Could a souped-up version of existing Covid-19 tests be our shortcut to tracking variants?

San Diego PCR
Nancy Pu, a senior scientist in a lab that is focused on fighting Covid-19, sets up a polymerase chain reaction, or PCR, at Sorrento Therapeutics in San Diego, Calif. Standard Covid-19 testing involves the PCR technique, which searches for a few characteristic genes in a given sample. ARIANA DREHSLER/AFP VIA GETTY IMAGES

Genomic sequencing is one of the best defenses against potentially deadlier or more transmissible variants of the coronavirus. It’s also expensive, slow, and currently almost nonexistent in the United States.

So some epidemiologists are advocating for an easier, cheaper, and faster way to help track variants’ paths through the country: a souped-up version of widely available Covid-19 diagnostic tests that can flag samples with any problematic genetic tweaks.

The idea is to complement — not to replace — the U.S.’s slow-growing genomic sequencing capacity, since sequencing remains the gold-standard for virus surveillance. In Europe, the U.K. and Denmark already use these tests as part of their national virus-tracking systems. Several diagnostic testing companies, including Bio-RadAgena and Roche, have also developed their own variant-specific screens in recent months.

“The reality is there are places that are just not set up for sequencing,” said Chantal Vogels, an epidemiologist at the Yale School of Public Health. “These assays can give a preliminary answer to ‘What variants are out there?’”

But some public health authorities are skeptical about the widespread adoption of a new surveillance technique during the pandemic’s final stages — especially if they’ve already worked to ramp up sequencing, said Kelly Wroblewski, director of infectious disease at the Association of Public Health Laboratories. “Sometimes you sort of have to pick a direction,” she said. “A majority of labs that have explored or entertained the idea have decided not to pursue it.”

Right now, even after concerted efforts to increase sequencing capacity, only about 3% of the country’s positive Covid-19 samples were sequenced in early April. That’s not just “unacceptable,” but “nearly worthless,” said Sam Scarpino, a bioinformatics assistant professor at Northeastern University and director of the school’s Emergent Epidemics Lab.

Especially, Scarpino added, considering the geographic bias plaguing national genomic sequencing. In the last 30 days or so, samples from four states alone — New York, California, Florida and Washington — represented about 30% of the country’s sequences, according to data from the United States Mutation Report.

When it comes to tracking variants, Scarpino said, “We’re largely in the dark.”

In part, the lag is a testament to the demands and complexity of establishing a robust nationwide genomic surveillance program. Genome sequencing involves reading and analyzing the 29,727 nucleotides in SARS-CoV-2’s genetic code. It can take days, and requires highly specialized equipment and trained specialists.

A year ago, many public health labs were not equipped to conduct such fine-grain genetic analyses. Today, hitting the benchmark of sequencing 5% of all positive Covid-19 samples (in a representative fashion) remains a lofty goal, some say. “There’s no way we have the resources or time,” said Mara Aspinall, an expert in biomedical diagnostics at Arizona State University.

On the other hand, the testing we use to diagnose someone with Covid-19 is far simpler and more ubiquitous. Standard Covid-19 testing involves a technique called polymerase chain reaction (PCR), which searches for a few characteristic genes in a given sample.

The proposed strategy of using targeted PCR testing for surveillance involves tweaking those diagnostic tests so they also look for genes that are specific to known variants. A B.1.1.7-specific PCR test, for example, would answer two questions: Does this person have SARS-CoV-2? And do they seem to have the B.1.1.7 strain? “There would be a lot of advantages,” said Duke University professor of medicine Thomas Denny.

To start, many public health laboratories are already equipped with the technology to run and read PCR tests, which would make the strategy simple to implement.

“It really is not difficult. It’s actually shockingly simple,” said Alan Wells, medical director for the University of Pittsburgh Medical Center Clinical Laboratories.

It’s also faster than sequencing — a matter of hours compared to a matter of days — making it a “more realistic” technique for many labs, said Vogels, who earlier this year co-authored a preprint laying out one possible design for variant-specific PCR assays. “With sequencing we’re about two weeks delayed. With PCR we’re two weeks early,” she said.

Proponents have suggested pairing the two technologies to have a double-layered surveillance grid: always-on, widespread PCR testing combined with complex, more targeted genomic sequencing. That way, we could account for variants while auditing them, too.

“We need both: We need to detect and we need to monitor,” Scarpino said. “Ideally, those two systems are coupled.”

In December, for example, Nevada’s sequencing wasn’t as fast as Mark Pandori, director of the state’s public health laboratory, would have liked. So he and his colleagues developed a PCR assay “as a screening test” that was specific to B.1.1.7 in order to keep a more timely eye on the variant. “If you just wanted to do a sweep,” Pandori said, “you could test a lot of specimens very quickly.”

Using targeted PCR-based testing, National Jewish Health in Denver has monitored as B.1.1.7 went from representing 19% of positive Covid-19 samples three weeks ago, to 35 percent two weeks ago, then to 73% last week.

“We can see that shift, and we can start to understand how, locally, things are changing,” said Reeti Khare, NJH’s infectious disease laboratory director. The hospital has also helped Wyoming health departments use augmented PCR as an initial screen for mutated forms of the virus. “It’s quick and that’s great for tracking variants in relatively real-time,” she said. “We feel like it’s definitely worth it.”

The strategy is not without its drawbacks.

Unlike sequencing — which allows scientists to read the virus’s genetic code in great detail and identify new, concerning mutations — PCR testing can only answer yes or no questions about the presence or absence of a specific, known mutation. In other words: It can only find what it’s asked to look for.

“We’re just looking for mutations we know about,” Khare said.

A new addition to the test would need to be developed every time there’s a new variant experts want to flag with PCR. “It’s going to be a constant whack-a-mole,” APHL’s Wroblewski said. Whether that’s a game worth playing will be up to individual local and state health authorities, she said.

Meanwhile, with the Covid-19 vaccine rollout in a race against rising cases, B.1.1.7 (which is known to be more transmissible and deadly) has grown from 3% of all sequences analyzed in the U.S. in January to more than 44% in late March, according to the CDC.

Pandori said Nevada is currently considering developing and deploying PCR screening for the two other strains of concern — B.1.351 and P.1 — that are, for now, much less widespread. “Those are scary variants and they exist in relatively low frequency,” he said. “You still have an opportunity there to cast a wide net. We see the value in it. I get the sense others might not recognize that.”

Scarpino said he worries that down the road, we could really need a PCR screening safety net if by the fall respiratory season we’re not close to herd immunity. “Then the tool we have to hold our lives together is high-resolution surveillance that allows us to respond quickly,” he said, by surging vaccines to any variant hotspots detected by PCR. “We need to be prepared for that scenario.”

After a year of public health chasing SARS-CoV-2’s considerable lead, some say this strategy could allow us to be just one step behind the virus. “If it’s easily implementable and you have the tools available, why not use it?” Vogels said. “It only helps to be prepared for what’s coming.”

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