Alessandro M. Carabelli, David L. Robertson, Sharon J. Peacock
A recent review on variants and mutations by COG-UK consortium members provides an update on our latest understanding on aspects of SARS-CoV-2 evolution linked to immune escape. We also provide an update on the latest improvements to the COG-UK Mutation Explorer tool.
SARS-CoV-2 has been evolving in the human population since it emerged in 2019. Highly deleterious mutations in the SARS-CoV-2 genome are rapidly purged, with most mutations being either neutral (have no effect on the virus’ biology) or mildly deleterious. But more than a year into the pandemic, we are increasingly focusing on rare large-effect mutations that contribute to virus adaptation and antigenic change. This includes changes leading to enhanced infectivity, transmissibility, ability to cause severe disease and immune escape.
These virus fitness-enhancing mutations are not new in the short history of the SARS-CoV-2 pandemic. The first major genetic change was detected within months of SARS-CoV-2 infection in humans. Specifically, D614G, a spike protein amino acid change, rapidly increased in frequency from as early as April 2020 and emerged several times in the global SARS-CoV-2 data. Now, it is present in at least 80% of all SARS-CoV-2 variants associated with human infection. Studies have since shown that D614G confers a moderate increase in infectivity and transmissibility. However, it took less time for the virus carrying this mutation to reach all corners of the globe than it took for us to understand why this occurred based on virus biology. At a time when rapid answers are needed to inform pandemic responses, it can still take time to understand the precise mechanisms by which a variant becomes more successful. This is complicated by the role of chance in terms of which variants are associated with epidemiological events.
This “lottery” element to variant success is exemplified by what came next in Europe with the emergence associated with travel to Spain and subsequent widespread European dissemination of lineage B.1.177. Was it more transmissible? If so, were any mutations responsible for this? Evidence to date suggests that although B.1.177 was associated with some unique mutations, e.g, S:A222V, this was very effectively spread by the high numbers of people travelling during the summer of 2020. This resulted in numerous introductions into the UK population at a time when infection rates were relatively low and so any onward infections were likely to be with B.1.177.
Next came a period of very significant SARS-CoV-2 change, essentially a second phase in the pandemic. From around October 2020 onwards, viral variants began to emerge in several geographically distant regions of the world that carried much higher numbers of mutations, many of which were the same, a process referred to as convergent evolution. These mutations arose in viruses from different lineages (or branches) of the SARS-CoV-2 evolutionary tree. It is highly likely that these variants were selected for because, after a period of intense global infection, parts of the human population were becoming increasingly immune to the original virus or they had evolved in the context of chronic infections. These variants were more successful because they spread more rapidly, and/or had some degree of immune evasion.
Globally, four “Variants of Concern” have been identified: B.1.1.7 (also named “Alpha” by the WHO) was first detected in Kent and is more transmissible than the original virus from Wuhan B.1.351 (“Beta”) and B.1 (“Gamma”) first detected in South Africa and Brazil, respectively, are more transmissible than the original virus and have some degree of immune evasion. Another variant, the B.1.617.2 (“Delta”), first detected in India, is now spreading in the UK and numerous other countries. The transmissibility of Delta is the topic of intensive study, but it is likely to be similar to/higher than Alpha. A fifth Variant of Concern has been designated by Public Health England for a sublineage of Alpha carrying S:E484K mutation. There are also numerous Variants of Interest/Variants Under Investigation, suspected to have at least some change in biology associated with mutations that are either present in Variants of Concern, or associated with experimental evidence of immune escape.
Countries with strict border controls can prevent ingress and infection, but on a global scale all Variants of Interest or Concern have travelled the globe. Furthermore, it is very challenging to predict with any degree of success what mutations could arise in the future. Public Health interventions remain vital, because they can slow the progression of transmission, and hence mutation, and provide a window of time to enhance vaccination coverage in at-risk populations. The ultimate key is widespread global vaccination.
Sequence data provides a vital public health tool to guide future vaccine strategies. A recent review by COG-UK consortium members and ongoing developments of our COG-UK Mutation Explorer aims to provide information to laboratory scientists, diagnostic test developers, vaccine manufacturers and policy makers. So, what new insights do these provide?
In the review from Harvey, Carabelli and colleagues (Ref. 1), the authors summarise the literature on mutations of the SARS-CoV-2 spike protein (the primary antigen) focusing on their impacts on antigenicity and providing context in terms of protein structure and observed mutation frequencies in global sequence datasets (Figure 1). Although prediction of mutational pathways by which a virus will evolve is extremely challenging, this review highlights the importance of collating knowledge from the experimental literature on the effect of SARS-CoV-2 spike mutations on antigenicity (immunity mediated by antibodies) and other aspects of the virus (e.g. ACE-2 binding affinity).
The integration of these data and emerging SARS-COV-2 sequences has the potential to facilitate the automated detection of potential Variants of Concern at low frequencies. Tracking the emergence of viruses flagged as potential antigenically significant variants will help guide the implementation of targeted control measures and further laboratory characterisation.
Figure 1. Amino acid substitutions that characterise Variants of Concern, their localisation in the spike protein (in red), associated antibody classes (four receptor binding classes and the N-terminal domain class), frequency, antibody accessibility, antigenicity, the effect on monoclonal antibodies (mAbs) and convalescent sera, and on ACE-2 binding.
The authors also provide up-to-date literature on the efficacy of vaccines and therapeutics against the known Variants of Concern. However, although recent data show that vaccines are effective at preventing the most severe symptoms of COVID-19, as Variants of Concern continue to infect people they accumulate changes over time, generating “variants of variants”. In this regard, it is important to monitor any mutation that might have an antigenic role, and provide the virus a mechanism to evade the host immunity. For instance, as reported by the COG-UK Mutation Explorer, some mutations are already accumulating in Delta (Figure 2). Epidemiological studies will allow us to verify this. Data on other Variants of Concern and Interest can be found in the dashboard.
Figure 2. Antigenic mutations on the top of B.1.617.2 defining mutations
Most of the mutations in Delta are at low frequency and therefore their percentage (over the total counts of that specific lineage) is also low (e.g. E484A, N501Y and A831V). Some mutations appear to have become more established, as in G142D and K417N. The latter is known to be located at the edge of the receptor binding domain (RBD), and reduces neutralisation by some monoclonal antibodies (mAbs), but enhances neutralisation by some other mAbs in Beta (Ref. 2 and 3). It is not known whether this mutation confers an advantage to Delta, especially in the context of a heavily vaccinated population. Experiments have already been started by COG-UK associates in order to assess the effect of these mutations on variant biology.
References
- Harvey, W.T., Carabelli, A.M., Jackson, B. et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol (2021).
- Chen, R.E., Zhang, X., Case, J.B. et al. Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies. Nat Med 27, 717–726 (2021).
- Starr, T. N. et al. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. Science 371, 850, (2021).
COVID-19 Genomics UK (COG-UK)
The current COVID-19 pandemic, caused by SARS-CoV-2, 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 academic partners providing sequencing and analysis capacity. A full list of collaborators can be found here. Professor Peacock is also on a part-time secondment to PHE as Director of Science, where she focuses on the development of pathogen sequencing through COG-UK.
COG-UK was established in April 2020 supported by £20 million funding from the COVID-19 rapid-research-response “fighting fund” from Her Majesty’s Treasury (established by Professor Chris Whitty and Sir Patrick Vallance), and administered by the National Institute for Health Research (NIHR), UK Research and Innovation (UKRI), and the Wellcome Sanger Institute. The consortium was also backed by the Department of Health and Social Care’s Testing Innovation Fund on 16 November 2020 to facilitate the genome sequencing capacity needed to meet the increasing number of COVID-19 cases in the UK over the winter period.
