200,000 and counting: how the UK has sequenced so many cases of coronavirus

In early March 2020, with the number of new COVID-19 cases in the UK at less than 100 per day, microbiologist Sharon Peacock and her colleagues across the UK started assembling a plan for a UK-wide effort to sequence samples from people infected with SARS-CoV-2. The goal was to follow any movement of and changes in the virus that could cause concern for public health officials. After multiple calls, emails, and meetings, the team delivered its proposal to UK government advisers March 15. By April 1, the project had been funded to the tune of £20 million ($27 million).

“Genomic sequencing will help us understand COVID-19 and its spread. It can also help guide treatments in the future and see the impact of interventions,” Patrick Vallance, the UK government’s chief scientific adviser, said when the COVID-19 Genomics UK (COG-UK) Consortium was unveiled on Mar. 23. By then, the first members of the consortium, which includes testing centers, hospitals, and academic labs, were up and running and had already sequenced 260 SARS-CoV-2 genomes.

At the time, some people doubted that the work would have much impact, Peacock, the executive director of COG-UK, recalls. Critics argued that the virus would mutate too slowly for the consortium to find anything interesting in the data. That was a risk, Peacock concedes. But she reasoned that even if the primary outcome of the project was lots of similar viral sequences, it would still have value. In fact, the team ended up collecting loads of data: by the end of January 2021, it had sequenced more than 200,000 samples and identified worrying mutations in key parts of the virus. The consortium has influenced public health policy in the UK and made critical contributions to the world’s understanding of the virus. “I think that what we didn’t reckon on is the fact that by now there’d be 100 million cases,” she says, referring to the global total and noting that it’s probably underestimated.

The group’s most high-profile discovery came in late 2020, when something odd had begun to happen with the number of COVID-19 cases in the UK. While numbers across most of the country were trending down, they continued to rise in London and the Southeast, despite severe restrictions on people’s movements. By the end of November, it had become clear that a surge in cases was associated with one particular strain of SARS-CoV-2, dubbed B.1.1.7. By December scientists realized that it caused the virus to become 30–50% more contagious, most likely because 8 of the 23 mutations it featured were in the code for the spike protein, which the virus uses to slip inside human cells. With a health system already under pressure and the threat of the new strain and how quickly it could spread, the UK government declared a strict national lockdown on Jan. 4, 2021.

Viruses are always going to mutate. But you don’t know how they’re mutating unless you’re looking for it, and that’s exactly what the UK’s sequencing efforts make possible. Members of the consortium check the viral sequences for any concerning features, but Peacock says that at first B.1.1.7 did not leap out as a problem. At the time, it was just one strain of many.

The consortium has been sequencing around 10,000 COVID-19 cases a week; before the November surge, that equated to around 10% of all identified COVID-19 cases in the UK. That level of coverage meant that although they only sequence a random sample of cases, the team could spot a cluster of similar genomes that correlated with the growing case numbers. Once they realized this cluster was part of a new strain of the SARS-CoV-2 virus, they could work backward to pinpoint where it originated. It was only in retrospect, Peacock says, “that we realized we sequenced it first on the 20th of September.” Having the ability to track the spread, she adds, was part of the plan.

“It was always a kind of a long-term passion that I wanted to see genomic sequencing used for public health purposes and integrated into how we thought and acted,” Peacock explains. She recalls putting together a proposal in 2013 for routine sequencing of tuberculosis to monitor antimicrobial resistance. A service to do that was launched in 2017. So when SARS-CoV-2 emerged, thinking about sequencing was already in Peacock’s DNA, she says.

“Each time the virus infects somebody, it has an opportunity to make a mistake,” Peacock says. It’s like typing out the same passage of text over and over again. Sometimes you accidentally hit the wrong letter on your keyboard or miss a few words. The same goes for the machinery producing the viral genome. Not all typos will change the virus’s properties, but, like a game of telephone, some will get passed on to the next infection and then the next. By following the typos, or mutations, researchers can watch how the virus is moving through communities.

But tracking an entire population requires running many tests, and they need to be done quickly, Peacock says. When a patient is tested for SARS-CoV-2 in the UK, the sample is sent to a National Health Service diagnostics lab or one of the country’s Lighthouse Laboratories, which run large numbers of the diagnostic polymerase chain reaction tests at the same time. A fraction of all UK positive samples are sent for full sequencing by one of the consortium’s 16 regional sequencing partners or by the Wellcome Sanger Institute, near Cambridge.

The challenge is less the sequencing itself than the logistics, according to Peacock. Among the questions they consortium has faced: How to manage the samples to make sure there is a representative sampling of the population? And how to manage the data flow to protect patient privacy while also sharing important information for public health investigations?

Peacock stresses that data sharing is highly regulated. “The data that we release publicly is not identifiable, other than the place that it was sequenced in,” she says.

The efforts Peacock oversees have become a model for vigilance in the pandemic. As new variants start to appear and spread, many other countries are now increasing their sequencing of coronavirus cases. The US has so far sequenced only a fraction of its cases, and while the Biden administration has pledged to boost those efforts, the current coverage is patchy and fragmented.

When looking for new variants, Peacock says, “it’s like walking a tightrope” between noticing an association with a new variant and an increase in numbers, finding a causal link, and weighing when to act on that information. After all, she says, there is no point in sequencing the data if it doesn’t inform decisions about public health.

There are practical requirements: equipment, analytical tools, the scientists to manage it all, and funding to pay for it. But Peacock also points to a “human story” behind the UK’s success. Science can be competitive, but the 600 scientists involved in the consortium cooperate and collaborate, she says. Other countries do not have to copy the nationalized COG-UK model, she says. Regional or state-based models could also work, but they must cover the whole population, and neighboring programs need to work together and share their data. “You have to be completely generous and give everything away,” she says.

As for what’s next, the consortium is continuing to sequence samples every week, tracking any new sequences that move through the population. While the B.1.1.7 variant that her team identified is more transmissible and has led to a worrying surge in cases, Peacock is more concerned about the strains that resist the antibodies we make from previous infection or vaccination. There is still more to learn about which mutations in the genome are significant, she says, and it’s likely that new mutations will arise over time in B.1.1.7. For example, her team has recently found a new mutation in a handful of cases of the B.1.1.7 variant. Named E484K, the mutation swaps a lysine for a glutamic acid at position 484 in the spike protein.

Another variant of concern, B.1.351, first identified in South Africa, also has the E484K mutation; public health officials are troubled by its possible implications for vaccine development. Last week, Novavax said data from a late-stage trial of its COVID-19 vaccine show that it is less effective against this variant. “I think that we will have a very proactive approach at detecting cases and detecting context of cases in this country for the variant first detected in South Africa,” Peacock says.

COG-UK recently received an extra £12.2M in government funds, and Peacock says the consortium is increasing the number of sequences members perform. The team wants to process at least 20,000 samples a week, with a stretch goal of managing 30,000 a week. As the number of cases in the UK decreases because of vaccinations and other public health measures, “there’s going to be an increasing focus on controlling a smaller number of cases,” Peacock says. “And then I think sequencing is going to be key to know [the identity of] the circulating variants and whether they’re of concern or not.”

For now, Peacock’s other research is on hold. Her research group, who helped her set up the consortium, have all been rolled into COG-UK, and the focus is the pandemic. Most days, you’ll find Peacock at home with her headphones plugged in, jumping from one video call to the next. “This is no time to rest,” she says, talking about the importance of her work. “So on a human level, I’m full pelt all of the time.” But tracking and countering bacterial infections and antibiotic resistance remains something to go back and tackle once this is over, Peacock says. For her personally as a microbiologist, she adds, “with the awful statistic of 100,000 deaths in the UK, this is not a time to be thinking about anything other than working on the pandemic.”