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EXPLAINER: SARS-CoV-2 mutations, what we have learned from new fast-growing lineages and the Spike N439K variant 

What do we know about the apparently fast-growing 20A.EU1 cluster? And why is it not enough to draw any biological conclusion?

In a recent preprint,  Hodcroft et al. described the 20A.EU1 SARS-CoV-2 ‘cluster’ (also designated as lineage B.1.177), which has been spreading in Europe and seems to have originated in Spain (Ref 1). This lineage is associated with a large number of infections and its detection in multiple countries, including the UK, suggests that this spread is associated with travel to/from Spain over the summer. There is currently no reason to believe that there is anything exceptional about the virus itself compared to previous variants.

Hodcroft et al. speculated, with appropriate caution, that the ‘success’ of the B.1.177 lineage may be associated with the presence of the A222V mutation which refers to an amino acid replacement at position 222 in the SARS-CoV-2 spike protein. The spike protein is known to interact with the hACE2 receptor to enable viral entry into host cells. A222V is present in all of the viruses in this lineage, but is otherwise uncommon among SARS-CoV-2 lineages. Conducting experimental work will be important to confirm that the biological properties of this virus and/or its ability to transmit and cause disease are not altered. Severe cases of COVID-19 infection are strongly associated with age and certain comorbidities, so there is no expectation that this variant will have an impact on disease severity (as shown for the previously studied spike protein variants such as D614G (Ref 2)).

Is SARS-CoV-2 changing?

Mutations are continuously accruing in the SARS-CoV-2 genome as the virus replicates and circulates among the human population. As is common for other viruses associated with large outbreaks, the vast majority of the mutations observed in SARS-CoV-2 have no effect on the virus and only a few are likely to change virus biology or infectivity. Much attention has focused on the D614G mutation of SARS-CoV-2, which refers to a switch in amino acid at position 614 in the sequence of the spike protein. Analyses from COG-UK and others have suggested that the switch made the virus slightly more transmissible (but not more likely to cause severe disease). The D614G mutation is now the dominant circulating form of the virus around the world and its success appears to be strongly linked to its early emergence. To monitor the evolution of viral variants associated with biological features that pose a greater threat to human health (e.g. through increased transmissibility or altering antigenicity), it is important to carefully characterise new mutations using experimental studies.

Why is it important to combine epidemiological studies to experimental work?

Considerable attention has been given to the spike protein whose receptor binding motif (RBM) is the most variable region of spike and is responsible for viral entry via its interaction with the  receptor (hACE2) on host cells. Mutations in the RBM do occur in SARS-CoV-2 circulating variants, demonstrating that they are tolerated and do not have a negative impact on viral replication or transmission. As of the 20th October, 2020, 10 vaccines are currently in Phase III clinical trials, while many antibody based treatments are in the discovery and development phase. Most of these potential therapies are programmed to target different regions of the spike protein. Since they were designed from the Wuhan reference genome (the earliest genome sequence of the virus), mutations affecting the spike protein may have the potential to confer the ability to evade the immune response induced by promising vaccines or antibody-based treatments. 

In a recent preprint from the COG-UK consortium, Thomson et al. in collaboration with Vir Biotechnology investigated another variant with a mutation in the spike protein (N439K) originating from lineage B.1, observed in March 2020 in Scotland, extinct in June, and now circulating in multiple countries including Europe as another large lineage and again independently in the USA  (Figure 1, Ref 3). Based on a comparison of all of the Scottish lineages, the authors found no evidence for a faster rate of growth for the N439K variant beyond that already determined for the D614G mutation which is also found in all variants carrying N439K. However, Thomson et al. demonstrated in the laboratory that N439K enhances binding affinity to the hACE2 receptor and is able to escape the neutralising activity of some monoclonal antibodies (mAbs), including one in clinical trials, and from antibodies present in sera from a sizeable fraction of people recovered from infection. In a large comparison of Scottish patients no increased disease severity was observed. It will be important to assess whether viruses carrying N439K have the potential to be resistant to the natural immune response, which may make them more likely to be associated with reinfections.

Figure 1. Phylogenetic tree showing relationship between global SARS-CoV-2 variants with N439K Spike variants highlighted in colour. Two significant N439K lineages, lineages i and ii, have been detected to date and several incidental infections. Vertical bars indicate the global lineage, presence of N439K  or presence of D614G. Visualisation by Áine O’Toole, University of Edinburgh

 

What is the right approach to identify mutations with epidemiological and clinical significance?

Although the N439K mutation only shows limited ability to evade immunity in laboratory tests, these findings highlight the need for surveillance focussing on the contribution of genetic factors at a molecular level and at a clinical level. The analysis of N439K represents an example of the systematic approach that scientists can take to guide development and usage of vaccines and therapeutics. If a virus is found to be resistant to specific vaccines or drugs, screening patients or populations for the presence of these variants might allow alternative therapeutic options to be considered. In this way, the combination of epidemiological studies which allow the identification of new variants spreading among communities and experimental work carried on by virology groups, is necessary to fully characterise SARS-CoV-2 mutations and their biological and clinical importance. 

 

References

  1. https://www.medrxiv.org/content/10.1101/2020.10.25.20219063v1
  2. https://www.medrxiv.org/content/10.1101/2020.07.31.20166082v2
  3. https://www.biorxiv.org/content/10.1101/2020.11.04.355842v1

 

COVID-19 Genomics UK (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.

Led by Professor Sharon Peacock of the University of Cambridge, 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 twelve academic partners providing sequencing and analysis capacity. A full list of collaborators can be found here: https://www.cogconsortium.uk/about/

COG-UK was established in March 2020 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