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A variant of the SARS-CoV-2 virus known as B.1.1.7 – or VOC202012/01 – has been identified in the UK and classified as a "variant of concern" by Public Health England (PHE).
The variant appears to be linked to the rising number of COVID-19 cases in the UK that ultimately led Prime Minister Boris Johnson to declare a nationwide lockdown on January 5.
What we know so far regarding the molecular biology of VOC202012/01 stems from a new preprint* study by researchers at Imperial College London, which suggests that this variant is more infectious, but does not cause a more severe case of COVID-19.1
What are variants and why do they occur?
Viruses need a host to survive and are subject to pressures that require them to mutate, resulting in the circulation of different variations of the same virus. This happens in common infectious diseases such as influenza. SARS-CoV-2, the virus that has caused the COVID-19 global pandemic, is no exception.
The steps required for SARS-CoV-2 infection involve a variety of molecular machinery. A genetic mutation resulting in a change to specific components of this molecular machinery can impact how the virus interacts with a cell, including its ability to infect the cell, which can be enhanced or reduced.
As SARS-CoV-2 has spread across the globe, variants have been tracked by surveillance groups across different countries. By sequencing the genomes of viral samples collected from patients, such groups can identify variants as they occur and study their scientific relevance. Do specific variants result in a virus with increased transmissibility? Are any variants associated with an increased severity of disease? How might variants influence the development of preventives or therapeutics for COVID-19? This surveillance process is crucial to navigating a global pandemic.
The majority of mutations identified thus far have not been a cause for concern. "We routinely find mutations in every patient sample, but many are trivial and of no biologic consequence. These variants co-exist within one isolate and suggest the virus routinely generates multiple variants at the same time. Why this happens and whether there is any biologic or clinical relevance is not clear," Dr Timothy Triche, director of the Center for Personalized Medicine at Children’s Hospital Los Angeles, told Technology Networks in an interview.
V0C202012/01: What do we know?
In contrast to other variants of SARS-CoV-2 that have been identified in the UK – such as the D1614G form – VOC202012/01 has a particularly high number of mutations: 23 in total. The Centers for Disease Control and Prevention (CDC) list these mutations as including but not limited to:
- A mutation in the receptor binding domain of the Spike (S) protein at position 501, replacing an asparagine amino acid with tyrosine, a mutation which is known as N501Y.
- Deletions at positions 69 and 70 of the S protein.
- A P1618H replacement at the S protein.
Whilst backward tracing suggests the variant first emerged in the UK in September, its association with an increasing number of cases first became apparent in November. "PHE was investigating why infection rates in Kent were not falling despite national restrictions. We then discovered a cluster linked to this variant spreading rapidly into London and Essex," PHE said in a press release.
Upon identification of VOC202012/01's rapid spread in specific areas of the UK, a group of scientists from research groups including Imperial College London, the University of Edinburgh, PHE, the Wellcome Sanger Institute, the University of Birmingham and the COVID-19 Genomics UK (COG-UK) Consortium teamed up to explore the novel variant and the impact of the 23 mutations. Their insights are published in a preprint* format which is yet to be peer-reviewed.
"There is no indication at this point of increased disease severity associated with the new variant. It is unlikely that this new variant will impact vaccine effectiveness, but this is currently being investigated by the PHE," - Lawrence Young. virologist and professor of molecular oncology at the University of Warwick.
The scientists conducted a variety of genomic and statistical analyses, focusing on 1,904 VOC whole genomes and data gathered from 48,128 genomes from samples that were collected between October and December 5 2020. The researchers used S-gene target failure (SGTF) in PCR testing as way of measuring VOC202012/01 cases vs non-VOC202012/01 cases across different areas.
What is S-gene target failure?
Mutations in the VOC202012/01 form of SARS-CoV-2 include S-gene deletions at genomic positions 21765-21770. Certain diagnostic assays that are being used in the UK, such as the COVID-19 TaqPath assay from Thermo Fisher, adopt a three-target assay approach, which includes targeting the ORF1ab, N and S genes. Therefore, the deletion of the S gene in VOC202012/01 results in a negative result for this section of the assay. The European Centre for Disease Prevention and Control states that, "The S-gene drop-out is unlikely to cause an overall false-negative result for SARS-CoV-2 as the S-gene is generally not used by itself for detection of the virus." The partially negative result can, however, be used to screen for the VOC202012/01 variant.
Their overall findings were that the rate of frequency of VOC202012/01 is "consistent with a transmission advantage over other circulating lineages in the UK". The estimated increase in reproduction number (R ) between VOC202012/01 and non-VOC202012/01 lineages ranges between 0.4 and 0.7.
What is the R number?
The reproduction number, also known as R, refers to the average number of secondary infections produced by a single infected person.
Are under-20-year-olds more at risk?
Analysis of the samples used in the preprint study suggests more cases of the variant form of VOC20012/01 in under-20-year-olds. The authors write, "We observe a small but statistically significant shift towards under-20s being more affected by the VOC than non-VOC variants, even after controlling for variation by week and region. However, as with our earlier results, this observation does not resolve the mechanism that might underlie these differences."
The team go on to postulate potential theories for this increased presence in under-20-year-olds, including: "Differences between the age-distributions of VOC and non-VOC community cases may result from the overall increase in transmissibility of the VOC (especially during a time where lockdown was in force but schools were open), increased susceptibility of under-20s, or more apparent symptoms (and thus a propensity to seek testing) for the VOC in that age range." Further exploration with a larger study cohort will be required to corroborate these suggestions.
Whilst the data implies that the new variant may be more infectious, at this stage, they did not find any evidence to suggest it leads to more severe cases of COVID-19.
Genetic contribution vs human behavior
The data assessed included samples collected up until December 5, and so sequencing of genetic samples from patients in the period since then will be pertinent to gather further information and fully evaluate the severity of the situation.
However, the authors emphasize that the higher infection levels seen in the data took place despite social distancing and lockdown measures. Monitoring every individual's level of adherence to lockdown and social distancing requirements is physically impossible, which poses a challenge for scientists; is enhanced transmissibility a result of genetic contributions, or human behavior – i.e., failing to adhere to restrictions? "In practice, we just have to deal with this," Julian Tang, associate professor and clinical virologist at the University of Leicester said of this matter.
What can we interpret from this data?
The research is yet to undergo peer review, and limitations such as sample representation and the use of simple models using assumptions are acknowledged by the study authors.
Experts in the scientific community have shared their thoughts on the findings. Dr Thomas House, reader in mathematical statistics at the University of Manchester, commented, "This is high quality work on the new variant, an issue that is still subject to considerable uncertainty. It involves a series of statistical analyses of multiple datasets with the aim of assessing increased transmissibility. Significant caution is required in the interpretation of these results due to the complexity of the data and models."
“The use of the SGTF approach might underestimate the number of positive cases,” said Tang. "Some labs (like ours) do not use any COVID-19 assays that target the S gene – exactly because we anticipated S-gene mutations evolving over the course of the pandemic." He added, "We are likely detecting new UK variant cases without identifying them as such (except via retrospective sequencing later) as we will not see this SGTF effect with our assays. There may be other labs like ours not using such S-gene target assays that may be underestimating this variant frequency also."
What about the vaccine?
As lockdown measures tighten across the country, the UK has commenced its rollout of two vaccines for COVID-19: Pfizer/ BioNTech's BNT162b2 and the University of Oxford/ AstraZeneca's ChAdOx1 nCoV-19 vaccine. Could the VOC202012/01 variant impact the effectiveness of a vaccine? At this stage it cannot be ruled out with complete certainty, but as Lawrence Young, virologist and professor of molecular oncology at the University of Warwick, said, it is unlikely: "There is no indication at this point of increased disease severity associated with the new variant. It is unlikely that this new variant will impact vaccine effectiveness, but this is currently being investigated by the PHE."
The World Health Organization notes that the N501Y mutation is in the receptor binding domain of the virus. As such, "Authorities are investigating the neutralization activity of sera from recovered and vaccinated patients against these variants to determine if there is any impact on vaccine performance." These studies are currently ongoing.
1. Volz et al. Report 42 - Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: insights from linking epidemiological and genetic data. Preprint at https://www.imperial.ac.uk/media/imperial-college/medicine/mrc-gida/2020-12-31-COVID19-Report-42-Preprint-VOC.pdf. 2020.