Looming unknowns with SARS-CoV-2 variants

Karen Titus

March 2021—Listening to experts and others make predictions about the pandemic, it’s easy to think they’re obsessed with surfing: How will we deal with the next wave?

The dangers are real. With SARS-CoV-2, the next wave might be swept in by emerging variants, with their uncertain but worrisome impact on transmission, severity of illness, treatments, and vaccine effectiveness. Laboratories are looking to approach these variants of concern in ways that will leave them feeling neither blinkered nor bludgeoned, as happened all too often in the past year.

There’s cause for hope, say those who’ve been doing genomic sequencing or are organizing efforts not only in their own labs, but on the state and regional level as well. Federal funds are beginning to flow; the CDC is, so to speak, back.

Nevertheless, the conversations are regularly punctuated by “Who knows?” and “No one knows.” (Also: “Who’s going to pay for this?”) One year after SARS-CoV-2 tore loose, labs are, in a sense, at a new starting line. They’re racing against a whole new set of concerns, all of them set against a sorrowful marker, as the number of U.S. deaths from COVID-19 surpassed 500,000 in late February.

Meanwhile, new unknowns keep washing ashore. “I guess it’s not really a surprise,” says Eric Konnick, MD, associate director, genetics and solid tumor laboratory, and director, genetics preanalytical services, Department of Laboratory Medicine and Pathology, University of Washington (where he’s also assistant professor). “We did expect variation to happen,” as it will with any RNA virus. “But we thought there were some biological aspects of this virus that would make it less likely to mutate in large ‘jumps,’ if you will.”

The real surprise, he continues, is that some of the variants have a cluster of different alterations, not just a single mutation, that seem to impact the biology of a particular strain. Also somewhat surprising, he says, is that these variants emerged in very specific populations and spread very quickly.

Says Dr. Konnick: “Who knows what the next year is going to look like? We’ve shifted from getting closer to the capacity we need for routine testing, at least in the United States. But now we have this whole different problem, that is quite a different scale.”

“The question is, are the curves going to change for the worse because of the variants?” asks James Crawford, MD, PhD, professor and chair, Department of Pathology and Laboratory Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and senior vice president of laboratory services, Northwell Health. “No one knows.”

In the meantime, labs are trying to prepare.

The need for sequencing seems obvious. Identify variants and stop outbreaks in their tracks. Keep new strains from outpacing the rate of vaccinations. Don’t let year two of the pandemic turn into a high-stakes chase.

For the laboratory community, however, the matter is more nuanced.

Just as form follows function, purpose precedes probes. Public health surveillance and monitoring is a different “ask” than clinically reporting, says Dr. Konnick, who is a member of the recently formed AMP COVID response steering committee.

“You can’t just pour buckets of money on the problem,” says Dr. Konnick (though money does help). “It’s multifactorial. You need to make sure you have everything in place.”

But in place to do what, exactly? Dr. Crawford says he asks the question every time he meets with medical colleagues, public health officials, and government leaders: What is the goal? It is, he says, an intense discussion.

Is it to do surveillance for public health purposes? Variants aren’t stopping at the border. B.1.1.7 (the so-called U.K. variant), B.1.351 (originally identified in South Africa), and P.1 (first linked to travelers from Brazil) are being identified across the United States. Yet another new variant (B.1.427/B.1.429) appeared to be surging in San Francisco and Southern California in late February, while B.1.526 seemed to be infiltrating New York City. Because so little sequencing has been done in the United States, it’s hard to know the true prevalence of variants or what else might be out there. States that aren’t reporting the appearance of variants of concern may truly be unaffected, or they may lack the resources to identify them.

Or is the goal to do sequencing in a CLIA-certified lab, with short turnaround times, to manage patient care? Right now, variants don’t determine treatment. But that could change. There’s also the matter of whether variants can affect the performance of diagnostic assays.

Another question sounds like fodder for a medical thriller—Can vaccines outrace the mutating virus?—though that dramatic query has a basis in reality. Some variants could elude vaccines, and if they become widespread, the vaccines in general will become less effective. “So it’s important to continue to do surveillance,” says Frederick Nolte, PhD, vice chair of laboratory medicine and director of the molecular pathology laboratory, Medical University of South Carolina, where he’s also professor of pathology and laboratory medicine.

As the questions pile up, the lab community continues to try to help the country test its way out of the pandemic—first diagnostically and now genomically. Every step feels like exiting a Victorian sitting room—from day to day, season to season, and now one year to the next, labs find themselves bumping up against any number of obstacles.

When he first started hearing about emerging variants, Dr. Nolte recalls, “It was, ‘Oh, this is interesting, but I don’t have to worry about it because it’s public health.’”

As the new year gained steam, so did the variants, and curiosity gave way to concern. Some appeared to be gaining a toehold, and reports of new variants have surfaced with unnerving regularity, like a Tom Brady Super Bowl appearance. Public health labs were, once again, under pressure to perform tests. “So maybe there are some reasons to be worried,” says Dr. Nolte, given the potential impact on patient care. (South Carolina, he notes, had the dubious distinction of being the first state to report the presence of B.1.351, in late January.)

The B.1.1.7 variant has had some impact on the diagnostic tests, Dr. Nolte notes, particularly those that included a spike protein target. “So one good reason for keeping an eye on the variants is to make sure our diagnostic tests don’t suffer from what I term ‘genotype bias,’” he says.

For labs, this is somewhat of an above-my-pay-grade issue. “We’re dependent on the manufacturers to help us with that,” says Dr. Nolte, who chairs the AMP steering committee. While labs might know the gene regions targeted by the molecular diagnostic test, the primer and probe information is typically proprietary. Most manufacturers appear to be doing their due diligence, he says.

Dr. Crawford reports hearing from two vendors that the platforms his lab uses detect both the P.1 and B.1.351 strains. “So from a PCR detection standpoint, it does not seem to be an issue.” He pauses. “At this time.”

Another pause. “But—we’ll pay attention.”

“I wish I had a crystal ball,” Dr. Nolte says, naming the one item that no one has successfully sourced this pandemic. “It seems like things are getting better in the U.S.,” he says, speaking in mid-February. “The sky isn’t falling, and the variants probably aren’t going to ruin all of our plans to vaccinate people.

“But who knows?”

The line separating public health and clinical care, never sharp to begin with, has only gotten blurrier in the pandemic. Public health labs have been performing sequencing, but as Dr. Nolte points out, each lab is basically an independent player, with disparate levels of funding and staffing. The CDC has contracted with LabCorp, Quest, and Illumina to perform sequencing of positive samples sent by state public health departments, but funneling testing through public health labs will still result in an uneven picture of which variants are emerging and where. That’s yet another reason clinical laboratories are entering the fray.

Or, in the case of Dr. Konnick’s lab, staying in the fray.

Washington was a first responder of sorts, identifying the first U.S. case of COVID-19 in January 2020. The UW clinical lab oversees clinical testing for the region, which includes screening samples that will be sequenced and reported to the state department of health. A separate UW program for testing and sequencing of community-collected samples as part of a public health initiative called the Seattle Coronavirus Assessment Network, or SCAN, is also contributing to the regional efforts. (Early on, this group used respiratory samples from the Seattle Flu Study to create a SARS-CoV-2 diagnostic assay.)

SCAN has worked closely with Trevor Bedford, PhD, at the Fred Hutchinson Cancer Research Center, to do SARS-CoV-2 sequencing almost from the start. Last spring, when UW sent its EUA applications for diagnostic tests, “All of the samples SCAN submitted to the FDA as our positives had whole genome sequencing at that point. So we’ve been ahead of things,” Dr. Konnick says.

Early sequencing efforts showed particular strains of the virus dying out, as patients who had tested positive quarantined and kept it from spreading. That’s not the case now, however; some observers have predicted B.1.1.7 will become responsible for the majority of new infections in the United States by April.

New York generated its own heavy headlines last spring. Dr. Crawford and others are drawing on those hard experiences to figure out a thoughtful approach to sequencing.

He asks the question writ large: What does the lab community need to be doing?

One answer is, apparently, hop on Zoom.

Like everyone else pushing through the pandemic, Dr. Crawford is in meetings all the time. He’s in regular conversation with colleagues in the New York State SARS-CoV-2 Testing Consortium (he’s the moderator and secretary), a group formed last spring by laboratory leaders from 12 academic medical institutions in the region. He’s also involved with the recently formed New York City Coronavirus Genome Collaborative.

Talking has led to surprisingly quick actions.

Both groups met Feb. 2. The following day, the New York City Department of Health and Mental Hygiene issued a request for applications from regional institutions to provide information on sequencing capacity and platforms—Northwell submitted an application, he says—while the city was charged with developing mechanisms for weekly, aggregate reporting of sequencing data for the city.

Consortium members have been asking three key questions as they ponder their role, Dr. Crawford says:

• What is going to be done differently if sequencing data become more widely available?
• Will such data change clinical management?
• How can labs meet sequencing needs in the region?

Even though he had no answers as of mid-February, Dr. Crawford expects matters to change speedily—in a matter of weeks, not months. “This is evolving rapidly. This story, even at the regional level, let alone the national level, is going to be unfolding quickly,” Dr. Crawford says, adding, “How it all lands remains to be seen.”

These questions aren’t New York-specific, nor are Dr. Crawford and colleagues alone in asking them. “I’m sure there are many, many, many other conversations occurring between the state and laboratories, and obviously the city and laboratories.”

Dr. Crawford urges labs to create a regional collaborative—“even just to talk to one another and share your experiences”—as sequencing ramps up. If last year was an every-lab-for-itself competition, this year is more akin to joining a kibbutz. “Work together for advocacy and communication,” Dr. Crawford says. “Learn from one another. Be a part of that regional discussion with civic authorities, departments of health especially. It’s critically important to open those lines of communication.”

Case in point: Last April, the consortium had a sought-after conversation with the state’s commissioner of public health, Howard Zucker, MD, JD, seeking guidance on diagnostic testing for the region. Dr. Zucker assigned the Greater New York Hospital Association to act as convening authority for academic labs in the state; it was joined by the Healthcare Association of New York State. By working closely with those two regional groups, labs have been closely aligned with the New York State Department of Health and the governor’s office throughout the pandemic.

“It’s a wide-open sharing of ideas, [and] challenges, and the ability to get feedback from the state, and to know our deliberations were helping inform state policy,” Dr. Crawford says. “That was in the heat of the first part of the pandemic, and we’re not done with it. Having that communication with civic leadership has certainly been beneficial to the New York region.”

Could the New York network of labs provide adequate capacity for sequencing? “If I do my own back-of-the-envelope arithmetic for how much capacity is available for the New York region,” Dr. Crawford says, “we could hit 20 percent of positives. But can we harness that? And if so, how? And under what leadership?”

The questions don’t stop there, Dr. Crawford says. “What is enough? What is success? What should you be shooting for?”

As Dr. Crawford well knows, no lab is an island (even one, like his, that’s located on Long Island). Figuring out the logistics of sequencing is a national effort.

One island—Great Britain—has been managing well, by most accounts, having launched (and funded) a national sequencing program in March 2020. “But we’re a bigger island,” Dr. Nolte laughs.