Alessandro M Carabelli and David L Robertson
SARS-CoV-2 mutations, the science behind the mink case
What do we know about the Danish ‘Cluster 5’?
The Danish government will cull 17 million farmed mink in the country after detecting variants of the SARS-CoV-2 in these animals with mutations that have been transmitted back to humans (corroborating recent reports from the Netherlands Ref 1 and Ref 2). The Danish prime minister described these viral variants as a potentially serious threat for the development of a future vaccine as they allegedly showed resistance to antibodies present in sera from people recovered from infection. However, the supporting evidence for this statement has not yet been provided.
Mink are highly susceptible to SARS-CoV-2, and there have been several outbreaks reported in mink farms in China, US, the Netherlands, Spain and Denmark. The Staten Serum Institut, supported by the Danish Ministry of Health, reported the presence of a cluster of variants, ‘cluster 5’, consisting of four mutations, defined by a two amino acids deletion (69-70) and three amino acid replacements in position 453, 692 and 1229 (Y453F, I692V and M1229I) in the Spike protein (the protein used by the virus to bind host cells), which are now spreading among farmed mink and small numbers of people in Denmark (Ref 3 and Ref 4). Danish scientists are particularly concerned about the variant containing all four of these mutations, at the moment found in only twelve people in Denmark, but not elsewhere.
Phylogenetic analyses by the COVID-19 Genomics UK (COG-UK) consortium show that the 69-70 deletion can also be associated with the N439K mutation at the spike receptor binding motif (RBM) (see glossary below). This mutation has recently been characterised by scientists in the COG-UK consortium and has raised attention because it increases binding affinity to hACE2 host cells receptor and confers resistance to some antibodies in laboratory studies, including one in clinical trials (Ref 5). A summary of our findings can be found in Ref 6. However, there is no evidence to date to indicate that this mutation will confer resistance to any vaccine in development. The consortium is waiting for further access to genome data and will provide an update on this as soon as possible.
The I692V variant seems to be observed only in the ‘cluster 5’, whereas M1229I is present throughout much of Europe, with a peak in the Czech Republic. While no experimental characterisation of the I692V and M1229I mutations is present in the literature, mutations in this region of the spike protein are not anticipated to have a significant effect on viral infectivity or antibody susceptibility because localised relatively far from the RBM.
The Y453K mutation, which occurs in the RBM, although rare, has been previously observed in SARS-CoV-2 genomes isolated in humans, including in the Netherlands. This mutation has arisen multiple times in several sublineages. Recently, this mutation has also been shown in laboratory studies to increase the affinity of spike protein binding to the human ACE2 receptor (Ref 7). Based on protein structure models, it has been speculated that Y453F may help the virus to infect mink, which have a slightly different ACE2 receptor from humans (Ref 8). However, presently available data are not sufficient to suggest a transmission directionality between mink and humans for this lineage, and it remains to be determined whether these are simply human viruses transmitted to mink. This variant does not seem to have expanded among the human population, but noting that many other replacements close to the RBM do occur in widely circulating variants, COG-UK will continue surveillance on Y453F (and all Spike mutations) to monitor for any further spread.
This report is based on current evidence, and may be updated as more information becomes available and experimental work follows up.
- Starr, T.N. et al. (2020) Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding. Cell. 182 (5) 1295-1310. https://doi.org/10.1016/j.cell.2020.08.012 (https://jbloomlab.github.io/SARS-CoV-2-RBD_DMS/)
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
Variant: a virus based on an earlier virus with one or more minor changes (mutations)
Mutation: a change in the virus’ genome which is the set of genetic instructions that contain all the information that the virus needs to function. When the virus replicates, this set of instructions needs to be copied, but errors can occur during this process. Depending on where in the genome mistakes happen, they can have a negative or positive impact on the virus’ ability to survive and replicate, or can affect regions that are targeted by immunity allowing the virus to escape.
Spike protein: The Spike protein is one of the major structural proteins of SARS-CoV-2. It is essential for the interaction of the virus with host cell receptors and subsequent fusion of the viral envelope with host cell membrane to allow infection.
Receptor Binding Motif (RMB): RBM is responsible for viral entry via its interaction with the receptor (hACE2) on host cells. This region is also targeted by several therapeutics in the development phase (monoclonal antibodies and vaccines).
Angiotensin-converting enzyme 2 (hACE2) receptor: Host cells receptor which interacts with SARS-CoV2 Spike and triggers viral entry into the host cell.