Talking COVID-19 and Genetic Variants With Dr Jeffrey Barrett

On March 4 2020, 84 cases of COVID-19 were confirmed in the UK. Lessons learnt from other countries across the world suggested that this number would not remain low for long. A team of scientists came together on March 11 to discuss how genomics could be applied to the study of COVID-19 and used to inform public health actions and policy decisions. This was the beginning of the COVID-19 Genomics UK Consortium (COG-UK).

COG-UK is a partnership between National Health Service (NHS) organizations, the four public health agencies of the UK, the Wellcome Sanger Institute and academic institutions across the UK. It applies rapid, whole-genome sequencing to samples obtained from COVID-19 patients that have been tested through "pillar one" and "pillar two" diagnostics pathways. The pillar one pathway comprises hospital diagnostic laboratories where samples are collected from patients that are unwell and presented to hospital. The pillar two pathway includes laboratories that receive swabs from individuals that have not been admitted to hospital and from individuals that are in long-term care facilities.

The Wellcome Sanger Institute is sequencing the genomes of tens of thousands of samples that are obtained via the pillar two pathway. Dr Jeffrey Barrett is the director and lead COVID-19 statistical geneticist of the COVID-19 Genomics Initiative at the Wellcome Sanger Institute. In this interview, he explains the importance of applying genomics tools to study pathogens, discusses the initiative's role in exploring variants of concern and outlines how the generated data is being applied to inform public health decisions.

Molly Campbell (MC): Please can you tell us about the COVID-19 Genomics Initiative, and your role as the director?

Jeffrey Barrett (JB): We are part of the COG-UK consortium, which brings together genomic, public health and virology expertise from around the UK. The Wellcome Sanger Institute is the largest sequencing centre in the consortium, and also develops analysis and software to help understand how the virus spreads, and whether new variants change how transmissible it is or whether they might escape vaccines.

MC: Why are genomics-based studies of SARS-CoV-2 important?

JB: The SARS-CoV-2 virus has an RNA genome of 30,000 letters. Most of the time it is exactly the same from one infected person to the next, but occasionally mutations happen, which are uncorrected spelling mistakes in the genome. Mutations happen all the time, and most don’t change the biological properties of the virus. We can use these mutations as a "barcode" to trace how the virus is transmitting from one person and place to the next. Occasionally, however, mutations arise that are concerning because they change the behavior of the virus.

MC: Which genomics tools are being used by the initiative?

JB: We use an experimental protocol called ARTIC, developed by COG-UK, to target the genome of the virus for sequencing. At Sanger, we have a high-throughput pipeline using Illumina NovaSeq sequencing machines that can produce 20,000 virus genomes per week. The data is all jointly analyzed on a bioinformatics platform using a consistent set of open-source bioinformatics pipelines.

MC: What has the initiative taught us about SARS-CoV-2's ability to mutate so far?

JB: The virus mutates relatively slowly: usually about two new mutations per month. But occasionally we see a large number of mutations happen together, and some of these are the variants of concern that have recently attracted attention. The same pattern of several mutations happening together has also been seen in particular individuals who have been chronically infected with the virus, so one hypothesis is that an event like that is the source of these variants.

MC: Can you talk about the initiative's role in exploring some of the variants that have been highlighted as variants of concern?

JB: We have been the largest sequencing site in the world in the pandemic, so our first contribution has been to produce the data that has fed into the analyses that discovered B.1.1.7 and evaluated its increased spread and possible increased mortality. We have also worked on statistical models to study these questions and contributed the output of those to public health teams for use in the pandemic response.

MC: The COVID-19 Genomics Initiative is monitoring mutations that could impact how a vaccine works. How might mutations do this? Are there challenges associated with this work considering the number of vaccines that are being developed?

JB: We can see that some of the variants of concern, especially B.1.351 are showing evidence both in the lab and in clinical trials of being more able to evade some vaccines. It’s not yet clear whether this is just infection, or if they can also evade the really excellent protection of the vaccines against serious disease. We think the most likely mechanism is when some mutations change the part of the virus’s spike protein where most of our antibodies are aimed.

MC: How do you envision genomics-based research will continue to serve the scientific community as we navigate through the COVID-19 global pandemic?

JB: It will be really important to monitor for additional possible vaccine escape mutations, and hopefully to provide that information to public health authorities to do everything we can to prevent them from becoming widespread. There are also already plans to produce updated vaccines that could be deployed as booster shots if a particular worrisome variant does circulate widely.

Jeffrey Barrett was speaking to Molly Campbell, Science Writer for Technology Networks.