Viruses constantly mutate, they live by mutating. A virus population is a cloud of mutants, with small genetic differences. Several thousand types of SARS-CoV-2 have already been detected. Most have no effect or interest.
Does the coronavirus mutate a little or a lot? A lot, but it depends on who you are comparing to.
The flu virus and HIV are likely to be the champions of variability. The former has an RNA genome, and the enzyme that copies it is very clumsy and introduces many errors in doing so. These are not repaired as efficiently as in viruses with a DNA genome (whose polymerase is a more precise enzyme).
In addition, the influenza virus consists of between 7 and 8 RNA fragments, which can frequently mix or recombine with each other when several viruses coincide in the same cell. This pathogen is typical of birds, but it frequents many other animals, which act as a storehouse and source of new strains. All this makes it one of the viruses with the highest frequency of mutation and recombination (in technical words, antigenic drift and deviation).
For its part, HIV also has an RNA genome, but its replication depends on a viral enzyme, reverse transcriptase or reverse transcriptase, which copies the RNA genome in the form of DNA. This one is even clumsier, and puts more mutations. In addition, HIV has two identical copies of RNA, which also increases its recombination capacity.
Compared to these two champions, coronaviruses mutate little. But they mutate, of course. They are also RNA viruses and they also have a clumsy polymerase, but their genome is just a very large RNA fragment of about 30,000 base pairs.
Since they cannot afford many mistakes, they have an enzyme whose job is to repair the ones made by the polymerase by making copies of the genome. This lower frequency of mutation and recombination allows us to speak of “genetic variants”.
Some have calculated that this mutation frequency is two mutations per month, which means that the variants that now circulate may have accumulated about 26 mutations compared to the original sequence of the first Wuhan isolate. Thousands have been described so far, most without any effect on the virus.
When we talk about mutations we mean the RNA or DNA genome. What mutates are the nucleic acids, not the proteins, although this is manifested in the form of changes in these.
Take the famous mutation in the coronavirus protein S called N501Y. What does it mean? The numbers refer to the number of the amino acid in the protein, and the acronyms to the type of amino acid . In this specific case, there has been a mutation in the gene that codes (which carries the information) for protein S, so that there is a change in amino acid 501 of the protein, and the amino acid Asparagine (N) is replaced by the Tyrosine (Y): N501Y.
Hunting for mutations and variants
Since February last year, SARS-CoV-2 genomes have been sequenced. This has made it possible to follow the real-time evolution of the virus and the appearance of new mutants. There are already more than 260,000 sequences available in the databases. These come from as many isolates obtained from human samples from February last year to the present time. Although nucleotide changes are the primary source of genetic variation for SARS-CoV-2, insertions, deletions, and even recombinations have also been detected.
These mutation analyzes allow phylogenies (kinship relationships) that can be used to:
- Make temporal estimates (when new variants emerge).
- Characterize how the virus spreads geographically.
- Reconstruct the epidemiological dynamics within a region.
- Analyze how it adapts over time.
The analysis of the SARS-CoV-2 sequences is unprecedented. There are more than 700,000 shared sequence data in the GISAID (Global Initiative on Sharing Avian Influenza Data) database. It is the first time that the evolution of a pandemic virus has been followed in real time.
What is interesting is to study what mutations appear in the SARS-CoV-2 genome over time and what effect they may have. The variants accumulate several of them. The term strain is reserved for variants with significant changes (antigenicity, transmissibility, virulence) and is not currently used with the coronavirus.
Variants of interest and concern
Of all the mutations, those that concern the most are those that affect the gene that codes for protein S. This interacts with the cellular receptor ACE2 (the gateway to the cell), which could affect its transmissibility.
Furthermore, since it is the most exposed protein, it is also the most antigenic, on which antibodies act. Most vaccines use it as a strategy to activate the immune system. Therefore, it is interesting to control the number of mutations that accumulate and the specific gene they affect.
The most relevant mutations at this time are N501Y and E484K, in the protein S gene. They are present in several of the genetic variants and the fact that they are appearing independently in several groups or lineages suggests that they confer an adaptive advantage to the virus.
Mutations and, therefore, new variants will appear spontaneously anywhere and at any time. We are going to find many. This is how the phylogenetic trees are being built that show how the virus genome evolves and differentiates itself into different groups or lineages.
When studying the variants, we distinguish what is called Variant of Interest (VOI) from Variant of Concern or Importance (VOC).
A variant of interest has mutations that lead to amino acid changes associated with suspected phenotypic implications. In addition, it has been identified as a cause of community transmission or detected in several countries.
A variant of interest would become worrisome if it is shown that, in addition, it is associated with an increase in transmissibility or virulence, a change in the clinical presentation of the disease or a decrease in the effectiveness of social and public health measures, vaccines and treatments included.
In recent months, new variants have been found that are worrisome because they are more infectious, that is, a person needs to inhale less virus to become infected. Others are more transmissible, which means that they increase the amount of virus that a person gives off. Others seem to have an easier time evading the antibodies of the immune system.
The variants that we could classify as worrisome at this time are the British (B.1.1.7), the Brazilian (P.1), and the South African (B.1.351).
Variations arise anytime, anywhere. Detecting them depends on our ability to search and find them by sequencing. As expected, for a few weeks other variants of interest have been described in different parts of the planet.
Thus, we speak of the California variant B.1.429 / 427, which seems to be somewhat more transmissible but there is no data, at the moment, that associates it with greater virulence and immune escape. New York’s B.1.526, also perhaps more transmissible and of concern because it has appeared in an area where there was a high level of immunity (that city was one of the hotbeds of the pandemic in the US last spring). There are still more, such as P.2 (Brazilian from Rio de Janeiro), B.1.525 (or Nigerian), VOC 202102/02 (very similar to the British one), C.16 (from Portugal) and A.23.1 (detected in the United Kingdom).
What is monitored in a new variant?
- The number of mutations (if you have many) and where you have them.
- If its frequency increases rapidly among the population.
- If it presents the same mutations as other variants, which may suggest, as we have commented, a phenomenon of convergent evolution and adaptive advantage.
- If it spreads in areas where there is already a high level of immunity against SARS-CoV-2 (because there has been a high level of natural infection or high vaccination coverage).
Only surveillance and research will show whether these new variants move to the next category of variants of concern. Scientific evidence is needed to demonstrate what effect these new variants may have on the infectivity, transmissibility and evasion of the immune system.
A term that they have coined in English is that of “scariants”, which we could translate as “terrifying variant”, and refers to those variants of which we actually still have very little experimental data and know very little, but which are news in the press and alarm suggesting that they will mean returning to the beginning of the pandemic.
Could occur? We do not know, but normally transmissibility and lethality do not usually evolve at the same time. Remember that the virus, regardless of the type of variant, is already very contagious and dangerous and the measures we have to take against the new variants are the same as against the native virus: avoid infections and vaccinate.
The effect that the variants may have on the development of the pandemic is still uncertain, we are in a delicate moment of uncertainty. It is too early to know how they might influence the effectiveness of vaccines, although there is evidence that antibodies from vaccinated people react somewhat less with some of these variants.
It must be taken into account that vaccines not only induce neutralizing antibodies, but also activate cellular immunity, which in the case of coronaviruses plays a more important role than antibodies. A prepublication pending peer review shows that the cellular immune response (dependent on CD4 and CD8 T lymphocytes) of people who have passed COVID-19 or have been vaccinated with the mRNA vaccines is not affected by the new SARS variants. -CoV-2.
For now, let’s spend the time sequencing and investigating and preventing the virus from spreading. The more infected people there are, the more viruses there will be in the environment and the more likely new variants will emerge. That is why you have to vaccinate, vaccinate and vaccinate.
Ignacio López-Goñi, Professor of Microbiology, University of Navarra
This article was originally published on The Conversation. Read the original.
