RNA viruses like SARS-CoV-2, which is responsible for the COVID-19 pandemic, all evolve over time through mutation. Indeed, many thousands of tiny mutations in SARS-CoV-2 have occurred globally since it first emerged in 2019. While only a small number of mutations are likely to change the virus sufficiently to affect infection rates or disease severity, rapid monitoring of virus evolution and population structure is essential for identifying new variants, understanding their transmission dynamics, and informing public health interventions and their impact, including vaccination. Viral genome sequencing coupled with epidemiological data is the most effective way to achieve this.

Through collaborative genomic surveillance, researchers at the Quadram Institute (QI) have been instrumental in supporting national and international responses to the COVID-19 pandemic. They have identified and tracked the emergence and spread of successive new variants of SARS-CoV-2, improving methodologies to provide results practically in near real-time. Their results have informed national strategy directly and helped safeguard public health in the UK and internationally.

“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.” Sir Patrick Vallance, Government Chief Scientific Adviser.

Contributing to the UK national response to COVID-19

Alp Aydin loading COVID-19 sequencing samples. Image: Jason Bye

In March 2020 as the COVID-19 pandemic first took hold, the UK Government made a substantial investment in the COVID-19 Genomics UK (COG-UK) consortium, a UK-wide public health surveillance initiative to generate and analyse large-scale SARS-CoV-2 sequencing datasets and map its occurrence and spread in the UK[i]. The consortium comprised 17 academic and research institutions including QI, NHS organisations across the UK, all the UK Public Health Agencies, and UK Research and Innovation.

This represented a huge undertaking with researchers and clinicians working together across regions to simultaneously inform both the national advice provided by the Scientific Advisory Group for Emergencies (SAGE) and also essential rapid responses at the local public health level, including the monitoring of outbreaks in near real-time. QI was a core academic partner in COG-UK with numerous staff and students involved[ii]. Dr Andrew Page (QI) and Prof. Justin O’Grady (QI/UEA) and their teams were responsible for sequencing and analysis of SARS-CoV-2 samples, initially from the Norfolk region, thereby contributing to local and national surveillance. This was achieved by working closely with the University of East Anglia (UEA), the Norwich Research Park (NRP) Biorepository and Norfolk and Norwich University Hospital (NNUH). QI and COG-UK also had access to a state-of-the-art cloud-computing infrastructure tailored for microbial genomics. The Cloud Infrastructure in Microbial Bioinformatics (CLIMB)-BIG DATA project is a multi-centre initiative, led by QI’s Prof. Mark Pallen and Co-investigator Dr Andrew Page, that enables analysis of the huge datasets produced from microbial genome sequencing.

The first wave, before Variants of Concern

From the start the QI team were committed to evaluating as many positive samples as possible from the Norfolk region’s hospitals, care organisations and drive-through testing facilities[iii]. Over 1,500 samples (42% of all positive cases) were analysed during the first months of the pandemic which, at the time, made Norfolk one of the most highly sequenced regions in the world; only five out of 103 countries (including the UK) had sequenced more SARS-CoV-2 genomes than had been sequenced by QI for the Norfolk region alone. This included early archived samples and multiple samples from the same individuals thus enabling unprecedented interpretation and insight into SARS-CoV-2 dynamics throughout the entire first wave of the pandemic (March-August 2020)^iv.

“We quickly put in place a robust, rapid pipeline for SARS-CoV-2 sequencing, with weekly sequencing data fed back into the national effort for pandemic management, whilst also helping local outbreak analyses” Dr Andrew Page, Group Leader, QI.

During the first wave the team found that there had been multiple introductions of the virus into the Norfolk region from other areas of the UK and Europe, though not directly from China, and identified 100 different lineages the majority of which became extinct or were replaced by others over time. A lineage is shorthand for a collection of related samples and is one way that epidemiologists can tell quickly whether genomes are similar or different. The timing of the first peak and subsequent decline in cases demonstrated that the first national lockdown and social distancing efforts had been effective in reducing transmission ^iv.

“Quadram’s ‘powerful’ analysis of local outbreaks has made it instrumental in contributing to the national picture and that a key part of its legacy will be in its continued research”. Prof Sharon Peacock, director of COG-UK.

It was possible to identify the mechanisms underlying local outbreaks using CLIMB-BIG-DATA to link sequencing data with anonymised epidemiological data (e.g age, sex, first half of the postcode) from the hospital sample archives in the Norwich Research Park Biorepository. For example, the QI team showed that virus genomes from an outbreak at a food processing factory were all highly related and different to those elsewhere in the region, indicating that the virus was spreading between factory workers but had not originated from the local community. This made it possible to track and identify the routes of transmission and gave local public health teams the evidence base they needed to confidently apply appropriate mitigation. In contrast, in an apparent hospital outbreak the genomes analysed were not closely related indicating that they had originated independently from outside the hospital and not as a result of transmission of a single lineage within the hospital ^iv.

“The COG-UK initiative to provide whole genome sequencing of SARS-CoV-2 provides improvement in hospital functioning by aiding Infection Prevention and Control efforts and clarifying intra-hospital transmission events as well as reduction of transmission of the virus from hospitals to the community” Dr Samir Dervisevic, consultant virologist at NNUH.

Using SARS-CoV-2 genomics in care home settings

Particularly important insights were made into cases in care homes the residents of which were the hardest hit members of our community and account for an estimated 30% of all COVID-19 deaths in England and Wales. QI’s sequencing work helped public health authorities pinpoint staff moving between homes, particularly agency staff, as sources of transmission, whilst also demonstrating that measures put in place to prevent transmission were effective^iv. In a meta-analysis of these data alongside other published datasets from care homes in UK, USA and Netherlands some very significant shared trends in transmission were identified. This analysis informed COG-UK recommendations to the UK SAGE Social Care Working Group, of which Dr Andrew Page was invited to participate, and was instrumental in providing scientific evidence for the effectiveness of genomics in care homes to help protect highly vulnerable residents during the peak of the pandemic^v.

What the meta-analysis of data from care home residents and staff showed[iv]

• Most COVID-19 infections in care homes did not come from hospitals but from the local community; where infections were high in the community, they were also high in care homes
• Infections were usually associated with a small number of introductions, rather than repeated ‘seeding’ of the virus. Occasional shared ‘clusters’ across different care homes suggested staff moving between the facilities may have carried the virus that led to the outbreaks
• A high proportion of cases in care home staff were without symptoms (presymptomatic or asymptomatic). By the time two symptomatic cases were identified in a care home, the outbreak was likely to be widespread.
• When the virus was established (in residents and staff) it tended to be dominated by one lineage.

There was no difference between virus lineages in the mortality rate of care home residents. The mortality rate of residents was always high.

Recommendations in response to meta-analysis findings^v

• Take steps to limit the spread of SARS-CoV-2 to care homes from the community, staff, healthcare workers and hospitals
• Treat all care home staff (not just those with direct contact with residents) as one group subject to the same infection control measures
• Residents whose rooms are located near the bedroom of a resident who is positive should be considered at very high risk
• Continue to use genomics in a targeted way in care homes to help identify, track and control the virus

The data behind this meta-analysis of COVID-19 cases in care homes was collected in 2020, and since then vaccination has been essential in providing an additional level of protection. In the UK, over 90% of care home residents and 80% of staff have now been fully vaccinated.

The rise of variants of concern

While the rollout of vaccination (December 2020 onwards) allowed UK society to begin lifting restrictions, this easing was associated with increasing case numbers and further restrictions resulting in a series of waves of infection. Throughout this QI continued to sequence samples both locally and increasingly nationally as a Surge Resilience Laboratory identifying and tracking the emergence, rise and fall of successive new variants of concern, i.e. those with profiles that stood out from the many others appearing which suggested they had the potential to affect virus properties like transmissibility.

This included the rise of the Alpha variant first identified in Kent in Nov. 2020 that became the predominant variant within weeks when it accounted for 45% of all cases. This was followed in April 2021 by the arrival of the Delta variant in the UK (first identified in India) and most recently the Omicron variant (first identified in Botswana and South Africa). By increasing capacity and honing their processes to maximise sample throughput QI were sequencing 5000 samples a week at their busiest; to date[v]  the COG-UK consortium group as a whole has sequenced 1,723,149 SARS-Cov-2 genomes.

“The hospital finds it extremely useful; Test and Trace finds it extremely useful; Public Health finds it extremely useful. But what’s really great is to see direct translation of science – we do a lot of scientific research and it’s not every day that your science is translated into something useful. Doing something in the lab at the bench and then two days later seeing that information being utilised to help control the spread of the virus – that is very satisfying.” Prof. Justin O’Grady (now working for Oxford Nanopore but was employed at QI/UEA at the time of this work)

Not only were QI sequencing as part of COG-UK national surveillance, but they also sequenced all the positive home swab tests from the REACT-1 study led by Imperial College. This included samples from more than 200,000 people taken during the third wave between May and July 2021 which showed how the Delta variant quickly replaced the Alpha variant. The results also showed that despite high case numbers vaccination limited disease severity and was effective against the Delta variant; the high rates of infection were being driven by infection in younger, unvaccinated people and more social mixing.

The whole genome sequencing of SARS-CoV-2 done by QI within COG-UK and other projects has informed policy on appropriate infection control measures, thereby improving hospital and care home functioning through improved infection prevention and control efforts. These findings from COG-UK will also help prepare the UK and the world for future pandemics.

“We’re proud co-authors in this important, ongoing REACT-1 study which demonstrates just how important it is for children aged 12 and above to get vaccinated to help curb the spread of infection. Vaccination makes a big difference, but we do still all need to take precautions in our daily lives and we need to keep up our surveillance to track changes in the virus and to ensure vaccines are a match for new variants.” Dr Andrew Page, Group Lead, QI.

Contributing to the international response to the COVID-19 pandemic

• Zimbabwe

One particular collaboration led by Prof. Rob Kingsley (QI/UEA) and scientists in the National Microbiology Reference Laboratory, Zimbabwe established a detailed picture of how SARS-Cov-2 variants were introduced into and subsequently spread in Zimbabwe during 2020. Their findings[viii] were based on the genomic sequencing of 156 positive samples taken across eight provinces in Zimbabwe between March and October 2020.  In addition to collaborative analysis, researchers at QI also provided training for scientists from Zimbabwe’s National Microbiology Reference Laboratory (NMRL) that enabled them to achieve genome sequencing and analysis of their own data for the first time.

“Our experience of genomic sequencing of SARS-CoV-2 highlights the value of being able to build a very detailed picture of the virus and track its mutations for the potential to increase transmissibility, change virulence or influence the development of effective vaccines.” Dr Tapfumanei Mashe, Research Scientist, National Microbiology Reference Laboratory, Zimbabwe.

The epidemiological analysis identified two distinct phases of the SARS-CoV-2 pandemic in Zimbabwe. The first phase between March and June 2020 saw at least 26 cases linked to international travel from Asia, Europe or the USA, and travel from neighbouring African countries and the second phase saw within-country community transmission.  Public health measures taken, such as quarantine and suspended air travel did delay the domestic spread but after July 2020 the virus was spreading fast in cities close to borders and airports.

“The UK has been able to sequence COVID-19 at considerable scale but far less is known about the epidemiology of this disease in Africa. This research, undertaken with our colleagues in Zimbabwe, helped track the spread and evolution of the virus and inform public health measures.” Prof. Rob Kingsley, Group Lead, QI/UEA. 

“The support QIB provided to the Zimbabwe Ministry of Health, and in particular to the National reference laboratory in Harare, has helped Zimbabwe in sequencing samples and tracking variants of concern. You have provided timely and critical expertise, knowledge and commodities on COVID-19 sequencing. Your initial support involved samples being sent to the UK, however more recently QIB has helped build local capacity – supporting the provision of critical equipment as well as training to undertake to support Zimbabwe to sequence samples in country, while at the same time providing remote quality assurance as local capacity was built. Data from the sequencing has been presented at the national weekly coordination meetings and has helped inform and guide local policy responses. The data has also been used by missions, such as our own, to inform thinking and planning.” Excerpt from a letter to QI from Giles Entickamp, Deputy head of mission, British Embassy, Harare, Zimbabwe, 2^nd September 2021.

“Data obtained has helped inform and guide UK policy responses including a recent decision to remove Zimbabwe from England’s red list. The news has been welcomes by travellers from the UK and Zimbabwe, some of whom will now be able to visit family members after long periods of separation.” Excerpt from a letter to QI from Vicky Ford MP, UK Minister for Africa, 22^nd Oct 2021.

• Bangladesh

The QI’s Dr Nicol Janecko and Prof. John Wain assisted collaborator Prof. Senjuti Saha from the Children’s Health Research Foundation (CHRF) in Dhaka, Bangladesh to undertake their own high throughput SARS-CoV-2 sequencing using Oxford Nanopore MinION sequencers. QI set up a specialist sequencing and analysis laptop and dispatched it, along with all the supplies needed to begin undertaking their own sequencing. Virtual bioinformatics training was provided over Zoom by QI’s Dr Thanh Le Viet to enable local scientists to analyse and interpret their own genomic data, truly building long lasting capacity in Bangladesh.

• Lebanon[ix]

The QI’s Dr Andrew Page along with Prof. Sima Tokajian from the Lebanese American University and their public health authorities undertook a largescale retrospective study of SARS-CoV-2 genomes. As Lebanon was undergoing severe challenges at the time, QI sequenced over 900 Lebanese samples providing a 10-fold increase in the number of genomes available from Lebanon. Without genomic epidemiology data for a country, policy makers and public health officials are hindered. Sequencing samples over a 5-month period showed different dynamics to those of other countries, such as the UK. Travel restrictions did appear to work to stem the flow of the Alpha variant from the UK. New variants of concern were also circulating in the community long before they were officially detected. This demonstrates the utility of genomic surveillance and highlights the fact that different countries face different virus dynamics and challenges.

• Pakistan[x]

QI’s Dr Muhammad Yasir, Dr Andrew Page and Prof Mark Webber collaborated with Dr Muhammad Bilal Sarwar and Prof. Shah Jahan from the University of Health Sciences in Lahore, Pakistan to understand the dynamics of the COVID-19 pandemic in Lahore and surrounding regions.  During the third wave in Pakistan (Spring 2021) just 12 genomes were available for the whole country of 200 million people, severely limiting the information available to guide public health authorities. The QI sequenced 102 samples collected over a single week to provide a snapshot of the lineages in circulation, finding that all of the samples were variants of concern, predominantly the Alpha variant. Eight of the samples were identical to genomes observed in Europe, seven of which were from the UK, indicating very recent transmission between the countries.

Funding

• On 1 April 2020, COG-UK received approximately £20 million in funding from the National Institute for Health Research (NIHR); the Medical Research Council (MRC), which is part of United Kingdom Research and Innovation (UKRI); and the Wellcome Sanger Institute. In early 2021 COG-UK received funding from the Testing Innovation Fund and the Department of Health and Social Care Test and Trace to bolster sequencing output.
• In October 2021 QI transitioned to providing surge capacity for UKHSA as a resilience lab to get the UK through the winter of 2021.
• The QI researchers are supported by the Biotechnology and Biological Sciences Research Council, part of UKRI.
• International sequencing support and training was facilitated through allocation of QI BBSRC Impact Accelerator Awards.

Listen to Dr Andrew Page discuss this work in his research group’s Podcast, found here.

References

[i] SAGE reports portfolio. SAGE Reports | COVID-19 Genomics UK Consortium (cogconsortium.uk)

[ii] COG-UK Quadram Institute contributors. Quadram Institute | COVID-19 Genomics UK Consortium (cogconsortium.uk)

[iii] Page, A., Mather, A., Le-Viet, T., Meader, E., Baker, J. Trotter, A., Rudder, S., Tedim, A., Kolyva, A., Stanley, R., Diaz, M., Potter, W., Stuart, C., Meadows, L., Bell, A., Gutierrez, A., Thompson, N., Adriaenssens, E., Swingler, T., Gilroy, R., Griffith, L., Sethi, D., Aggarwal, D., Brown, C., Davidson, R.., Kingsley, R., Beford, L., Coupland, L., Charles, I., Elumogo, N., Wain, J., Prakash, R., Webber, M., Smith, L., Chand, M., Dervisevic, S., O’Grady, J. Large scale sequencing of SARS-CoV-2 genomes from one region allows detailed epidemiology and enables local outbreak management. The COVID-19 Genomcs UK (COG-UK) consortium. medRxiv 2020.09.28.20201475; doi: https://doi.org/10.1101/2020.09.28.20201475

[iv] Aggarwal, D., Myers, R., Hamilton, W. L., Bharucha, T., Tumelty, N., Brown, C., … Page, A. J. (2020, November 23). The role of genomics in understanding COVID-19 outbreaks in long term care facilities. https://doi.org/10.31219/osf.io/7y9rk

[v] As of 21^st Dec 2021.

[vi] Real-time Assessment of Community Transmission (REACT) Study. https://www.imperial.ac.uk/medicine/research-and-impact/groups/react-study/

[vii] Elliott, P., Haw, D., Wang, H., Eales, O., Walters, C. E., Ainslie, K. E.,

Christina Atchison, Claudio Fronterre, Peter J. Diggle, Andrew J. Page, Alexander J. Trotter,Sophie J. Prosolek, The COVID-19 Genomics UK (COG-UK) Consortium, Deborah Ashby, Christl A. Donnelly,Wendy Barclay, Graham Taylor, Graham Cooke, Helen Ward, Ara Darzi, Steven Riley. Exponential growth, high prevalence ofSARS-CoV-2, and vaccine effectiveness associated with the Delta variant. Science 374, 1463 (2021) 17 December 2021. https://doi.org/10.1126/science.abl9551

[viii] Mashe, T., Takawira, F., de Oliveira Martins, L., Gudza-Mugabe, M., Chirenda, J., Munyanyi, M., V Chaibva, B., Tarupiwa, A., Gumbo, H., Juru, A., Nyagupe, C., Ruhanya, V., Phiri, I., Manangazira, P., Goredema, A., Danda, S., Chabata, I., Jonga, J., Munharira, R., Masunda, K., Mukeredzi, I., Mangwanya, D., Trotter, A., Le Viet, T., Rudder, S., Kay, G., Baker, D., Thilliez, G., Gutierrez, A., O’Grady, J., Hove, M., Mutapuri-Zinyowera, S., Page, A.J., Kingsley, R.A. and Mhlanga, G. Genomic epidemiology and the role of international and regional travel in the SARS-CoV-2 epidemic in Zimbabwe: a retrospective study of routinely collected surveillance data,  The Lancet Global Health, Volume 9, Issue 12, 2021, Pages e1658-e1666, ISSN 2214-109X, https://doi.org/10.1016/S2214-109X(21)00434-4

[ix]  Merhi, G., Trotter, A., De Oliveria Martins, L., Le-Viet, T., Abou Naja, F., Al Buaini, M., Prosolek, S.j., Fareed Alikhan, N., Lott, M., Tohmeh, T., Badran, B., Jupp, O. J., Gardner, S., Felgate, M. W., Makin, K. A., Wilkinson, J. M., Stanley, R., Sesay, A. K., Webber, M.A., Davidson, R. K., Ghosn, N., Pallen, M., Hasan, H., Page, A. J., Tokajian, S. Replacement of the Alpha variant of SARS-CoV-2 by the Delta variant in Lebanon between April and June 2021. MEDRxiv Preprint. https://doi.org/10.1101/2021.08.10.21261847

[x] Sarwar, M. B., Yasir, M., Alikhan, N. F., Afzal, N., de Oliveira Martins, L., Le Viet, T., Trotter, A. J., Prosolek, S. J., Kay, G. L., Foster-Nyarko, E., Rudder, S., Baker, D. J., Muntaha, S. T., Roman, M., Webber, M. A., Shafiq, A., Shabbir, B., Akram, J., Page, A. J., & Jahan, S. (2021). SARS-CoV-2 variants of concern dominate in Lahore, Pakistan in April 2021. Microbial genomics, 7(11), 000693. https://doi.org/10.1099/mgen.0.000693