Mutants, Variants, Recombinants and Other Figurants: Five Definitions and Five Key Concepts to Better Understand the Evolving Pandemic

Alpha, Beta, Gamma, Delta... who would have thought, when we studied the Greek alphabet at school, that we would be consulting again its letters (many) years later in an attempt to follow the evolution of a virus that has made us hold our breath for more than two years. But, in addition to variants with Greek letters, it now turns out that there are sub-variants with number sequences that are impossible-to-remember and recombinants that start with the letter X, as if they were an emoji.

To avoid being overwhelmed by each new variant, subvariant or recombinant making it to the headlines, these five definitions and five basic concepts may help.

Five definitions

Mutation

A random change in the genetic material (in this case, in the virus’s RNA) that may or may not result in a change in the protein it codes for, thereby potentially improving - or impairing - the protein’s function.

Variant

A viral variant is a virus isolated from a sample that has a number of differences in its genetic sequence compared to the virus of reference. The term variant does not necessarily imply changes in the behaviour of the virus.

Variant of concern

This term is used only when a variant’s increase in transmissibility, pathogenicity or ability to evade immunity is suspected or confirmed. At present, five SARS-CoV-2 variants of concern have been described: alpha, beta, gamma, delta, omicron. The omicron lineage comprises the BA.2 subvariant, which is not different enough to deserve a Greek letter on its own, but has around 20 mutations that distinguish it from the original BA.1 variant. BA.2 in turn has given rise to other subvariants that are spreading rapidly in South Africa (BA.4, BA.5) and in the US (BA.2.12.1).

To avoid being overwhelmed by each new variant, subvariant or recombinant making it to the headlines, these five definitions and five basic concepts may help

Strain

A strain is a variant with unique and stable characteristics (i.e. distinct behaviour than the original virus). There is currently only one strain of SARS-CoV-2.

Recombinant

Viral recombination occurs when two different variants of the same virus infect the same cell and exchange entire fragments of their genetic material. It is an "accelerated" form of viral evolution. The likelihood of this happening increases when different variants circulate at the same time and the same place. Recombinant XD is the combination of delta with omicron, whereas XE is the combination of Omicron BA.1 and BA.2 subvariants.

SARS-CoV-2 variants depicted in a tree scaled radially by genetic distance. 1 December 2021. Soupvector / Wikimedia Commons.

And five basic concepts

Mutations are normal and to be expected, but only a few mutations confer a selective advantage.

Mutations are part of the evolutionary process of any organism. Among viruses, RNA viruses have the highest mutation rate, although some coronaviruses (including SARS-CoV-2) have a "self-correcting" system, so they mutate less rapidly than other RNA viruses. It is important to emphasise that many of the mutations are deleterious (i.e. they negatively affect the virus' ability to replicate), some are neutral (i.e. they neither affect nor favour it) and only a few confer a selective advantage. Most of the advantage-conferring mutations are concentrated in the viral protein Spike (key to infecting human cells and the target of the majority of vaccines), but mutations in other regions of the virus can also affect the transmissibility of the virus.

Which mutations prove advantageous depends on the context.

There are two ways in which the virus can have a transmission advantage: by getting better at infecting host cells and/or by getting better at evading immunity. In the early stages of the pandemic, variants with greater infectiousness (such as Alpha) were favoured. As the human population acquires immunity to the virus, the most successful variants are those that are also better able to evade immunity (such as Omicron). Perhaps if the already extinct beta or gamma (with good immune evasion properties) had emerged later in the pandemic, they would still be among us. Thousands of SARS-CoV-2 variants have been identified, many of which disappeared almost immediately because they were not able to compete with the dominant variant.

Uncontrolled transmission and immunocompromised hosts are fertile ground for new variants.

Thanks to its "self-correcting" system, the virus accumulated relatively few mutations at the beginning of the pandemic, as expected. However, the evolution of SARS-CoV-2 has accelerated considerably. Two factors contribute to this: on the one hand, uncontrolled transmission in the general population (the virus has replicated in billions of people in a relatively short time). On the other hand, chronic infections in immunocompromised patients have been shown to allow the virus to accumulate a large number of mutations in an environment of suboptimal immunity.

The evolution of SARS-CoV-2 is still unpredictable.

What is striking is that, so far, no new variant has originated from the previously dominant variant. In other words, Delta did not arise from Alpha, nor Omicron from Delta. By a phenomenon of evolutionary convergence, they share some mutations that are favourable to the virus, but they have all originated from versions of the original variant. In fact, Omicron is so radically different from the other variants that it is not clear how it could have circulated "under the radar" for so long. A prolonged infection in an immunocompromised patient is one possible explanation. But there is another possibility - the virus can infect other mammals (such as white-tailed deer), so it could have evolved in animal reservoirs before re-infecting humans. It is therefore impossible at this stage to predict what the next variant of concern will look like, whether it will be derived from omicron or whether it will be completely different.

Viruses do not necessarily evolve towards lower pathogenicity.

Contrary to popular belief, viruses do not always evolve to become less virulent. This depends on several things, including the way the virus replicates and is transmitted. SARS-CoV-2 is transmitted before a person becomes seriously ill, so a variant that kills more will not necessarily be at a disadvantage. Omicron is perhaps intrinsically a little less virulent than Delta, but it lower virulence is also due to the fact that we have by now a certain level of protective immunity.

The one thing we can be sure of with respect to the evolution of the virus is that we need to continue to monitor it closely to identify possible variants, subvariants or recombinants of concern and act in time

The one thing we can be sure of with respect to the evolution of the virus is that we need to continue to monitor it closely to identify possible variants, subvariants or recombinants of concern and act in time. This means strengthening genomic surveillance systems in all countries, and not only in humans but also in animals susceptible to infection.