COVID-19: Where Could the Next Variant of Concern Come From?

Interview on the emergence of new variants of the SARS-CoV-2 virus, which causes COVID-19, with three researchers from the END-VOC project: François Balloux, Director of the Institute of Genetics at University College London, and his colleagues Lucy van Dorp and Damien Richard.

SARS-CoV-2, the virus that causes COVID-19, has shown a remarkable capacity to adapt to its human host over a short period of time. François Balloux, director of the Genetics Institute at University College London, and his colleagues Lucy van Dorp and Damien Richard, have been closely watching the virus since the early days of the pandemic. They form part of the EU-funded END-VOC project, which aims to evaluate the circulation and impact of emerging SARS-CoV-2 variants. In this interview, they give us valuable insight on what is driving viral evolution and what to expect in the future.

Let’s start by defining the term viral “variant”

What we call variant is more restrictive than what most people or the media have in mind. We use the term to describe the SARS-CoV-2 ‘Variants of Concern’ (VoCs) flagged by the World Health Organisation (WHO) because those lineages proved to be more transmissible, more virulent, and/or better at evading previous immunity. Five VoCs have been identified to date and all have received a Greek letter: Alpha, Beta, Gamma, Delta and Omicron. Pi, the next one in line, will probably not look like Omicron or any of its sub-lineages (including XBB1.5). One criterion for a VoC should be that it becomes dominant over other SARS-CoV-2 lineages in circulation.

What is the current situation regarding SARS-CoV-2 viral variants?

Since it jumped into the human population in late 2019, SARS-CoV-2 has evolved a myriad of lineages. The vast majority have been unremarkable and most disappeared. A few, though, were highly successful and dominated locally or globally, before being in turn displaced by other viral lineages. At this point in time, only Omicron is actively circulating in humans. However, it is of note that Omicron has been dominant globally since late 2021 and now encompasses a high diversity of subvariants including BA.1, BA.2 and BA.5 (and their descendants such as XBB.1, which resulted from a recombination of two BA.2 lineages).

Has the virus increased its mutation rate since the start of the pandemic, and if so, why?

Mutation rate refers to the number of genetic changes occurring per unit of time. Early estimates of the mutation rate of SARS-CoV-2 suggested the accumulation of about two mutations per month per genome (similar to other human coronaviruses). This is fairly slow for an RNA virus: two- to six-fold lower than influenza viruses for instance. There is mixed evidence on whether the mutation rate of SARS-CoV-2 has varied significantly since the beginning of the pandemic. Some regions of the genome, for example the Spike protein that allows the virus to attach to host cells, acquire mutations more readily than other genes. Further, the host’s innate immune system can directly induce mutations in the SARS-CoV-2 genome through the action of certain enzymes. But the number of target sites for these enzymes is finite, so this effect is likely to stabilise with sustained human-to-human transmission. So, the answer is: we are not sure. Of note, the emergence of the Alpha, Delta and Omicron were all accompanied by a burst of new mutations, which allowed the virus to become more transmissible (Alpha, Delta), or better at escaping immunity elicited by vaccination or infection by prior lineages (Omicron).

How much room is there for more mutations, notably in the Spike protein?

At this stage of SARS-CoV-2 evolution, every possible mutation has emerged at every position in the viral genome, including in the Spike. In fact, most of these mutations have emerged multiple times in unrelated lineages. It is implausible that any mutation conferring an advantage to the virus has not reached high frequency at this stage. There are, however, two major complications. First, mutations are not independent of each other. Thus, as SARS-CoV-2 continues to evolve, there is potential for some mutations to become advantageous in the future because they work well in combination with other mutations. Second, the selective pressures on SARS-CoV-2 are constantly changing, with host immunity being shaped through recurrent vaccination against COVID-19 and infection with new SARS-CoV-2 lineages. As the immunogenic landscape of the population continues to evolve, it is likely that further mutations within the Spike protein will become advantageous even if they weren’t previously.

How do you expect SARS-CoV-2 to continue evolving? Is it becoming predictable?

Evolution of respiratory viruses such as SARS-CoV-2 is a complex process driven not only by the genetics of the virus but also by the level of population immunity. Nonetheless, some emerging properties of SARS-CoV-2 are useful for predicting future evolution. Notably, over the course of the pandemic the selective advantage balance has shifted from mutations that enhance transmissibility to those that help evade prior immunity. The initial evolution of the virus tended towards the former, with Alpha as a good example of a VOC with enhanced transmission potential compared to the original strains. However, as more and more people acquire immunity through infection, vaccination against COVID-19 or both, the selective pressure on the virus has shifted away from simply being more transmissible towards escaping host immunity. Viral evolution can occur via big (antigenic shifts) or small (antigenic drift) changes. The emergence of Omicron in late 2021 represents an antigenic shift: in one go, it acquired numerous mutations that allowed it to largely bypass recognition by neutralising antibodies generated through vaccination or infection by previous variants. Since Omicron became dominant, it has been evolving via antigenic drift, whereby the virus slowly but constantly acquires individual mutations conferring better host immunity evasion. This pattern is largely in line with that of other endemic coronaviruses and is far more manageable, as the successive waves of cases remain moderate and tend to become seasonal. However, future SARS-CoV-2 antigenic shifts cannot be ruled out, particularly given the risk of new variants emerging from uncharacterised sources.

What are the possible sources for a new Variant of Concern (i.e. Pi)?

Currently, all emerging lineages are evolving from Omicron. However, prior to Omicron, all other VoC were evolutionarily distinct (no new VoC has originated from the previously dominant one). It is therefore possible that the next VoC could emerge from outside of the lineages currently in our radar. Based on what we’ve seen, one situation we need to monitor carefully are chronic infections in COVID-19 patients who are often immunocompromised. Such a setting gives the virus an extended period of time during which it can acquire rare combinations of mutations. What we suspect is happening is that many mutations that would be deleterious in isolation can accumulate during chronic infections and form favourable combinations. This may allow SARS-CoV-2 to reach new fitness peaks that may not have been attainable through sequential transmission in immunocompetent hosts. This scenario has been proposed for the emergence of Alpha and Omicron. Another setting that needs close monitoring are animal reservoirs. Indeed, SARS-CoV-2 has been found to infect a plethora of mammals, including mink and white-tailed deer. While mass culling was employed to mitigate transmission in mink farms, SARS-CoV-2 continues to circulate widely among white-tailed deer in the USA and Canada. In this process, the virus acquires animal-specific mutations that may lead to concerning phenotypes if it spills back into humans. There is also concern that co-circulation of SARS-CoV-2 with other coronaviruses in animals could provide the opportunity for recombination, leading to hybrid viruses with enhanced virulence or immune escape potential. Finally, there is a possibility that a new variant emerges from the current circulating lineages but that we fail to detect it promptly due to poor genomic surveillance in several regions of the world. Hence, there is a need to improve SARS-CoV-2 surveillance so as to cover regions of the world for which there is little genomic data, for example through the sampling of incoming travellers.