News

Spread of COVID-19 mapped in hospitals to ‘break the chain’ of transmission

The trial will evaluate the effectiveness of rapid sequencing and analysis of SARS-CoV-2 genomes in reducing hospital outbreaks 

A first-of-its kind clinical trial, led by scientists at UCL, will evaluate the use of ‘real time’ viral genomic data to reduce the spread of COVID-19 within hospitals. The study’s findings could help the NHS reduce further transmission of the virus by determining if an individual caught the virus from someone else within the same hospital.

The trial, led by Professor Judith Breuer, Director of UCL/UCLH/GOSH Biomedical Research Centres funded Pathogen Genomics Unit (PGU/UCLG), together with the UCL Comprehensive Clinical Trials Unit (CCTU), forms part of the Government’s £20 million COVID-19 Genomics UK Consortium (COG-UK) – which has established a network of rapid genome sequencing centres across the UK – allowing scientists to map the virus’ spread across the country.

“Spread of COVID-19 infections in hospitals is now recognised to be a major problem for both healthcare workers and patients, and ‘breaking the chain’ of these transmissions is critical.

“Tried and tested procedures to minimise infection spread in hospitals are already in use,  including separating COVID-19 infected patients from uninfected patients, extensive cleaning, the use of PPE, and continual hand washing.

“Despite these measures, COVID-19 transmission to patients and staff is still occurring and has sadly proven fatal.  So it is essential that we try out new tools such as viral sequencing to find out why this is happening and to help reduce hospital spread.”

Professor Judith Breuer, an expert in the use of genomics for tracking hospital infection

The importance of this research area has been recognised by the National Institute for Health Research (NIHR). This study is one of a number of COVID-19 studies that have been given urgent public health research status by the Department of Health and Social Care.

The COG-UK Hospital Onset COVID-19 Infection (HOCI) trial has been developed with the NIHR UCL/UCLH BRC supported Pathogen Genomics Unit at UCL in collaboration with Imperial College Healthcare Trust, Sheffield Teaching Hospitals NHS Foundation Trust with The University of Sheffield, and the Glasgow Royal Infirmary with the MRC-University of Glasgow Centre for Virus Research. COG-UK HOCI will involve over 15 hospitals linked to COG-UK sequencing hubs across the UK.

Each site will analyse the COVID-19 sequences in nasal and throat samples from all known COVID-19 patients in the hospital, along with newly infected hospital patients and frontline NHS staff. The trial will evaluate whether results from whole virus genome sequencing of all COVID-19 samples (now available within 24-48 hours) reduces the number of hospital outbreaks compared with standard methodologies. Specifically, the genomic data is likely to enable clinical teams in each hospital to see if newly infected patients have picked up the virus from a known positive COVID-19 patient within the hospital, or from outside the hospital.

There is already evidence emerging from COG-UK that COVID-19 sequences can help teams to control hospital infections better. The COG-UK HOCI trial will quantify by how much sequencing helps, how important it is to return results rapidly, what is the best way to implement COVID-19 sequencing across the NHS, and how much it costs. This information will help to make more precise plans as to how to use COVID-19 sequencing in the future.

“We already know that comparing the sequence of letters that make up one COVID-19 virus genome with the sequence of letters from COVID-19 in another sample, can tell us whether the two viruses are the same or different.

“Therefore by sequencing COVID-19 viruses rapidly, we hope to establish how hospital staff and patients became infected. This will allow hospitals to put effective measures in place faster, to try to interrupt onward transmission of the virus and reduce the number and size of outbreaks. Such measures might include more regular deep cleans, checking and double-checking the effectiveness of PPE equipment, and moving other vulnerable patients out of the hospital entirely to another setting.”

Professor Judith Breuer

COVID-19 viruses that are closely related (transmitted from one patient to another or to a healthcare worker) will have the same sequence, while COVID-19 viruses from two people that have different sequences will rule out the possibility of COVID-19  transmission between patients or healthcare workers.

“The understanding and prevention of hospital onset COVID-19 infections will be an important aspect of any recovery strategy for hospitals.

“Established infection prevention methods and surveillance approaches used to track and trace infections and antimicrobial resistance will be applied, but now supported with the additional information provided by genetic fingerprinting.”

Professor Alison Holmes, Director of the NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, based at Imperial College London

The COG-UK project is made up of NHS, Public Health Agencies and academic institutions – including UCL and UCLH – and will deliver large scale sequencing of COVID-19, and intelligence sharing with hospitals, regional NHS centres and the government. In COG-UK samples from patients with confirmed cases of COVID-19 are being sent to a network of sequencing centres all over the UK.

“Using viral genomics we can now track how COVID-19 spreads in hospitals as well as in national and international settings. Our trial will hopefully provide valuable information for the hospitals involved revealing the chains of transmission that must be stopped in order to control COVID-19.”

Professor Judith Breuer

The following NHS Trusts have confirmed they are participating in the HOCI trial:

  • Imperial College Healthcare NHS Trust
  • Sheffield Teaching Hospitals NHS Foundation Trust
  • NHS Glasgow and Greater Clyde
  • NHS Lothian
  • Guy’s and St Thomas’ NHS Foundation Trust
  • Manchester University NHS Foundation Trust
  • University College London Hospitals NHS Foundation Trust
  • Royal Free London NHS Foundation Trust
  • University Hospital Southampton NHS Foundation Trust
  • Newcastle Hospitals NHS Foundation Trust
  • Royal Devon & Exeter NHS Foundation Trust
  • Norfolk and Norwich University Hospitals NHS Foundation Trust
  • Liverpool University Hospitals NHS Foundation Trust
  • Leeds Teaching Hospitals NHS Trust

UCL is in discussion with a further six NHS trusts about participating in the trial.

Further Information

Notes to Editors

For more information or to speak to Professor Judith Breuer, please contact Henry Killworth, UCL Media Relations. T: +44 (0) 7881 833274 E: h.killworth@ucl.ac.uk

Selected websites

  • About UCL – London’s Global University

    UCL is a diverse community with the freedom to challenge and think differently.

    Our community of more than 41,500 students from 150 countries and over 12,500 staff pursues academic excellence, breaks boundaries and makes a positive impact on real world problems.

    We are consistently ranked among the top 10 universities in the world and are one of only a handful of institutions rated as having the strongest academic reputation and the broadest research impact.

    We have a progressive and integrated approach to our teaching and research – championing innovation, creativity and cross-disciplinary working. We teach our students how to think, not what to think, and see them as partners, collaborators and contributors.

    For almost 200 years, we are proud to have opened higher education to students from a wide range of backgrounds and to change the way we create and share knowledge.

    We were the first in England to welcome women to university education and that courageous attitude and disruptive spirit is still alive today. We are UCL.

  • COVID-19 Genomics UK Consortium (COG-UK)

    The current COVID-19 pandemic, caused by the SARS-CoV-2 virus, represents a major threat to health. The COVID-19 Genomics UK (COG-UK) consortium has been created to deliver large-scale and rapid whole-genome virus sequencing to local NHS centres and the UK government.

    COG-UK is made up of an innovative partnership of NHS organisations, the four Public Health Agencies of the UK, the Wellcome Sanger Institute and over twelve academic partners providing sequencing and analysis capacity. A full list of collaborators can be found here: https://www.cogconsortium.uk/about/

    COG-UK is supported by £20 million funding from the UK Department of Health and Social Care (DHSC), UK Research and Innovation (UKRI) and the Wellcome Sanger Institute, administered by UK Research and Innovation. For more information, visit: https://www.cogconsortium.uk

  • The National Institute for Health Research (NIHR)

    The National Institute for Health Research (NIHR) is the nation’s largest funder of health and care research. The NIHR:

    • Funds, supports and delivers high quality research that benefits the NHS, public health and social care
    • Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research
    • Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future
    • Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services
    • Partners with other public funders, charities and industry to maximise the value of research to patients and the economy

    The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR supports applied health research for the direct and primary benefit of people in low- and middle-income countries, using UK aid from the UK government.

    Please visit https://www.nihr.ac.uk/covid-19/ to learn about other studies that have been given urgent public health status and the single, national prioritisation process that has been established to prevent duplication of effort and to ensure that the resources and capacity of the health and care system to support COVID-19 research are not exceeded.

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    [secondary_title] => Commentary for report 12 &ndash; 15th October 2020
    [excerpt] => As of 22nd October, the COVID-19 Genomics UK (COG-UK) Consortium has sequenced more than 81,000 SARS-CoV-2 virus genomes from the UK, representing about 45 per cent of the global total.
    [byline_text] => Commentary
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    [content] => As of 22<sup>nd</sup> October, the COVID-19 Genomics UK (COG-UK) Consortium has sequenced more than 81,000 SARS-CoV-2 virus genomes from the UK, representing about 45 per cent of the global total.
Report 12 presents details of three separate studies using the genome data, and a summary of nationwide outbreak investigations that have used COG-UK genome data.
The information shows the ongoing state of the research, and has not been peer-reviewed. Conclusions may change as more evidence becomes available.
The first study is into a genetic mutation of the virus, termed N439K. This mutation results in a change to the Spike protein of the virus – the protein it uses to enter human cells. Because of its location, this mutation could affect a person’s immune response to the virus. The report stresses the need for systematic monitoring of virus mutations, especially when vaccinations begin.
The second study details the use of viral genomic data in Norfolk, where the data has enabled local outbreak management. The third study assessed respiratory disease in cats, associated with human-to-cat transmission of SARS-CoV-2. Finally, there is a summary showing COG-UK data and tools have been used in over 120 SARS-CoV-2 outbreak investigations in the UK.
<h3>N439K Mutation</h3>
Researchers around the world have been monitoring genetic changes in the virus, which accumulate as it replicates and transmits. The aim is to understand if any changes, or mutations, have an effect on the virus’s function, the severity of disease it causes, or transmission. So far, no mutation seen has altered the disease severity that the virus causes.
There is a focus on changes that affect the virus’s characteristic Spike protein. Like all coronaviruses, the SARS-CoV-2 virus has proteins that stick out of its core. These Spike proteins are the ‘crowns’ that give coronaviruses their name. It is this protein that allows the virus to attach to, and then enter, human cells. Any mutations that affect the Spike protein are vital to monitor, as they could potentially affect its function. It is also a part of the virus that our immune systems can ‘see’ and respond to. It <a href="https://www.cogconsortium.uk/news_item/commentary-cog-uk-report-9-25th-june-2020/">was reported previously</a> that a mutation in the Spike protein called D614G has increased in circulating viruses, in a way that is consistent with a slight increase in the rate of transmission.
COG-UK researchers, led by <a href="https://www.gla.ac.uk/researchinstitutes/iii/staff/davidrobertson/">Professor David Robertson</a> and <a href="https://www.gla.ac.uk/researchinstitutes/iii/staff/emmathomson/">Professor Emma Thomson</a> at the University of Glasgow, assessed all mutations in the Spike protein. One of these - N439K – was of particular interest. N439K results in a change to the part of the Spike protein that binds to human cells. It is stable in the current virus population; it was seen in over 500 samples in Scotland early on in the UK epidemic, but then died out following the lockdown in March. It is now present again in virus samples from across Europe, the UK and the US. The wide spread of this mutation indicates the virus can thrive with such mutations – there is no detriment to its function.
Once vaccinations begin at scale, the Spike protein will be under ‘selective pressure’, as many vaccines are targeted against it. It is possible that viruses with certain mutations will fare better under a vaccine-primed immune response than others. Ongoing, early-stage, laboratory studies support this hypothesis. Work has shown that virus with the N439K mutation is able to resist monoclonal antibodies – like those being trialled as treatments - yet still bind to its target on human cells. But unlike a monoclonal antibody treatment, vaccines will prompt the immune system to make a range of antibodies, and so even if the Spike protein can resist one, it is likely another will be able to neutralise the virus.
The researchers stress the importance of systematically monitoring Spike protein mutations, finding and assessing new ones to understand their effects. This will be essential in the run up to any vaccine being introduced. The COG-UK team has set up a group, and systems, with the dedicated aim of monitoring new and existing mutations, prioritising those that need in-depth analyses.
<h3>Local Outbreak Management</h3>
Researchers led by <a href="https://quadram.ac.uk/people/andrew-page/">Dr Andrew Page at the Quadram Institute</a> in Norwich, report on the analysis of 1,035 SARS-CoV-2 genomes collected in Norfolk between March and August 2020.
They combined genome sequence data with clinical data to understand the origin, genetic variation, transmission and spread of SARS-CoV-2 in the region. They confirmed an outbreak at a food-processing facility and ruled out a hospital setting as the source of another outbreak. Long term follow up found no evidence of reinfection.
The team also found 16 viral variants, or lineages, in health care workers that were not present in patients, showing that PPE and infection control measures work to stop transmission of the virus.
For full details, view the study on <a href="https://doi.org/10.1101/2020.09.28.20201475">MedRxiv</a>.
<h3>Human to cat transmission</h3>
<a href="https://www.gla.ac.uk/researchinstitutes/iii/staff/margarethosie/">Professor Margaret Hosie at the University of Glasgow</a> and colleagues looked at transmission of SARS-CoV-2 between humans and cats. Two cats from different COVID-19 infected households in the UK were shown to be infected with SARS-CoV-2 from humans.
There is no evidence of cat-to-human transmission, or that any domestic animals play a role in the epidemiology of human infections with SARS-CoV-2.
For full details, view the study on <a href="https://www.biorxiv.org/content/10.1101/2020.09.23.309948v1.full">BioRxiv</a>.
<h3>Summary of studies using COG-UK genomic data</h3>
COG-UK data and tools have been used in more than 120 live and retrospective SARS-CoV-2 outbreak investigations. This includes outbreaks in hospitals, communities, workplaces and settings managed by local authorities. For examples, see ‘<a href="https://www.cogconsortium.uk/wp-content/uploads/2020/09/8th-September-2020-Report-COVID-19-Genomics-UK-COG-UK-Consortium.pdf">COG-UK genomic surveillance in action</a>’.
As the speed and scale of SARS-CoV-2 genome sequencing increases, the ability to use genomic data to investigate a wide range of scientific and public health questions is also growing. COG-UK aims to provide a large scale genomic surveillance service to support the investigation of more live outbreaks in the UK.
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Hannah Olinger on Unsplash.com
Blog23 Oct 2020

Commentary: COG-UK report 12 – 15th October 2020

As of 22nd October, the COVID-19 Genomics UK (COG-UK) Consortium has sequenced more than 81,000 SARS-CoV-2 virus genomes from the UK, representing about 45 per cent of the global total.

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    [secondary_title] => <b>Please Note:</b> This report is provided at the request of SAGE and includes information on the ongoing state of the&nbsp;<span title="... research being carried out. It should not be considered formal or informal advice. The conclusions of the ongoing scientific studies may be subject to change as further evidence becomes available and as such any firm conclusions would be premature.">...</span>
    [excerpt] => COG-UK genome sequence data and tools have been used in more than 120 retrospective and live public health outbreak investigations in the UK since March 2020. Analysis of COG-UK and GISAID data highlights the need to establish a systematic approach for monitoring the appearance and spread of all variants of the SARS-CoV-2 virus
    [byline_text] => Report by the COVID-19 Genomics UK (COG-UK) Consortium
    [byline_date] => 20201016
    [main_image] => 1183
    [teaser_image] => 
    [content] => <h2>Executive Summary</h2>
<ul>
 	<li>COG-UK genome sequence data and tools have been used in more than 120 retrospective and live public health outbreak investigations in the UK since March 2020.</li>
 	<li>A viral lineage carrying a mutation, N439K, a probable antigenic variant owing to its location in the receptor binding motif of the SARS-CoV-2 spike protein, is now spreading in Europe (including 500+ infections in the UK). While there is no evidence that this variant will affect the efficacy of vaccines currently in development, it does highlight the need to establish a systematic approach for monitoring the appearance and spread of all variants and prioritising mutations of interest for further characterisation, in particular when selective pressure from mass vaccination programmes begins.</li>
</ul>
<hr />
&nbsp;
<h2>COG-UK summary</h2>
As described in <a href="https://www.cogconsortium.uk/wp-content/uploads/2020/09/8th-September-2020-Report-COVID-19-Genomics-UK-COG-UK-Consortium.pdf">COG-UK Report #11</a>, in addition to retrospective investigations, the consortium has been providing crucial support for the genomic surveillance of active SARS-CoV-2 outbreaks. An email survey of COG-UK site leads was used to collate information on the number of outbreaks in which investigations by the consortium using genomics have added value (Table 1). In total, COG-UK data and tools have been used in 120-166 live and retrospective SARS-CoV-2 outbreak investigations in public health and hospital settings in the UK to date.
[caption id="attachment_1162" align="aligncenter" width="1024"]<a href="https://www.cogconsortium.uk/wp-content/uploads/2020/10/table1.jpg"><img class="wp-image-1162 size-large" src="https://www.cogconsortium.uk/wp-content/uploads/2020/10/table1-1024x143.jpg" alt="" width="1024" height="143" /></a> <strong>Table 1:</strong> A summary of live and retrospective outbreaks in the UK for which COG-UK and PHA researchers have used consortium genomic data and tools. Exceedance describes defined outbreaks, for instance in a workplace. Surveillance programmes describe requests to look at everything in a local authority area, school, care home etc. Ranges are reported as some sites were only able to provide estimates.[/caption]
For a description of specific examples of the value added through the use of genomics by consortium members during outbreak investigations see <a href="https://www.cogconsortium.uk/wp-content/uploads/2020/09/8th-September-2020-Report-COVID-19-Genomics-UK-COG-UK-Consortium.pdf" target="_blank" rel="noopener">‘COG-UK genomic surveillance in action’, COG-UK Report #11</a>.
As the transition to a new operational phase continues through late 2020 and into 2021, COG-UK will provide large scale genomic surveillance service to support the investigation of a growing proportion of live outbreaks in the UK.
As described in the recent NERVTAG paper to SAGE, co-authored by COG-UK (<em>Is there evidence for genetic change in SARS-CoV-2 and if so, do mutations affect virus phenotype?</em>), there is increasing interest in monitoring mutations arising in the SARS-CoV-2 genome and determining whether these mutations have an impact on the biology of the virus, its transmission and the severity of the disease that it causes (See also ‘<em>A preliminary analysis of SARS-CoV-2 spike protein N439K lineages and surveillance of receptor binding mutations.</em>’ below). A COG-UK working group is being established to ensure that new and existing mutations are monitored in a systematic manner and that mutations of particular interest are prioritised for in depth analysis.
As the speed and scale of SARS-CoV-2 genome sequencing increases, the ability to use genomic data to investigate a wide range of scientific and public health questions is also growing. Accordingly, COG-UK is strengthening its interactions with other SAGE sub-groups, research consortia and public health bodies in the UK, and globally, so that the opportunities provided by integrating genomics can be realised. Dr Andrew Page of the Quadram Institute, Norwich has recently agreed to represent COG-UK on the SAGE sub-group focussed on social care homes. Dr Ewan Harrison of the Wellcome Sanger Institute represents the consortium on the sub-group focussed on ethnicity, and  Professor Judith Breuer of University College London on the nosocomial infection sub-group.
All five Health and Social Care Trusts in Northern Ireland are joining the SIREN study (the PHE priority study to determine if prior SARS-CoV-2 infection in health care workers confers future immunity to re- infection), and the Belfast Health and Social Care Trust is expected to join COG-UK’s Hospital-Onset COVID-19 Infections study. Northern Ireland will therefore be represented in both of these important UK-wide studies, with viral genome sequencing/analysis via COG-UK.
<hr />
&nbsp;
<h2>Analysis updates</h2>
<h3>A preliminary analysis of SARS-CoV-2 spike protein N439K lineages and surveillance of receptor binding domain mutations.</h3>
<h4>Study leads</h4>
David L Robertson<sup>1</sup>, Sebastian Maurer-Stroh<sup>2</sup>, Ana da Silva Filipe<sup>1</sup> and Emma C Thomson<sup>1</sup>
1. MRC-University of Glasgow Centre for Virus Research;
2. Bioinformatics Institute, Agency for Science, Technology and Research, Singapore
<h4>Question addressed</h4>
SARS-CoV-2 is continually accruing mutations as it replicates and transmits among the human population. While the majority of observed mutations have no effect on the biological properties of the virus and the rate of change is relatively slow, it is important that there is a systematic approach to identify new genetic changes and to assess their biological significance. While much attention has been focussed on the SARS-CoV-2 spike protein D614G mutation (See <a href="https://www.cogconsortium.uk/wp-content/uploads/2020/05/14th-May-2020-Report-COVID-19-Genomics-UK-COG-UK-Consortium.pdf" target="_blank" rel="noopener">COG-UK report #6</a>, <a href="https://www.cogconsortium.uk/wp-content/uploads/2020/07/25th-June-2020-Report-COVID-19-Genomics-UK-COG-UK-Consortium.pdf" target="_blank" rel="noopener">report #9</a> and Ref 1), other mutations in the spike protein may be of epidemiological and clinical relevance. This analysis describes the assessment of transmission and likely biological significance of one such mutation: N439K in the spike receptor binding motif is an example of a stable and circulating mutation in the receptor binding motif that binds to the ACE2 receptor on the surface of host cells to enable viral entry.
<h4>Methodology</h4>
Preliminary assessment of sampling proportions, phylogenetic distribution and the relationship between N/K at position 439 of the spike protein.
<h4>Findings</h4>
N439K was initially identified in a single lineage first detected in March 2020 and until recently was almost unique to Scotland where it infected more than 500 individuals (Figure 1).
[caption id="attachment_1163" align="aligncenter" width="1024"]<a href="https://www.cogconsortium.uk/wp-content/uploads/2020/10/phylogenetic_tree_5000_scottish_genomes.jpg"><img class="wp-image-1163 size-large" src="https://www.cogconsortium.uk/wp-content/uploads/2020/10/phylogenetic_tree_5000_scottish_genomes-1024x395.jpg" alt="" width="1024" height="395" /></a> <strong>Figure 1:</strong> Phylogenetic tree of 5000 Scottish SARS-CoV-2 genomes from COG-UK dataset (17/07/20) highlighting D614G lineages (left panel) and N439K lineages (right panel). Note that the K-439 lineage and most N-439 lineages are also G-614.[/caption]
This lineage also carries the D614G variant that has been associated with an increase in frequency among the population.
In line with the cessation in viral transmission in Scotland coincident with the lockdown in spring 2020, this UK lineage is now extinct and has not been observed since the 20th June in South Lanarkshire. However, N439K has now been identified in another fast growing lineage that has been sampled between late June and mid-August in Romania, Norway, Switzerland, Ireland, Belgium, Germany and now in all parts of the UK (Figure 2). The apparent sudden rise in August/September appears to be linked to relaxation of  control measures, the degree of sampling in these countries and its recent emergence in the UK with a high sampling rate. N439K has also been detected in four linked infections in the US and sporadically in genome data from elsewhere.
[caption id="attachment_1164" align="aligncenter" width="1024"]<a href="https://www.cogconsortium.uk/wp-content/uploads/2020/10/phylogenetic_gisaid.jpg"><img class="wp-image-1164 size-large" src="https://www.cogconsortium.uk/wp-content/uploads/2020/10/phylogenetic_gisaid-1024x551.jpg" alt="" width="1024" height="551" /></a> <strong>Figure 2:</strong> A) Phylogenetic tree of SARS-CoV-2 genomes from the COG-UK data in the context of the GISAID dataset highlighting the original Scottish N439K lineage and the more recent and currently spreading European N439K lineage associated with multiple UK lineages. B) Number of weekly cases and country location of the two N439K lineages from mid-March to 02/10/2020.[/caption]
Investigation of clinical outcomes from &gt;1600 Scottish patients infected with either the lineage defined by 439K versus the wild-type lineage (439N) showed no significant difference in disease severity. Phylodynamic analysis demonstrated that the Scottish N439K lineage has a relatively fast growth rate in spreading through the population (analysis by Sam Lycett, Roslin Institute), but this is likely due to the D614G background  of this lineage (Ref 1). Competitive virus growth experiments of these different mutants are underway at the MRC-University of Glasgow Centre for Virus Research.
Investigation of clinical outcomes from &gt;1600 Scottish patients infected with either the lineage defined by 439K versus the wild-type lineage (439N) showed no significant difference in disease severity. Phylodynamic analysis demonstrated that the Scottish N439K lineage has a relatively fast growth rate in spreading through the population (analysis by Sam Lycett, Roslin Institute), but this is likely due to the D614G background of this lineage (Ref 1). Competitive virus growth experiments of these different mutants are underway at the MRC-University of Glasgow Centre for Virus Research.
<h4>Key Conclusions</h4>
While SARS-CoV-2 genetic variation is accumulating, it is relatively constrained for an RNA virus.
Some spike amino acid replacements do seem to be changing the biology of the virus (e.g. D614G), although there is no current evidence that N439K, or other variants in the receptor binding motif (such as T478I and V483I, shown to have antigenic significance) have increased the potential for transmission or altered disease severity.
Importantly, these spike receptor binding domain variants appear to be relatively stable amino acid replacements that are not detrimental to viral fitness and are well tolerated in circulating lineages in the UK. This is a potential concern as vaccination programmes designed using these regions as targets begin to apply selective pressure on these lineages (see below for further discussion).
<h4>Discussion</h4>
In addition to N439K, other mutations are being observed in the spike receptor binding motif: S477N (&gt;300 UK sequences), T478I (&gt;100), S494P (&gt;20), E484Q (&gt;10), S477I (&gt;10), E484Q (&gt;10) and others at lower frequencies (Figure 3).
[caption id="attachment_1165" align="aligncenter" width="1024"]<a href="https://www.cogconsortium.uk/wp-content/uploads/2020/10/fig3.jpg"><img class="wp-image-1165 size-large" src="https://www.cogconsortium.uk/wp-content/uploads/2020/10/fig3-1024x715.jpg" alt="" width="1024" height="715" /></a> <strong>Figure 3.</strong> Receptor binding surveillance for UK complete genomes. Mutations resulting in amino acid replacements in or near SARS-CoV-2’s spike receptor binding motif that have been observed by 2020-10-06 are shown. Replacements occurring at least twice are listed (top).[/caption]
Collectively these demonstrate that mutations in the spike receptor binding motif are tolerated. The circulation of the N439K lineages demonstrates these viruses do not necessarily exhibit any apparent fitness cost. This is potentially concerning as this region is soon to be under selective pressure from a range of vaccine programmes.
Some of the mutations in the receptor binding domain have been documented to confer resistance to neutralising antibodies and to influence interactions with the ACE2 receptor, which may facilitate the evolution of additional mutations in the surrounding region that can lead to viruses able circumvent the impact of those neutralizing antibodies. Support for this concern has been provide by laboratory experiments showing that it is possible to select for SARS-CoV-2 spike protein mutations in the receptor-binding domain (including N439K) that remain functional and able to bind ACE2 receptors but can confer resistance to monoclonal neutralising antibodies or convalescent plasma (Refs 2 and 3).
It is therefore essential that a systematic approach is taken to identify and assess new genetic changes, in particular in regions important for host infection, viral transmission and for antigenicity. Whilst limited genomic diversity has emerged to date, this may change in the next phase of the epidemic as selective pressures exerted by vaccines, treatments and non-pharmaceutical interventions increases. As such, it is particularly important that surveillance of antigenic change is established in the lead up to the roll out of a vaccination program in the UK, since many of the vaccines under development target the spike protein.
Accordingly COG-UK has established a working group to establish a mechanism to ensure that new and existing mutations are monitored in a systematic manner and that mutations of particular interest are prioritised for in depth genomic, phylodynamic and virological analyses.
<h4>References</h4>
1. Volz, E. M, <em>et al</em>. Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity (2020) <em>medRxiv</em>, doi: <a href="https://doi.org/10.1101/2020.07.31.20166082" target="_blank" rel="noopener">https://doi.org/10.1101/2020.07.31.20166082</a>.
2. Weisblum, Y., Schmidt, F., <em>et al</em>. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. (2020) <em>bioRxiv</em>, doi: <a href="https://doi.org/10.1101/2020.07.21.214759" target="_blank" rel="noopener">https://doi.org/10.1101/2020.07.21.214759</a>.
3. Li, Q. <em>et al</em>. The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity. (2020) <em>Cell</em>, doi: <a href="https://doi.org/10.1016/j.cell.2020.07.012" target="_blank" rel="noopener">https://doi.org/10.1016/j.cell.2020.07.012</a>
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<h2>COG-UK recent publications</h2>
<h3>Large scale sequencing of SARS-CoV-2 genomes from one region allows detailed epidemiology and enables local outbreak management</h3>
<em>MedRxiv</em> - doi: <a href="https://doi.org/10.1101/2020.09.28.20201475" target="_blank" rel="noopener">https://doi.org/10.1101/2020.09.28.20201475</a>
<h4>Authors:</h4>
Andrew J Page, Alison E Mather, Thanh Le Viet, Emma J Meader, Nabil-Fareed J Alikhan, Gemma L Kay, Leonardo de Oliveira Martins, Alp Aydin, David J Baker, Alexander J. Trotter, Steven Rudder, Ana P Tedim, Anastasia Kolyva, Rachael Stanley, Maria Diaz, Will Potter, Claire Stuart, Lizzie Meadows, Andrew Bell, Ana Victoria Gutierrez, Nicholas M Thomson, Evelien M Adriaenssens, Tracey Swingler, Rachel AJ Gilroy, Luke Griffith, Dheeraj K Sethi, Rose K Davidson, Robert A Kingsley, Luke Bedford, Lindsay J Coupland, Ian G Charles, Ngozi Elumogo, John Wain, Reenesh Prakash, Mark A Webber, SJ Louise Smith, Meera Chand, Samir Dervisevic, Justin O'Grady, The COVID-19 Genomics UK (COG-UK) consortium
<h4>Summary:</h4>
Between March and August 2020, over 3,200 COVID-19 cases were reported in Norfolk. 1565 positive clinical samples from 1376 cases were collected in four major hospitals, multiple minor hospitals, care facilities and community organisations within Norfolk and the surrounding area were collected and subjected to whole genome sequencing. 1035 cases resulted in genomes of sufficient quality for phylogenetic analysis, which revealed the presence of 26 distinct global lineages and 100 distinct UK lineages, with local evolution at a rate of 2 SNPs per month. Sequence data was combined with clinical metadata to understand the origin, genetic variation, transmission and spread of SARS-CoV-2 within the region. Highlights from this county-level analysis included the identification of a single sub-lineage associated with cases in 6 care facilities; confirming an outbreak at a food-processing facility; the ruling out of a nosocomial origin for another outbreak; and the identification of 16 lineages in health care workers not present in patients, demonstrating the effectiveness of infection control measures. The analysis also found that the D614G spike protein variant dominated in the samples, while longitudinal samples showed no evidence of reinfection.
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<h3>Respiratory disease in cats associated with human-to-cat transmission of SARS-CoV-2 in the UK</h3>
<em>BioRxiv</em> - doi: <a href="https://doi.org/10.1101/2020.09.23.309948" target="_blank" rel="noopener">https://doi.org/10.1101/2020.09.23.309948</a>
<h4>Authors:</h4>
Margaret J Hosie, Ilaria Epifano, Vanessa Herder, Richard J Orton, Andrew Stevenson, Natasha Johnson, Emma MacDonald, Dawn Dunbar, Michael McDonald, Fiona Howie, Bryn Tennant, Darcy Herrity, Ana Da Silva Filipe, Daniel G Streicker, Brian J Willett, Pablo R Murcia, Ruth F Jarrett, David L Robertson, William Weir, the COVID-19 Genomics UK (COG-UK) consortium
<h4>Summary:</h4>
During the COVID-19 pandemic, naturally occurring infections following transmission have been reported in domestic and non-domestic cats, dogs and mink. In this study, two cats from different COVID-19-infected households in the UK were shown to be infected with SARS-CoV-2 from humans. Infection was demonstrated using a range of approaches, including immunofluorescence, in situ hybridization, PCR testing. Post-mortem tissue samples for cat 1 displayed pathological and histological findings consistent with viral pneumonia, while cat 2 presented with rhinitis and conjunctivitis. Whole genome sequencing and analysis of the virus from cat 2 revealed five single nucleotide polymorphisms (SNPs) compared to the nearest sequenced UK human SARS-CoV-2 isolate (from the same UK county), although comparison with genomes from 9 other feline SARS-CoV-2 isolates revealed no shared cat-specific mutations. At present, there is no evidence of cat-to-human transmission or that cats, dogs or other domestic animals play any appreciable role in the epidemiology of human infections with SARS-CoV-2.
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<h3>Download a PDF of this Report</h3>
<ul>
 	<li><strong><a href="https://www.cogconsortium.uk/wp-content/uploads/2020/10/15th-October-2020-Report-–-COVID-19-Genomics-UK-COG-UK-Consortium.pdf" target="_blank" rel="noopener">15th October 2020 Report – COVID-19 Genomics UK (COG-UK) Consortium.pdf</a></strong></li>
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Report16 Oct 2020

Report 12: 15th October 2020 – COVID-19 Genomics UK (COG-UK) Consortium

COG-UK genome sequence data and tools have been used in more than 120 retrospective and live public health outbreak investigations in the UK since March 2020. Analysis of COG-UK and GISAID data highlights the need to establish a systematic approach for monitoring the appearance and spread of all variants of the SARS-CoV-2 virus