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-Rad, Agena 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.”
To the title of this excellent, thorough article “Could a souped-up version of existing Covid-19 tests be our shortcut to tracking variants?” : the answer is yes, yes, yes, and yes. And the US needs to hop on this asap and thoroughly – we are very embarassingly and inadequately much behind Europe and Asia !
The article brings to mind a question – we have a lot of variants and may get more – in terms of our immediate problem fighting the epidemic, in a sense we do not care what the variants look like – we just want to know if they escape the immune systems of people who were sick before, or were vaccinated.
Can we do that without any new types of testing, just by comparing new infections, old infections, and vaccination rates? I realize controlling for all variables in an outbreak may be difficult, but mask use is observable, social distancing is partly observable, shutdowns are a matter of record, etc, etc.
We need to know if/when variant driven outbreaks occur, and we need to know before things get really bad, and the article makes it sound like that will not happen as things now stand.
I thought this article did a great job of addressing the testing issues and the advantages provided by tests with speedy results in identifying the variants. The beauty of the approach is that, if not identified by the existing tests, there is a new variant to define, the requirement to develop a new test for it, and track it and the impact of the alternative vaccines and treatments. I can’t conceive of a failure to adopt the approach, but there are always buy-in and cost issues.
I can barely grasp 5% of the material in the text. I’m not a biology expert by any means and its frustrating wrestling with such an important subject as virus variants. Maybe the authors are being more technical than needed and missing a large part of their audience.
I am very worried about some of the variants. P1 and B1351 might evade vaccines we use. This could be a disaster. It is unclear if we will have large quantities of vaccines made specifically for the dangerous variants before we get an outbreak from them.
But it sounds like we will not. Moderna says they will likely have another mRNA vaccine tweaked to stop the current variants of concern – “before the end of the year” It seems pretty likely we could have a big outbreak before then. It all depends on if the current vaccines work, and from what I see, that is not proven.
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