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“Variants” is the latest term to leap from the infectious disease lexicon to the general public as a result of the coronavirus, as the effects of mutations on transmission and vaccines have emerged as top global concerns.

But researchers like Emma Hodcroft, a molecular epidemiologist at the University of Bern, have been looking out for genetic changes to the SARS-CoV-2 coronavirus since the beginning of the pandemic. The virus, like any virus, has picked up mutations as it spread, but it’s only been in the past few months that it has been altered in ways that could dramatically shift the dynamics of the Covid-19 pandemic.

Tracking the subtle changes to the virus’ RNA is like global detective work, requiring health officials around the world to sequence a selection of viral samples and share them broadly. Without that, scientists are flying blind.

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“A lot of places that have had big outbreaks are places where we do not have good sequencing, and the only way to monitor for new variants is through sequencing,” Hodcroft said.

Projects like Nextstrain and GISAID already gather data on pathogen evolution, but with all the interest in SARS-2 variants, Hodcroft and colleagues have built another site, CoVariants.org, to highlight select mutations and variants of interest. On the site, users can dive into where the mutations and variants have been found, how they may influence factors like transmission and immune protection, and what their impact on viral proteins looks like.

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STAT spoke with Hodcroft last week about CoVariants.org and all things viral evolution. Excerpts from the conversation are below, lightly edited for clarity.

How sufficient are the data that are now being shared about variants and mutations? I know one thing that’s been made clear is that the U.S. doesn’t do a lot of genomic surveillance, so we don’t know what might be out there.

Emma Hodcroft
Molecular epidemiologist Emma Hodcroft Courtesy Oliver Hochstrasser

It’s hard to know what we’re missing when we don’t have the data. And I would say the U.S., it’s not terrible, it’s just really disparate. Some states are doing a pretty good job, comparable at least to many European countries — maybe not as much as we would like ideally, but certainly not nothing. But there are other states where we have like 10 sequences over the course of the year, and that tells us almost nothing about what’s going on in those states. So what that means is we just have blind spots in some places. If a variant arose there, how long would it take for us to notice?

It’s worth saying there’s nowhere in the U.S. that’s coming close to the sequencing effort that the U.K. or Denmark are putting in. That’s truly remarkable.

But even in countries where we do have a reasonable number of sequences, another problem we’re encountering is bias. For example, for a long time, in some countries, we only had sequences coming in from one lab in one city, so you can’t necessarily extrapolate that that’s the situation across the whole country. More recently, we’ve had another problem with bias in that everyone is super interested to find which sequences might be the variants of concern, and so they’re preferentially sequencing samples that might have a travel history or have a particular signature on PCR tests. What we lose in the process is the actual surveillance and monitoring — well, what else is going on? What other variants might be out there?

The idea of mutations and variants has reached general public awareness in the past month or two. What is the public not understanding about variants, or the three variants that are getting the most attention?

One thing I get asked a lot is why have we gotten three variants now. But the first part to keep in mind is we’ve already had variants. We’ve been tracking variants since the summer of 2020, but none of these seemed to have a strong effect on, for example, clinical outcomes. They can still be incredibly useful — they can teach us how the virus is spreading, how the virus is moving — but they didn’t make headlines really. There have been variants, people just may not have heard about them.

The other thing that’s important to consider is that the environment that the virus is operating in has changed. Mutations arise randomly, they’re typos. The virus can’t control what mutation it has. But whether a mutation goes on to spread and become prominent in a population, that depends on whether that mutation gives the virus an advantage, or it can also be pulled along by chance. But one of the things that’s changed at this point in the pandemic is what gives that virus an advantage. As an example, at the beginning, there was not really any advantage in being able to reinfect people. Everyone was vulnerable. You can imagine now in some parts of the world, where a lot of people have been infected and have at least some partial immunity, there might be an advantage for the virus now to reinfect people.

There’s also an element of chance. There’s a hypothesis that the [B.1.1.7 variant], which emerged in the U.K., might have originated in a patient who was immunocompromised and chronically infected. For that, an immunocompromised patient would have to get infected; and then they would have to be chronically infected; then they would have to develop exactly these mutations that not only help the virus in the person, but improve transmission among people with healthy immune systems; and then it would have to transmit out of that person to someone else and into the wider population. All of these are kind of rare events. You can imagine at any point, the next step wouldn’t happen. But when we keep cases really high, we up our chances of rolling three 6s in a row. When we’ve kept cases this high for a year, sometimes we’re going to get the perfect alignment of events that might lead to a mutation spreading in a population that we wish wasn’t there.

You and colleagues recently wrote a paper about public health strategies to control variants, with a particular focus on B.1.1.7, which appears to be significantly more transmissible than other SARS-2 types. What’s different in these recommendations versus what communities have been told to be doing for the past year or so?

I think a lot of them are probably not so different. The good news/bad news about the variants is that they can be controlled in very much the same way that SARS-CoV-2 original versions could be controlled.  The good news is that we have an idea of what works. The bad news is that getting populations on board with that, helping people to have the resources so they can maintain social distancing, not have to go to work — putting these in the place and having them accepted is a different story.

But I do think there is a reason to make these recommendations again even if they’re not a revolution in how to deal with the virus. We really want to be paying attention right now. We really should be preparing. You want to be prepared for this variant hitting and spreading.

  • There are lots of variants, but has anyone seen a recombinant with another circulating coronavirus yet?

    • There are two popular systems for naming variants: Nextstrain clades (https://nextstrain.org/blog/2021-01-06-updated-SARS-CoV-2-clade-naming) which aims for a smallish number of categories that are fairly stable, and Pango lineages (https://cov-lineages.org/) which are more fine-grained and rapidly updated, intended to correspond to specific outbreaks. The Nextstrain clade designation for the variant first detected in South Africa is 20H/501Y.V2 (previously 20C/501Y.V2 before they added the new 20H) and the Pango lineage is B.1.351.

    • ‘Nomenclature’ – the devising or choosing of names for things, especially in a science or other discipline is complex at the best of times.

      Naming all the variants of COVID-19 is an extreme example.
      Coronaviruses have the largest known genomes of animal RNA viruses, ranging from 26-32 kilobases (kb)

      As this link (below) demonstrates even the scientists acknowledge this can cause confusion.

      ‘A bloody mess’: Confusion reigns over naming of new COVID variants
      As more lineages emerge, researchers are struggling with a patchwork of nomenclature.
      https://www.nature.com/articles/d41586-021-00097-w

    • Confusion increases if one starts discussing ‘variants’ and ‘mutations’.

      https://www.researchgate.net/post/Clear_cut_definition_for_genetic_variant_and_mutation

      This is science at the cutting edge, not to mention the need for a high-level understanding of statistical methods to interrogate data.
      And, almost paradoxically, an acceptance of uncertainty in science.

      Consequently, the members of the general public are being asked to trust the experts. And in this time, with its anti-Enlightenment tendencies, many seem reluctant to do so.

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