The US Has a Covid ‘Scariants’ Problem. Here’s How to Fix It

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LATE LAST YEAR, while the US was plunged into its worst days of the pandemic, new, more insidious versions of SARS-CoV-2—first identified in the United Kingdom and South Africa—silently arrived on its shores. For months now, Americans have been anxiously watching them spread. But recently, the specter of homegrown horrors have begun to steal the show.

Last week, The New York Times reported on two not-yet-peer-reviewed studies detailing a new variant that had been identified in Manhattan and was gaining ground in the city. Speaking to reporters on Tuesday about the variant, Dave Chokshi, New York City’s health commissioner, struck an ominous chord: “With the number of New Yorkers being vaccinated increasing every day, there is real reason for hope for better months ahead. But on the periphery of this growing light, there is also a shadow,” he said. This came a week after reports emerged of a deadlier and more contagious strain expanding through Southern California. Charles Chiu, the UC San Francisco infectious disease doctor who discovered it, told The Los Angeles Times “The devil is already here.” (A few outlets, including WIRED, were provided access to a manuscript describing studies conducted by Chiu and his collaborators, but it has not yet been posted publicly.)

If you were following all this news, you would not be blamed for believing that SARS-CoV-2 had mutated all the way into the antichrist. And some scientists are not happy about that—specifically, the part where impatient researchers and eager journalists pounce on any variant that seems even the slightest bit more dangerous, hyping them before careful and comprehensive studies show there’s real cause for alarm.

Eric Topol, founder and director of the Scripps Research Translational Institute, says this parade of “scariants” serves more to snag headlines and frighten the public than to further scientific understanding of the coronavirus. On Twitter this week, one of his colleagues, Scripps evolutionary biologist Kristian G. Andersen, called out news stories about the California and New York variants for “atrocious reporting and sloppy science.” Jim Musser, chair of the department of pathology and genomic medicine at Houston Methodist Hospital had his own term for this barrage of coverage: “mutant porn.”

And yes, the media bears some responsibility here. Everyone is scared of variants, so reporters are incentivized to track down the latest and scariest science, no matter how preliminary. But not every genetic change is a dangerous one. Most aren’t, in fact. And the question of how scary certain collections of mutations are can’t be answered by a single study. The proliferation of American variant news in recent weeks exposes this more fundamental problem with the US coronavirus response: a disconnect between the scientists who are out there hunting emerging variants and the ones who run the experiments necessary to know whether those never-before-seen strains actually pose a significant threat. But now, WIRED has learned, a national consortium is in the works with aims of closing that gap.

For the first nine months of the pandemic, the US had nothing resembling a national strategy for genomic surveillance. Any sequencing that did happen was patchy, under-funded, and inadequate to track where new variants were spreading. But starting in mid-December, the US Centers for Disease Control and Prevention started signing contracts and releasing funds for a rapid ramp-up in sequencing capacity. Since then, the US has gone from 3,000 viral genomes sequenced per week to more than 7,000. An infusion of $200 million from the Biden administration should soon push that number to 25,000, CDC director Rochelle Walensky told reporters last month.

This sequencing boost is helping scientists map in finer detail the mutational landscape of the coronaviruses circulating around the country. So it’s not surprising that they’re starting to turn up more surprises. But as the pace of generating genomic data has accelerated, there has not yet been a similar, concerted push forward in what’s called “variant characterization.”

Sequencing can help you identify mutations that might be problematic. But it can’t tell you if those mutations make that version of the virus behave differently than others. For that, you need to conduct studies with antibodies, living human cells, and animal models. Each type of experiment or analysis requires a unique set of skills, and there are many different methods for measuring the same things. You need immunologists, structural biologists, virologists, and a whole bunch of other -ologists, too. And, ideally, you’d want them to all adhere to the same scientific standards so you can compare one variant to the next and determine if a new strain is concerning from a public health standpoint or merely interesting

In the US, the CDC is the primary body with authority to designate any emerging strains as either of “variants of interest” or “variants of concern.” Crossing that threshold requires strong evidence that a particular constellation of mutations confers the ability to do any one of four things: spread faster and more easily, inflict more severe disease, weaken the effectiveness of Covid-19 treatments, or elude antibodies produced either from vaccination or during prior infection with an older version of the virus.

So far, the agency has only elevated three new versions of SARS-CoV-2 to the most concerning category: B.1.1.7, which was first detected in the UK, B.1.351 from South Africa, and P.1 from Brazil. (Though there’s an ongoing fight over which code-naming system to use, most scientists have agreed to steer clear of the “insert-place-name-here” nomenclature for its imprecision and stigmatizing effect. For simplicity’s sake, we’ll refer to B.1.1.7, B.1.351, and P.1 from here on out as the Big Three.)

But the agency is currently tracking additional variants of interest—including B.1.256 out of New York and B.1427/429 in California—and keeping tabs on ongoing studies to assess these strains’ ability to evade immune responses and erode the protections afforded by existing vaccines. As new data becomes available, the agency may bump up any particularly worrying variants to this top tier. “The threshold for designating a variant of interest should be relatively low in order to monitor potentially important variants,” a CDC spokesperson told WIRED via email. “However, the threshold for designating a variant of concern should be high in order to focus resources on the variants with the highest public health implications.”

The spokesperson did not provide details on what the agency considers “strong evidence,” but said the CDC has been involved with international partners including the World Health Organization in discussing criteria for variant designation.

In other words, it’s not just a matter of finding new variants, it’s a matter of characterizing their biological behavior—what does it mean for someone to get infected with one versus another? “Getting sequences is just the beginning of the story,” says Topol. “There’s much more science that has to happen to know if a mutation is meaningful. And right now, lots of labs that are publishing on this are just looking at one part of the story, because that’s the quick thing to do. But what’s quick can also be misleading.”

For example, a number of studies in recent weeks have shown that antibodies trained to attack older versions of the virus have a much harder time recognizing the B.1.351 and P.1 variants. That’s raised alarms about vaccine effectiveness. But just because antibodies don’t fight these new mutants as well in a test tube doesn’t mean your immune system will have the same problems in a real-world Final Boss Fight. The immune system is more than antibodies, and far fewer labs have the expertise necessary to conduct tests with live T cells, the other major player in developing Covid-19 immunity. These cells, which clear the virus by culling herds of infected cells, are finicky to grow outside the human body. So it’s taken a little while longer to understand how they respond to the variants. But new data suggests they respond just fine.

In a preprint study posted online Monday, scientists at the La Jolla Institute for Immunology used the genomes of the Big Three variants of concern, plus the one spreading in California, to make lots of little protein fragments of each variant. This mimics a process that infected cells use to flag down help from the immune system, in which they grab pieces of their viral occupier and send them to the surface, where T cells can spot them. Then the researchers combined those variant fragments with blood isolated from people who’d recovered from an older version of Covid—Covid Classic, if you will—and blood from people who’d been vaccinated with either the Moderna or Pfizer shot. The T cells in those people’s blood had no problem spotting any of the four variants.

“It would have been horrifying to find out that—on top of a decrease in the neutralizing capacity of antibodies—that the T cell response was also wiped out,” says Alessandro Sette, an immunologist who led the research. “So the great news is that the T cells are in fact on the job. And that means that even if you do get infected, they should be able to decrease the severity of disease.”

Even though the experiments only examined the T cell response produced by the Moderna and Pfizer shots, Sette says the results help explain some of the interesting patterns observed in clinical trials of Johnson & Johnson’s vaccine. In the US, the company reported that its vaccine prevented 72 percent of moderate to severe cases of Covid-19. In South Africa, where B.1.351 was circulating during the trial, effectiveness dropped to 64 percent. But, across both trials, not a single person who received the shot in either country was hospitalized or died of Covid-19 during the study’s 28-day post-injection follow-up. “The J&J data totally fits with what we found,” says Sette.

With B.351’s genetic changes making it harder for antibodies to recognize it, the variant may have an easier time slipping into cells and establishing an infection. More people, then, might get sick. But once cells have been infected, the T cells seem to be able to still swing into attack, orchestrating an immune defense to fend off the worst symptoms. No hospitalizations, no deaths. “It doesn’t negate the fact that these variants are concerning,” says Sette. “It’s still best not to be infected. But the great thing is that the vaccine is still 100 percent effective against death.”

T cell studies are an important part of understanding the extent to which new variants will threaten vaccination efforts. But Musser says even those are not enough. “The real power in all this genomic info is to mate it up as much as we can with information from the patient side of the equation,” he says.

You can think of it this way: If a genomic sequence sketches the outline of a variant, lab studies then start to fill in the shapes and shadows, maybe a glimmer of a fang here or the flash of a talon there. But it takes real-life data from hospital records and contact tracing to get a clear picture. Only then can you know whether you’re looking at a gargoyle or a bunny rabbit.

Since the beginning of last March, Musser has led a uniquely ambitious effort at Houston Methodist Hospital to bank and sequence samples from all of its Covid-19 patients. So far, his team has sequenced more than 20,000. Along the way, they’ve matched up any variants they found with information about how the patients infected with it have fared. Instead of having to look at experiments in cells and animals for clues about the effects of variants on things like prevalence, mortality, resistance to drugs, and potential for reinfection, he can just see what happened in real people.

Those types of analyses are currently underway, says Musser. So far, he says, one preliminary finding is that B.1.1.7 has been no more deadly in the Houston Methodist patients infected with it than those infected with other strains, contrary to recent reports out of the United Kingdom that suggest B.1.1.7 is linked to higher rates of hospitalization and death.

It will be a little while before the full results are out—but they should be really interesting. According to a study his team posted online Tuesday that has not yet been peer-reviewed, Houston is the first US city where all the major variants, including the Big Three plus those recently found in California and New York, are currently circulating.

Until then, Musser is urging scientists and reporters to just “ratchet down” the variant-mania. “It’s fine and good for people to be ‘sequence-gazing’—that can yield some important initial insights,” he says. 

There are some good reasons why scientists might want to get the word out early about new discoveries. Such data could alert test manufacturers and vaccine makers that they may need to retool their products. Public health officials can use that information to more closely monitor strains with potential to do more damage in their communities. And it could even persuade the public that it’s still too soon to abandon masks and hit the bars. In an emergency situation, it might be better to be too cautious than to miss a dangerous escape variant while it’s still containable.

“Part of the motivation to post the preprint was so that other labs could follow up with more experiments,” says Anthony West, a computational and structural biologist at Caltech, who built a genome-scanning software tool that identified the new variant of interest in New York. Between Covid-19 capacity restrictions and other research commitments, the lab he works in wasn’t going to be able to make studying the new variant a priority. West also alerted New York City and state public health officials in early February, prior to posting a preprint describing what his team had found. Researchers at Columbia University also independently discovered the variant by sequencing samples from patients at their medical center. (The authors of that second study, as well as Chiu of UC San Francisco, did not respond to WIRED’s requests for interviews.)

Still, in the race to understand an evolving enemy, Musser worries scientists are flooding the field with incomplete intelligence and bogging down the whole endeavor. “Without having the entire context behind a viral genome, we’re not going to be able to adequately move the needle,” he says.

He’s not the only one who’s worried about that.

“Right now, while we’re in an emergency, it would be helpful to have a coordinating body that could make sure any variant that’s popping up is being characterized in a standardized and timely way,” says Lane Warmbrod, a senior analyst at the Johns Hopkins Center for Health Security and coauthor of a new report that reads like a policy roadmap for how to stay ahead of variants. In it, she and her colleagues argue that the US needs to establish a risk assessment framework for SARS-CoV-2, like the one the CDC began developing in 2010 to help scientists swiftly and systematically evaluate new influenza variants for pandemic potential.

For SARS-CoV-2, the first priority, says Warmbrod, should be to look for any enhancements in transmissibility. Does a new variant spread faster or more easily? Next would be trying to understand if it kills more frequently, eludes immune system responses, or resists antiviral treatments. A central coordinating agency could not only set standards for what kinds of experiments should be run to answer those kinds of questions, but it could also manage resources and delegate the study of each variant to different labs so that nothing slips through the cracks. “Nothing like that is happening now,” she says.

But it could be—very soon.

Topol and Andersen of Scripps have been working with the Rockefeller Foundation in New York to organize a national network of public, academic, and industry labs tasked with coordinating genomic surveillance and research into how new variants spread, evade drugs and immune cells, and make people sick. On February 16, the Rockefeller Foundation convened a virtual meeting of potential participants, including academic researchers and representatives from the Association of Public Health Laboratories, Illumina, LabCorp, the National Institutes of Health, and the CDC.

The idea, says Topol, is to link up a handful of regional sequencing centers that are already deeply involved in decoding coronavirus genomes with the research labs best-equipped to run those kinds of experiments. In essence, it will create what Topol calls an “immunologic phenotyping corps.” He says he expects plans for the consortium to go public in a matter of days.

A spokesperson for the Rockefeller Foundation declined to provide specifics, but did confirm that an announcement about the foundation’s work toward improving the US’s genomic surveillance systems will be made on Monday. In October, Rockefeller pledged a billion dollars over three years to address the Covid-19 crisis and its aftermath, including investing in pandemic preparedness.

Topol is hoping that at some point in the near future, the CDC and NIH will both get on board. With $200 million in dedicated genomic surveillance funds from the Biden administration, the CDC could be a powerful partner. (A spokesperson from the CDC declined to comment.) “I’m optimistic that with that funding we’re going to see better genomic surveillance. But we can’t just run with that. We have to get these immunotyping assays in high gear,” says Topol. “Otherwise we’re just going to have a lot of interesting sequences and not know what to do with them.”

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