‘Genetic mutation’. The phrase may inspire lurid tabloid headlines or conjure up memories of Hollywood B-Movies from the 1950s, but evolving changes in COVID-19’s genetic make-up are helping scientists to tease apart the complex picture of coronavirus spread in the UK, and rapidly evaluate ways to reduce the disease’s impact.
The COVID-19 Genomics UK Consortium (COG-UK) launched in March 2020, backed by £20 million of Government funding, and partners academic institutions such as the University of Birmingham with the NHS and Public Health Agencies to deliver large scale, rapid sequencing of samples from patients with confirmed cases of the virus.
Real time genome sequencing at a network of sequencing centres which includes Birmingham, Belfast, Cambridge, Cardiff, Edinburgh, Exeter, Glasgow, Liverpool, London, Norwich, Nottingham, Oxford and Sheffield provides valuable intelligence on the spread of the disease to hospitals, regional NHS centres and the Government. The University of Birmingham itself contributes a facility capable of sequencing genomes of the virus causing COVID-19 from patients in the West Midlands in less than 24 hours.
The COG-UK Collaboration has already created a databank of more than 50,000 samples that are proving invaluable in the UK’s fight against COVID-19. Birmingham is playing a pivotal role in the partnership, thanks to its expertise and knowledge in viral sequencing and genomics.
Nick Loman, Professor of Microbial Genomics and Bioinformatics, commented: “Our most important work is the ongoing sequencing to help inform the UK’s public health response. There is a relatively small number of cases in the UK and as new cases appear, we analyse whether and how they are related.
“Genomic sequencing is hugely useful in providing real-time understanding of the virus’ spread so that action can be taken to keep the number of cases down. It helps us to differentiate an ‘outbreak’ – where we see an increase in cases sharing the same viral ‘ancestor’ – from a ‘surge’ of fresh cases with lots of different genetic lineages.
“UK public health strategy is focussed on keeping cases down and avoiding a dangerous second wave through localised interventions; genomic sequencing can provide the intelligence to help make vital strategic decisions – whether in workplaces or healthcare settings.”
A COG-UK study showed how and when the COVID-19 virus entered the UK - mostly from European countries during March 2020. It showed that the UK epidemic was sparked by international travellers entering the country, before growing through local transmission within the UK. The contribution of China and other Asian countries to the number of importations was found to be very small.
The Birmingham-led ARTIC project puts genomics at the heart of outbreak response. Professor Loman’s colleague Dr Josh Quick developed a method for sequencing coronavirus which builds on work previously successfully used to trace epidemics of Ebola virus in East Africa and Zika virus in Brazil.
The methodology used to track COVID is almost identical to that used by the Birmingham academics to track the spread of Zika through north-east Brazil in 2016. Both protocols require extremely sensitive measuring capability, given the very small amount of virus in each sample and both are built around nanopore sequencing, in part developed by the University of Birmingham and Oxford Nanopore Technologies.
With the Birmingham methodology adopted around the world, the team has been working with researchers and sequencing labs from Brazil and the US to Kenya and South Africa.
“There has been a widespread adoption of our approach developed under the ARTIC project and over 100,000 genomes have been sequenced since January – some 50,000 of which were here in Britain using COG-UK protocols,” added Professor Loman.
“The major difference between Zika and COVID is that the former is mosquito-borne, whilst human-to-human transmission is the defining aspect of the latter. In this sense, the public health response to COVID is similar to Ebola in that it focussed on reducing contact between people to control the spread of the disease.”
Birmingham expertise provides a further key element in the COG-UK partnership through the CLIMB (Cloud Infrastructure for Microbial Bioinformatics) project. This provides the data analysis pipelines, computing and storage capacity required to analyse the large genome datasets produced by the consortium.
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The Birmingham team has been instrumental in tracking mutations in the virus – one notable discovery being a new strain - known as D614G – which appears to be speeding up outbreaks across the world but is not thought to increase the risk of death or lengthen hospital stays.
Genomic analysis revealed that the mutated virus showed an increased impact on the spike protein to increase the rate of host infection. Using the database of sequenced genomes, the team was able to stage a computer-modelled ‘race’ between the mutated and non-mutated forms of the virus.
“We started with a computer-modelled hypothesis that the mutated virus might exhibit increased virulence and cell culture experiments suggested that there could be up to 10 times more infections,” explained Professor Loman. “Using the database of over 50,000 sequenced genomes, we linked this information to outcomes and found no more deaths or lengthier hospital stays.
“We found that there was a slightly higher growth rate for D614G – increasing the ‘R’ rate by 120% - and this allowed us to dampen the hysteria that was beginning to build around the discovery of a new mutation.”
With COG-UK funded for 18 months of operations, the collaboration’s focus is very much on making sure that response times are as low as possible to help provide swift answers to major public health questions around COVID-19, such as whether new cases are linked and represent an ‘outbreak’ or a ‘surge’.
With public health professionals keen to avoid a repeat of the virus racing unchecked through hospitals and care homes, genome sequencing could provide invaluable combined with track-and-trace measures in keeping COVID cases segregated from patients and residents who are uninfected. For example, were a case to occur on a dialysis ward, the measures could help health staff establish whether the infection had been transferred from another part of the hospital or brought in from the community.
“With comprehensive genomic sequencing and regular testing of staff and patients, it should be possible to keep COVID patients separate and more effectively operate ‘hot’ and ‘cold’ areas in hospitals,” added Professor Loman. “The virus has a much greater impact on elderly and vulnerable people; we need to be doing everything possible to ensure that these groups are protected from COVID-19.
“Understanding viral evolution is critic in analysing how the virus is spreading - locally, nationally and internationally. Genomic sequencing will help us understand COVID-19 and its spread, as well as helping to guide future treatments and see the impact of interventions.”
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