SARS-CoV-2 and its variants: an overview

Viruses, especially RNA viruses such as Coronaviruses, constantly evolve through mutations in their genome. Indeed, mutations of the SARS-CoV-2 virus have been observed around the world since the pandemic has started, although news of the virus variants has only recently found space in national and international newspapers, with the improper names of “English variant”, “South African variant”, “Brazilian variant”.

Illustration of a virion (the single viral infectious particle) of SARS-CoV-2, complete and in section. Photo credit: https://www.scientificanimations.com/wiki-images/.

It is a perfectly predictable phenomenon that viruses evolve over time by accumulating mutations, and the emergence of variants of SARS-CoV-2 should therefore not be surprising. For this reason, the World Health Organization (WHO) and its international network of experts closely monitor the situation, in order to report immediate and appropriate interventions to address the spread of variants.

Why do viruses mutate? What are the variants of SARS-CoV-2 currently most concerning? What to do to limit their spread? We analyze it in this overview.

Viruses mutate, and that's normal

When a virus infects a cell, its purpose is to make nuove copies of the virus itself, in order to have a progeny capable of perpetuating the species: everything that was present in the virus that infected the cell, including its genetic material (RNA, in the case of Coronaviruses), must be “copied” and assembled to form new viral particles.

The complex of proteins essential to synthesize new RNA is found in various forms in all organisms and it is called RNA polymerase (i.e. “enzyme that forms long RNA chains”). However, every time this enzyme makes a copy of the original genetic material it makes mistakes, so the copy has some differences from the original.

These changes in the gene sequence of the virus are called mutations; a virus with one or more mutations and capable of spreading in the population is referred to as a “variant” of the original virus.

The RNA polymerase enzyme of the virus synthesizes a copy of the genetic material of the virus, an RNA molecule made up of four different nitrogen bases. The enzyme takes the RNA strand to be copied and the individual molecular units (nucleotides) complementary to it appear one at a time according to the A:U and G:C pairing (in the figure, the rectangles with different colors pair yellow with blue and red with green). Sometimes RNA polymerase mismatches these bricks, and this leads to a mutation in the viral “offspring”. If the mutation is beneficial for spreading of the virus, it will be maintained. For more info: RNA polymerase, the SARS-CoV-2 “sloppy photocopier”.

Do these spontaneous mutations have consequences for the virus? It depends. While most mutations do not have a significant impact, some may give the virus some characteristics such as a selective advantage over the original virus, for example by conferring greater transmissibility, or the ability to circumvent the immunity previously acquired by an individual, either by natural infection or by vaccination. This causes cause for concern and viral variants must be monitored carefully (they are called “variants of concern”).

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The greater the number of people who are infected, the greater the likelihood that the virus will undergo mutations which, if advantageous for the spread of the virus, take over and can jeopardize the effectiveness of the vaccines currently in use. This is why it is essential to always observe the rules for containing the infection, including the use of the mask, preferably the double mask.

SARS-CoV-2 variants

Hundreds of variants of this virus have been identified around the world so far. To date, the most concerning variants (and therefore the most studied) are three:

• B.1.1.7. This viral variant was first identified in southeastern regions of the UK in December 2020 in conjunction with a rapid increase in the number of new confirmed cases of SARS-CoV-2 infection. Also known as VOC 202012/01 “Variant of Concern, year 2020, month 12, variant 01”), it is defined by the presence of numerous mutations affecting the Spike protein and other regions of the viral genome. The presence of cases of SARS-CoV-2 infection caused by this variant have been reported in almost all countries of the European Union, including Italy (where it is present in over half of recent cases), and in the USA. This variant has been shown to have greater transmissibility than those previously circulating; Additional studies are underway to evaluate a possible greater severity of the disease, not confirmed to date.

• B1.351. Emerging independently of B.1.1.7, this variant has largely replaced other SARS-CoV-2 viruses circulating in South Africa and cases attributable to it have been detected outside the country, including the United States. It is currently unclear whether it causes differences in the severity of the disease, while it has been found that it cannot be neutralized by antibodies induced by the vaccine produced by AstraZeneca/Ofxord.

• P.1. For the first time described in January 2021 in some travelers who arrived in Japan from Brazil. Studies carried out to date have shown a potential greater transmissibility or propensity for reinfection while no evidence is available on the severity of the disease.

Most of the mutations identified in these variants involve the Spike protein, that is the “key” that the virus uses to infect cells, exploiting the link with the ACE2 receptor present on the cell surface.

The antibodies produced by our body, following natural infection or vaccination, bind to the Spike protein, preventing interaction with the receptor and therefore infection. This viral protein is therefore the target of most vaccines currently approved or under investigation. It is therefore important to monitor the mutations that accumulate in Spike, because they could affect its structure and alter the effectiveness of vaccines. In fact, several studies are underway [1; 2] to confirm the efficacy of vaccines on these three main variants.

Summary of the main variants of SARS-CoV-2 currently under study. Modified from: CDC - Centers for Disease Control and Prevention, SARS-CoV-2 Variants. Last updated: January 27, 2021.

A constant update on SARS-CoV-2 mutations and variants is available at this link.

The nomenclature challenge

In early January, the WHO convened a meeting dedicated to the emergence of variants of SARS-CoV-2; among the points under discussion, also the drafting of a coherent and universal naming system.

Media and politicians have begun to refer to the variants based on the countries in which the first cases were detected: “English”, “Brazilian”, “South African variant”. The same also happened at the beginning of the pandemic, speaking of the “Chinese virus”.

Such attitude is understandable, in a period in which new data are continually emerging to be communicated quickly. However, associating viruses with geographical and cultural references is not only a scientifically inaccurate practice, but above all carries the risk of stigmatizing countries and people.

In the absence of shared guidelines, research groups around the world are each developing their own nomenclature. For example, Tulio de Oliveira’s team named 501Y.V2 the variant they identified: it means that at site number 501 of the virus’ Spike protein, the variant has the amino acid tyrosine (in biochemistry denoted by Y) instead of the original asparagine. The name has helped bring together hundreds of researchers studying the effects of the mutation but, de Oliveira himself admits, it also omits other important changes in the variant.

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At the beginning of the pandemic, the same challenge was presented for the disease of the new Coronavirus: on that occasion, the name SARS-CoV-2 was correctly chosen to indicate the virus and Covid-19 for the disease, avoiding any association with geographical areas, animals, individuals or groups of people.

Agreeing on a common nomenclature will allow researchers to communicate and understand each other more effectively, and to prevent any kind of stigmatization.

What to do to limit the spread of SARS-CoV-2 and its variants?

To limit the spread of new variants, Italy has ordered specific public health actions, as illustrated by the Ministry of Health:

• strengthen laboratory surveillance (i.e. sequencing the viruses present in diagnostic nasopharyngeal swabs) against the new SARS-CoV-2 variants

• provide indications for implementing research and contact management activities for suspected/confirmed Covid-19 cases for viral variant infection

• limit the entry into Italy of travelers from the countries most affected by viral variants

• carry out rapid prevalence surveys to correctly estimate the spread of viral variants in our country

• arrange containment measures (red areas) in the most affected areas of the country, including at the municipal level

As seen above, some viral variants can be transmitted more easily; to date, however, the disease presents with the same characteristics and symptoms for all variants of the virus although there has been an increase in infections of young people, with clinical consequences still to be evaluated.

The emergence of these – and any future – viral variants confirms and strengthens the importance of strictly respecting the health and socio-behavioral measures we have acquired during the pandemic (use of masks, physical distancing, hand hygiene). Continuing to observe these responsible behaviors is (and will be) the best way to protect us and those around us.

Article written in collaboration with: Prof. Guido Poli and Dr. Elisa Vicenzi, Viral Pathogenesis and Biosecurity Group of the San Raffaele Hospital, Prof. Carlo Signorelli, Director of the Postgraduate School in Hygiene and Preventive Medicine, Dr. Massimo Degano, Group leader Biocrystallography Unit of the San Raffaele Hospital.

References

[1] Xie, X., Liu, Y., Liu, J. et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nat Med (2021). https://doi.org/10.1038/s41591-021-01270-4

[2] Dagan N. et al., BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med (2021). Doi: 10.1056/NEJMoa2101765

For more info:

• Ministero della Salute - Che cosa sappiamo sulle varianti del SARS-CoV-2
• See WHO’s Disease Outbreak News for reports on variants.
• 25 gennaio 2021: WHO, An update on SARS-CoV-2 virus mutations & variants - The latest on the Covid-19 global situation& the emergence of new mutations & variants
• CDC - Centers for Disease Control and Prevention, About Variants of the Virus that Causes COVID-19
• 15 gennaio 2021: “‘A bloody mess’: Confusion reigns over naming of new COVID variants”. Nature News https://www.nature.com/articles/d41586-021-00097-w#ref-CR1
• 19 Gennaio 2021: “The world needs a single naming system for coronavirus variants”. Nature Editorial https://www.nature.com/articles/d41586-021-00105-z
• World Health Organization, Coronavirus disease (COVID-19): Virus Evolution
• CDC - Centers for Disease Control and Prevention, SARS-CoV-2 Variants