Covid-19: An unpredictable winter under the seal of Omicron's massive and unprecedented diversification

Mircea T. Sofonea, University of Montpellier and Samuel Alizon, Center national de la recherche scientifique (CNRS)

A certain amount of "pandemic fatigue" has overtaken part of the population, but SARS-CoV-2 continues to evolve. While France is experiencing its eighth wave (the fourth in 2022), dominated by the Omicron BA.5 sub-variant, it is seeing rapid progress in another sub-variant, named BQ.1.1. Samuel Alizon, Director of Research (CNRS, CIRB) and Mircea Sofonea, Senior Lecturer (University of Montpellier, MIVEGEC), look back at the health situation ahead this winter, and highlight the challenges of monitoring and research in our country. What are the consequences?

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The Conversation: As summer draws to a close, Covid and its variants are back in the news. We're now talking about BQ.1.1 and XBB. What can we say about these "sub-variants"? And how are they being followed?

Samuel Alizon: Since September, SARS-CoV-2 has diversified considerably, with the emergence of numerous sub-variants of the Omicron variant.

BA.4.6, BA.2.75, BA.5.2 and even B.1.1.529., renamed BQ.1.1 according to the Pango nomenclature, which proposes an identification system to track SARS-CoV-2 genetic lineages of epidemiological interest...

All these lines, which predominate in various parts of the world (BQ.1.1, for example, is currently on the rise in France), officially belong to the Omicron variant. They are therefore sub-variants, but in reality, they could easily be described as variants.

TC: What do we know about these new sub-variants? Do they represent an epidemiological threat?

SA: At this stage, much of what we know about these new strains must be treated with caution, as they are, at best, pre-publications, not peer-reviewed. Little is known about their virulence and, of course, virtually nothing about the long-term effects of their infections.

We are certain, however, of the mutations that are present in the genomes of these lines, since it is these that define them. The BA.5 variant, for example, had fixed a mutation at position 452 of the Spike protein. This mutation was much studied, as it was characteristic of the Delta variant at the time of its appearance.

In the case of BQ.1.1, a whole other series of mutations can be observed in this protein's Receptor Binding Domain (RBD), i.e. the part of the Spike protein that interacts with ACE2, the "lock" located on the surface of cells infected by SARS-CoV-2. This is particularly true of the S:R346T mutation. As indicated in a pre-publication from a consortium of Chinese teams, these mutations appear to confer significant immune evasion potential on this lineage. What's more, BQ.1.1 may not be sensitive to the monoclonal antibody treatments available in France (such as the tixagevimab-cilgavimab combination (Evusheld)).

Among the sub-variants monitored for their potential immune escape properties, we should also mention the XBB lineage, which results from recombination between viruses of the BJ.1 and BM.1.1 lineages during co-infection of the same cell.

TC: How are these worrying sub-variants monitored? Where do epidemiological data come from?

SA: On the epidemiological front, the quality of the UK surveillance system continues to be outstanding. Their latest report of October 7, 2022, combining screening and sequencing data, offers a particularly clear view of their epidemic situation.

Phylogeny of SARS-CoV-2's radial phylogeny based on GISAID data shows that the diversification of Omicron lineages is far greater than that of the Delta (blue) or Alpha (purple) variant.

For other countries, including France, we rely on sequencing data shared on the GISAID platform. A number of websites, including and the excellent covSPECTRUM site run by Prof. Tanja Stadler's team in Switzerland, offer real-time visualization of variant dynamics (within the limits of the data provided by each country).

Mircea Sofonea: It's worth noting that, unlike previous waves caused by the arrival of a new variant, screening data from RT-qPCR screening (which identifies previously defined mutations, and is therefore used to track down variants that are already known) can no longer distinguish these new lines.

This deprives us of an early and therefore valuable signal to inform models in real time of current replacement dynamics. This can only be ascertained by sequencing, with a delay of at least a week after sampling (itself arriving several days after the onset of infection) and on a sample which, for material reasons, is small - the Flash surveys carried out by the EMERGEN consortium cover 1000 to 2000 interpretable sequences.

The problem is that, this time, France is the first to experience the predominance of the new (sub)variant (BQ.1.1). So we can no longer count on the trends observed across the Channel!

At a time when the genetic diversity of SARS-CoV-2 is once again putting our surveillance and care system to the test, the technical-scientific chain, from individual sampling to population analysis, on which our collective anticipation relies, needs immediate investment commensurate with the public health challenge.*%22%7D%2C%22samplingStrategy%22%3A%22AllSamples%22%7D%2C%22countries%22%3A%5B%22France%22%5D%2C%22logScale%22%3Afalse%7D&*%26%22%7D

TC: How do these variants fit in with the general trend observed for Omicron?

SA: Until then, we often had one dominant line and fairly pronounced variant replacements: Alpha replaced all the lines that preceded it, then Delta replaced Alpha and so on.

Here, as can be seen on the website, the sub-lines derived from BA.2, BA.4 and BA.5 seem to co-circulate on a global level.

Frequency of Nextstrain clades
Frequency of main clades according to based on GISAID data.

As for the reasons for this diversification, it is obviously impossible to be certain. The study of biological diversity is a field in its own right, but we can put forward two hypotheses.

On the one hand, parasite diversity is often correlated with host diversity. Human populations are now more diversified than ever in terms of their immunity, whether from vaccinal or post-infectious sources.

On the other hand, the diversification of the virus is also proportional to the number of new infections, and currently, in many countries, the virus is circulating uncontrollably.

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TC: Could we have expected such a situation?

MS: While it's impossible to predict the precise evolutionary trajectory of a coronavirus at present, and certainly for many years to come, the diversification dynamics observed since the spring are not necessarily surprising.

The first two years of the pandemic were marked by strong selective pressures on transmission - Alpha and Delta were only able to emerge because their particularly high contagiousness enabled them to compensate for social distancing and masks.

Omicron, which comes from an old branch of the SARS-CoV-2 phylogenetic tree and not from these two variants, has spread in a context where population immunity (post-infectious and vaccinal) has become an additional brake on viral propagation. Since spring 2022, this immunity has been the only remaining brake.

Thanks to the combination of its high contagiousness and strong immune escape, Omicron BA.1 has virtually driven the other lines to extinction, benefiting from circulation without much constraint beyond the humoral and cellular immunity developed against them.

Since every infection is a source of (random) mutations, the conditions were ripe for a "conveyor belt" of diversification fueled by immune escape.

TC: Is there no end to this capacity for diversification?

SA: This question takes us back to the debates of 2020 and even 2021, when some people predicted that the virus would "run out of steam", and that its mutational potential would diminish.

In fact,viral evolution is always difficult to anticipate, as each mutation can completely alter the virus' "adaptive landscape", i.e. its evolutionary possibilities. In addition to genetic constraints, there are also environmental constraints and the variability of populations infected by the virus.

An interesting point in the current diversification of viral lineages is that there are a number of cases of parallel evolution, i.e. lineages that independently fix the same mutation.

TC: What are the possible consequences for this winter? Are forecasts still possible?

SA: It's very difficult, because quite apart from the scientific difficulty, research teams in France have virtually no basic annual funding (known as "recurrent" funding), and many projects have been turned down this year. In short, we're no longer in a position to explore forward-looking scenarios. And unlike 2020 and 2021, there is no longer a scientific advisory board to solicit such analyses. The unknowns about how the winter will unfold are therefore enormous.

What we can say, however, is that the current wave (which began in mid-September) is still dominated by the BA.5 lineage, which had already caused the third epidemic peak of 2022, in July. This fourth wave probably has multiple origins, but it did coincide with the start of the new school year, with circulation observed primarily in children.

As to why the same variant was able to generate a new wave so soon after the previous one, it's likely that social factors were the determining factor. Summer probably broke up the previous wave, and the return to school favored the resumption of viral circulation. The persistence of post-infection immunity to BA.5 from the summer wave probably explains why the peak was reached so quickly in children (before the end of September).

For adults, the epidemic logically got off to a later start, with a spillover from the children's epidemic. Unfortunately, this time the epidemic peak was slow to emerge. Sequencing data are still patchy, but as the visualizations on the covSPECTRUM website suggest, the rise of the "new" variants mentioned above (such as BQ.1.1) may be the cause.

Proportion of infections caused by BQ.1.1
Proportion of BA.5 infections caused by the BQ.1.1 lineage inferred by the covSPECTRUM site using GISAID data. ?nextcladePangoLineage=bq.1.1*&

If this is confirmed, there is a risk that a fifth wave in 2022 will be superimposed on the fourth, even if the school vacations are expected to delay the situation. In the absence of a national vaccination campaign, the magnitude of this wave would be directly correlated to immune evasion, or more precisely, to the intensity of cross-immunity between BA.5 and new variants.

MS: Short-term forecasts (i.e. within a two-week horizon) are always possible, taking advantage of the epidemic's inertia and the history of past waves. The current eighth wave has so far been on a par with its predecessors in terms of intensity and duration.

Projections on a monthly scale, on the other hand, require certain assumptions to be made, notably concerning the kinetics of post-infectious and vaccinal immune decline, reshaped by the new sub-variants... Which cannot be properly informed at present, while inference from hospital and screening data is ever more delicate, and, alas, support for developing more automated and robust approaches is lacking.

TC: Winter is also a prime season for other epidemics... Are there any joint thoughts on the influenza and Covid epidemics?

SA: Yet another topic that makes us regret the lack of support for epidemiological modeling teams in France! Yes, the co-circulation of influenza and SARS-CoV-2 is a cause for concern this year, as early data from the Southern Hemisphere suggest that, unlike 2021 and, especially, 2020, we're likely to have "normal" influenza circulation.

Two types of effects are to be feared: some direct, as co-infection by the two viruses could be more virulent, and others indirect, with hospital capacities likely to saturate more quickly.

MS: Influenza has been circulating again since last year, and the previous season was particularly unusual, with a late peak in March-April, when we gradually relaxed attention and protective measures relating to SARS-CoV-2 (wearing masks, hand washing, etc.) - which also prevent transmission of the influenza virus.

At present, influenza circulation indicators in mainland France (with Réunion and Martinique in epidemic phase) are comparable to pre-Covid-19 pandemic levels.

Between thecurrent bronchiolitis epidemic, which is affecting the whole of continental France, and the forthcoming influenza wave, the potential ninth wave of Covid will further complicate the work of caregivers, who have had to endure almost three years of tense workflows.

There is an urgent need to strengthen the means of surveillance, anticipation and simultaneous control of respiratory viruses. The methodological challenges posed by this public health issue are highly specific, and we unfortunately don't currently have the resources to meet them.

While it is perfectly legitimate and desirable - not least so as not to accentuate "pandemic fatigue" - for daily attention not to be focused on Covid, it is vital that, in the background, we are able to support this transition towards controlled endemic circulation, rather than being subjected to it as we are at present. A horizon that research can help to bring closer.

Mircea T. Sofonea, Senior Lecturer in Epidemiology and Evolution of Infectious Diseases, MIVEGEC Laboratory, University of Montpellier and Samuel Alizon, Director of Research at CNRS and head of the Ecology and Evolution of Health team at the Centre interdisciplinaire de recherche en biologie (CIRB) UMR 7241 - U1050 Inserm, Center national de la recherche scientifique (CNRS)

This article is republished from The Conversation under a Creative Commons license. Read theoriginal article.