the MERS-CoV plans in its 2014 grant proposal that NIH approved, and also noted the intended studies in its fourth year progress report. Yet The Intercept, which recently obtained these documents with a public records lawsuit, reported that in September, EcoHealth spokesperson Robert Kessler had said the group did not conduct the MERS-CoV studies described in the grant proposal.

Daszak calls that a straightforward “mistake,” adding: “The actual permission for us to do this work was requested in a letter to NIH at the end of year 3 of the grant. NIH allowed the work to move forwards. Robert Kessler didn’t have access to that letter at the time – he’s a spokesperson, not a scientist.”

Daszak also told ScienceInsider the MERS-CoV chimeric studies were conducted in WIV’s biosafety level-3 labs, the same level of biosafety required in the United States for such research.

Q: What will happen next?

A: Daszak told ScienceInsider that EcoHealth submitted a response on 26 October. The last progress report, dated in August but covering work in 2018–19, noted plans to test MERS-CoV chimeric viruses in live mice, so there may be some data on that in EcoHealth’s response.

The debate over the MERS virus experiments may give more impetus to revisiting the HHS policy on potentially risky pathogen research. A Senate report accompanying a bill funding NIH’s 2022 budget calls for such a review by the National Science Advisory Board for Biosecurity (NSABB), a panel of outside advisers that helped develop the current policy. NSABB last met in late January 2020 to discuss whether federal decisions about ePPP research should be more transparent—just as COVID-19 had begun its global spread.

The Senate demand will have to survive the budget reconciliation process, which may not be done until the end of the year. NIH Director Francis Collins and Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told The Wall Street Journal in September that they’re open to reviewing the policies.

–with reporting by Jon Cohen

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