Variants of SARS-CoV-2: An exceptional virus, or one that is behaving normally?

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This blog will consider the new variants of SARS-CoV-2. The disease associated with this virus has been named ‘COVID-19’. It will also introduce the work of the COVID-19 Genomics UK Consortium (COG – UK), part of a larger worldwide effort, which was set up at the start of the pandemic to track the genetic mutations and ‘lineages’ of the virus. It will also consider some implications of new variants alongside what we already know about increased transmissibility. But as you will see, predictions about how ‘natural selection’ operates within the viral world are problematic because of the sheer speed, unpredictability and volume of mutations.

Note, this blogpost is a little longer than regular SPICe Spotlight blogs, due to the scientific detail. Please use the contents pop-out below for ease of navigation.

Before we go any further, some definitions might be helpful. However, it should be noted that the nomenclature of viruses is not a settled matter in genetics communities.

Variants, mutations, lineages and strains: some definitions

Strain – this refers to the type of severe acute respiratory syndrome-related (SARS) type of coronavirus it is. There are many categories of coronavirus. The strain responsible for the disease COVID-19 is SARS-CoV-2.

Mutation – is used to describe a replacement (substitution) of a base in the genome, or a deletion or insertion event. Duplications and movement (transposition) of genetic material are also possible.

Base – The bases are found in DNA and there are four types: adenine, cytosine, guanine, and thymine—often abbreviated as A, C, G, and T, the letters of the genetic ‘alphabet’. These are what carry the genetic information. However, coronaviruses are RNA-based (single stranded) – simpler in form – and the bases are A,C,G and U, ‘u’ standing for uracil, instead of thymine.

Viral variant – refers to a distinct virus, which may have a combination of different mutations. But it is still SARS-CoV-2.

Lineage – this refers to the many thousands of variants of the SARS-CoV-2 strain of coronavirus. Because viruses replicate so quickly, mutations are frequent. Also, RNA viruses are particularly error-prone during replication. Many lineages vary only slightly with a small number of defining mutations. They are called lineages because they look a little like family trees when mapped. From these family trees – or viral genomic sequences – it has been possible to track the course of the virus over actual geography as it has moved across the world.

The new variant and NERVTAG

Much like a year ago, the news of a new, more easily transmissible variant of SARS-CoV-2 started quite quietly in early December 2020, when COG-UK identified a distinctive cluster of viruses in south east England, that they called the ‘B.1.1.7 lineage’. You may also see it referred to as VUI-202012/01 or VOC-202012/01. VUI stands for Variant Under Investigation, and VOC stands for Variant of Concern. I will return to the arcane matter of naming and classifying a bit further on.

NERVTAG (New and Emerging Respiratory Virus Threats Advisory Group) is an expert committee of the UK Department of Health and Social Care that advises the UK Chief Medical Officer and Ministers. They have met monthly over the past year and they most recently met on 18 December 2020 to consider evidence on the new variant, B.1.1.7.

The Group considered three different papers:

This meeting, along with continuing rising cases, led us into the current tightened restrictions after Christmas.

What is COG-UK?

Led by Professor Sharon Peacock of the University of Cambridge, COG-UK comprises a partnership of NHS organisations, the four Public Health Agencies of the UK, the Wellcome Sanger Institute, and 12 academic partners providing genome sequencing and analysis capacity for government and collaborators across the world. It was established specifically for sequencing SARS-CoV-2 viral genomes as quickly as possible. The MRC Centre for Virus Research at the University of Glasgow is a partner, as is the University of Edinburgh.

It held a public ‘showcase’ event in mid-December discussing the work done so far in tracking the genome of the virus and its many variants, or lineages caused by many mutations. So far they have sequenced over 131,000 viral genomes of SARS-CoV-2. These have been rendered into a visual map for the Global Initiative on Sharing Avian Influenza Data (GISAID) with details of each recorded genome and where it has arisen. It is a global centre, set up in 2008 for the sharing of influenza data and for collaboration between scientists. It has been the site for sharing data relating to SARS-Cov-2.

The image below provides an impression of the growth and spread of SARS-CoV-2 lineages over time (link for interactive version). Each dot represents a sequenced genome along the various lineages of the virus (shown as grey branches) over the past year.

Mutations are the norm, and each of these genomes is like a small branch of a family tree, whereby the generations aren’t measured in years, but in days and weeks. From this work in sequencing, the scientists have been able to identify with remarkable precision how and where the virus has spread, in its quickly changing form. These changes might be a single mutation or a number of mutations. Some lineages are already extinct, some are thriving, having some small adaptive advantage. One of these major advantages is transmissibility.

What type of mutations are happening?

Nature published a paper in February 2020 warning caution about jumping to conclusions that a mutation is automatically dangerous or unusual. It also highlights that the effect of mutations and making predictions about any effect is far from straightforward. Sometimes a single mutation can have a significant impact, but at other times, multiple mutations, as we have seen in the number recorded already for SARS-CoV-2, have none or little impact. Many are neutral markers used for contact tracing and mapping the movement of the virus. Certain mutations, because they confer a selective advantage to the virus, have cropped up in the new variants

The mutations that are particularly concerning with the new variants are those appearing on the so-called ‘spike’ protein of the virus. This is the part of the virus that attaches to the ‘receptors’ on the cells in the body and also, crucially, the part of the virus that vaccines are targeting. So, if, as is thought, the protein binds more effectively, a person is more likely to become infected if exposed, and would require less exposure to become infected. It is this ability that makes the virus more transmissible.

It is also possible that other mutations are increasing transmissibility in other ways. The more infections – the better the virus spreads, the more opportunities there are for further random mutations to occur; ultimately a variant could emerge that the vaccines can’t generate immunity against. Mutations can also occur that would affect the body’s ability to ‘fight off’ the disease, by affecting the ability to produce antibodies for example, or by rendering antibodies from a previous infection ineffective. It is this latter issue that is of concern with the current variants.

It is easy to forget that a proportion of people who test positive (and who aren’t tested) will be asymptomatic. This article in the British Medical Journal (BMJ) discusses the complexities of the clinical assessment of someone testing positive, and reminds us that testing is usually to confirm a clinical diagnosis, not to assess infectiousness, and that the relationships between viral load, viral shedding, infectiousness and duration of infectiousness are not well understood. The vaccines add a further relationship into this mix. The current thinking is that around 20% of infections are asymptomatic.

Variants of note of SARS-CoV-2

The World Health Organisation  (WHO) have published an overview on variants of SARS-CoV-2. This also includes information on the variants associated with mink in Denmark and with information on one identified in South Africa. In the week or so we have also learned of the Brazil variant which has prompted further concern.

A number of variants have been highlighted since the beginning of the pandemic. The first was back at the start, in late January or early February 2020 (WHO).

A mink-associated variant was identified in June 2020, in Denmark, and had been transmitted from humans to mink, but with the possibility that it could transmit back again. Denmark, the Netherlands, Spain, Sweden, Italy and the United States of America have reported SARS-CoV-2 in farmed minks to the World Organisation for Animal Health (OIE).  In Denmark, as well as culling 19 million farmed mink, surveillance was stepped up and the genome sequences were rapidly shared. Only 12 human cases were identified in Denmark in this so-called ‘Cluster 5’ variant.

On 14 December 2020, the UK reported a variant they had named SARS-CoV-2 VOC 202012/01. The variant contains a high number of mutations appearing over a short time. This article pinpoints the use of convalescent plasma in very ill patients as a possible contributory factor in the number of mutations. The two earliest sampled genomes that belong to the B.1.1.7 lineage (VOC 202012/01) were collected on 20 September 2020 in Kent and another on 21 September 2020 from Greater London, and within a few weeks began to replace other virus lineages in the south east. As of 26 December 2020 the variant had been detected across the UK and by 30 December had been reported in 31 other countries/territories/areas. In the UK the percentage of those testing positive with the new UK variant is being recorded and reported by the Office for National Statistics.

Hot on the heels of this news was information on a new variant in South Africa on 18 December 2020. South Africa has named this variant 501Y.V2, referring to a particular mutation in its lineage. While SARS-CoV-2 VOC 202012/01 from the UK also has this mutation, analysis has shown that 501Y.V2 from South Africa is a distinct variant. Transmissibility is the issue of concern rather than seriousness of disease. One of the mutations, also present in the South African variant but not the UK variant, is present in the Brazil variant, and once again on the spike protein, making it better able to evade any present antibodies, and therefore enter cells more easily.

Viral variants – are they normal?

There is nothing exceptional about SARS-CoV-2 in its behaviour in the context of evolution. Mutations occur, and natural selection will mean that mutations that aid transmissibility will thrive; the virus has become more successful. Just because new variants are arising does not necessarily mean that in and of themselves they affect morbidity or the risk of mortality rates. So, at the moment, the percentage of those infected who need hospitalisation has not increased. But the overall number, as we are sadly seeing, is rising because of the increased transmissibility, and the known severe effects of the disease on some people.

It also makes sense that the disease that develops where the new variants are present is not more severe. If the host dies, then that host can no longer provide the means for the virus to replicate or transmit. But viruses evolve at very different rates and very different ways. Herpes simplex, for example, can remain latent indefinitely following infection and initial symptoms, so has adapted to survive within the body. Other viruses, like norovirus, spread very rapidly, with little adaptation within the body.

However, over time, for this reason, viruses tend to become less harmful rather than more so, as immunity builds up within a population or adaptation of the virus is limited and its consequences are predictable, if deadly. That said, as adaptations have increased transmissibility, this becomes moot when the disease itself, combined with the body’s response, and immune response to it can remain so devastating. The new UK variant appears to be seen in a higher proportion of under 20 year olds, not that this necessarily means anything other than that they testing positive.

SARS-CoV-2 appears to be particularly adept in a number of ways: it has mutated to become more transmissible, it can ‘hide’, in not causing severe or any illness in many (while remaining highly transmissible) But it also causes devastating acute and chronic symptoms, regardless of mutation, in those who are susceptible, and it did this from the outset.

What is striking is the focus there is on tracking and mapping the mutations and genomes of this strain of coronavirus, and the sheer number of genome sequences identified. If nothing else, in time, with the efforts and knowledge applied to this particular virus and its variants, much more will be known to inform future pandemic planning. However, it was noted in the NERVTAG meeting on 4 December 2020 that while COG-UK is tracking all the mutations, there isn’t yet a body looking at the consequences of them:

there is no systematic mechanism in the UK to explore the phenotypic consequences of genotypic changes. COG-UK carry out sequencing, there is an immunology consortium to investigate the immunobiology of the virus, but there is no group tasked to investigate the molecular virology of the virus.”

It was noted at this meeting though, that one particular mutation appeared to result in increased transmissibility, one that had been identified early in the pandemic.

Are the tests still effective for new variants?

Following a rapid evaluation, Public Health England has confirmed that lateral flow devices, LFDs, used in the mass testing in Liverpool is effective in detecting the new variant (VOC 202012/01).

PCR, or polymerase chain reaction tests generally detect more than one gene target and are designed in the knowledge that mutations are frequent. They can be readily adapted and detect the virus itself, not an immune response to a virus (antibodies). Guidance has been issued to laboratories on testing for the new variants.

Are the vaccines still effective against the new variants?

This is a key question. Every year the influenza vaccine has to be altered (even though it is a different type of virus). The jury is not completely unanimous – it is very early days in the roll-out of the vaccine, so for any variants, true efficacy will only become clear once most people have been vaccinated.

Whether a vaccine has to be altered will depend on a number of factors. However, the consensus, as put forward by the WHO Chief Scientist, seems to be that because the vaccines stimulate a broad immune response, the vaccines that have been approved should provide protection against new variants. Also, the consensus appears to be that vaccines will be relatively easily adapted to the UK variant. As noted above, concern arises when the body’s ability to produce antibodies is interrupted by virus mutations, as has been suggested in relation to the particular mutation identified in the Brazil and South African variants.

For information on the mechanisms of how two of the approved vaccines act to stimulate an immune response, see the Medicines and Healthcare Products Regulatory Agency (MHRA) reports on the Pfizer/BioNTech vaccine and on the Oxford AstraZeneca vaccine.

A very recent paper that has yet to be peer-reviewed suggests that it is more likely that vaccines might need to be reviewed and adjusted. The study, by researchers in South Africa, found that the variant that is circulating there (with a handful of cases identified also in the UK) might be able to evade existing antibodies, making reinfection more possible. Antibody response stimulated by the vaccines might also be rendered ineffective against infection.

Another small ray of light – our immune response to previous infection might protect us from further infection

Public Health England reported on 14 January 2021 that having had COVID-19 confers immunity, possibly up to around 80%.

Many questions about the virus are still unanswered and now the new variants add more questions to the list:

  • Why are some apparently unaffected by COVID-19, even if infected?
  • Will the vaccines confer long-term immunity?
  • How long is the duration of immunity from natural exposure?
  • What will be the effect of future mutations?
  • Might the virus mutate into something that we barely notice in years to come, with only mild symptoms, such as a cough or temporary loss of smell for a while?

These are questions that can be applied more generally to immunology, but the ability to sequence genomes at such pace, to produce vaccines in such a short time-scale and to track the course and lineages of this particular virus across the globe will surely equip us better, ahead of any other viral pandemic.

Anne Jepson, Senior Researcher, Health and Social Care