How the Omicron BA.2 variant pushed back the initial limits of Covid-19

The Covid epidemic may have faded from the headlines, but it's not over yet. SARS-CoV-2 continues to circulate and evolve rapidly. Researchers at the "Infectious Diseases and Vectors: Ecology, Genetics, Evolution and Control" unit (University of Montpellier, CNRS, IRD), Mircea Sofonea, lecturer, and Samuel Alizon, research director, specialists in the epidemiology and evolution of infectious diseases, take stock of Omicron now that it has conquered the world. How do we explain its sub-variants, and what do we now know about its capacities and the effectiveness of our immune system in the face of future variants?

Samuel Alizon, Institute of Research for Development (IRD) and Mircea T. Sofonea, University of Montpellier

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The Conversation: What's the latest on the circulation of SARS-CoV-2 variants, in France and more generally?

Samuel Alizon: All over the world, since December 2021, the Omicron variant, and more precisely the BA.1 (or 21K, in Nextstrain classification) line, has supplanted the Delta variant (B.1.640 line). This replacement is even more rapid than that of the Alpha variant by Delta during 2021. In France and elsewhere, its BA.1.1 sub-line has also been spreading since January.

Even more unexpectedly, in countries such as Denmark, South Africa and India, a cousin line noted BA.2 rapidly became the majority. While the divergence of BA.1.1 from BA.1 is recent (around October 2021), the common ancestor of BA.1 and BA.2 is thought to date back to March 2021. In short, these two lineages have a common origin (they share more than 30 mutations) but are already almost as divergent as Delta was from Alpha (by more than 35 mutations).

In France, thanks to collaboration with the CERBA laboratory and Montpellier University Hospital, our team estimated that the Omicron/BA.1 variant became the majority variant during the 3rd week of December, and hegemonic shortly thereafter. Since the end of January, the percentage of BA.2 among screenings has doubled every ten days in January, becoming the majority by the end of February.

North America, Russia, Europe, Australia and South Africa are the regions most affected by Omicron
The Omicron variant has been in the majority on the planet since the third week of December, with its BA.1 lineage. BA.2 is now the fastest-growing. (Worldwide presence of Omicron as of February 11, 2022. In dark red, 100,000 confirmed cases and more; in grey, no data)., CC BY-SA

T.C.: In addition to BA.1 and BA.2, there is talk of a third branch within the Omicron Group: BA.3. What is this?

Mircea T. Sofonea: The Omicron BA.3 sublineage has been known since November 18, 2021, the date of its first sequencing in South Africa, less than a month after the detection of BA.1 in Botswana. It has 34 mutations in its Spike protein (shortened by six amino acids) compared with the original reference strain of SARS-CoV-2 (Wuhan-Hu-1), a number intermediate between the BA.1 (39) and BA.2 (31) sublineages, against which it has just one mutation of its own.

It is on the basis of these arguments that some authors suggest a recombination between BA.1 and BA.2 as the origin of BA.3.

Although it is present in at least twenty countries (in southern Africa, Europe and the USA) and has a priori ( in silico approaches) a mutational profile making it more transmissible than BA.1, it remains ultra-minority. Only 543 BA.3 sequences have been deposited in the GISAID database as of March 5, 2022, representing less than 0.05% of Omicron sequences worldwide. In France, 17 BA.3 sequences had been reported by February 28, 2022, mostly from the same cluster.

This low rate of spread makes it impossible at this stage to quantify precisely its transmission advantage or virulence differential, but it does give an optimistic indication of the risk that this sub-lineage represents in the short term. This rules out its classification as a variant in its own right.

T.C.: The fact remains that this "Omicron package" is highly diverse... More so than previous variants? Can we consider that there are in fact several Omicron variants?

M.T.S.: For the moment, the World Health Organization (WHO) designation "Omicron variant" refers to all the BA.1, BA.1.1, BA.2 and BA.3 lineages... But it's important to emphasize the differences not only between the Omicron group and the other variants, but also between BA.1 and BA.2, which are significant in virological and epidemiological terms.

It should be remembered, against the fantasized intuition of a linear viral evolution, that the Omicron group did not originate from the Delta variant, but probably emerged at the same time: either in the early months of 2020, throughchronic infection of an immunocompromised host or retrozoonosis from a murine reservoir.

These two hypotheses would indeed help explain the large accumulation of mutations in this group at the time of its detection: at least 31 on its Spike protein alone, more than double that of the Delta variant.

Structural and functional studies of Omicron's Spike protein (using high-resolution cryo-electron microscopes, which are sorely lacking in France) have highlighted the many (synergistic) consequences of these mutations on its virology, pathogenicity and epidemiology.

3D view of the Spike protein
Some 30 mutations have been localized to the Omicron Spike protein alone (yellow: substitution of one amino acid for another, red: loss, green: gain).
Opabinia regalis, from Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein, in Cell, CC BY-SA

T.C.: Now that we've got a bit more perspective, what information can we glean from studying these mutations?

M.T.S.: Many of Omicron's capabilities have indeed been identified or clarified:

● Increased affinity for the human cell receptor ACE2 but reduced membrane fusion capacity,

● Exploitation of a second route of entry into cells by endocytosis (independent of an enzyme required forentry of other variants),

● Increased replication potential in the epithelium (tissue composed of joined cells) of the upper airways (mouth, nose, throat, etc.) and decreased in that of the lower airways (lungs, etc.),

● Inter-contamination time (serial interval) reduced from 4.1 (Delta) to 3.7 days,

Immune escape, resulting in a significant reduction in neutralization by antibodies of post-infectious, vaccine or therapeutic origin (monoclonal antibodies).

The combination of these properties means that Omicron's transmissibility is multiplied by a factor of two to three, and its lethality is reduced by around 70% compared to the Delta variant.

British colleagues have shown that the risk of hospitalization due to Omicron infection is equivalent to that of Delta in the under-10s, but four times lower in the 60-69 age group.

T.C.: What about vaccination with Omicron?

M.T.S.: According to the latest British public review, vaccine efficacy against symptomatic infection with Omicron is low and declining rapidly. With only two doses, protection is only 10% after 6 months, compared with over 40% for Delta. However, it remains above 40% for up to 6 months after the3rd dose. Fortunately, vaccine efficacy against hospitalization exceeds 75% up to six months after the booster dose.

Based on current knowledge, these estimates are equivalent between the two main Omicron sublineages, BA.1 and BA.2, which present comparable severities. The two notable differences between them are a 40% relative transmission advantage for BA.2 - linked to more rapid replication in the nasopharynx, and an even shorter serial interval(3.3 days) - and a lack of detectable neutralization by the only monoclonal antibodies still active against BA.1, namely sotrovimab and tixagevimab/cilgavimab dual therapy.

T.C.: Are we still immune to new strains?

M.T.S.: Between post-infectious immunity and vaccine immunity, less than a tenth of the French population is now immunologically "naïve" to the Covid-19 virus.

The wave of Omicron BA.1 conferred collective cross-immunity to BA.2, with reinfections being rare. However, this immunity is only temporary, as can be seen with the vaccine.

As SARS-CoV-2 cannot be eradicated (high contagiousness, imperfect and declining immunity, animal reservoirs), new variants will emerge, selected in particular for their ability to bypass the immune response. The timing of their appearance and their antigenic properties are currently unpredictable.

Vaccination renewal, if possible in updated or more robust forms, will always be topical, at least for vulnerable people. In fact, we should already be working on optimizing the schedule for future vaccination campaigns, and the criteria for temporary, localized reintroduction of barrier measures in the event of epidemic resurgence.

T.C.: You speak of the emergence of new variants, which will continue. Is coexistence between variants possible?

S.A.: A lot will depend on cross-immunity. According to the theory of population dynamics, in the simplest situations, two species cannot coexist if they exploit the same "ecological niche". Omicron variants seem to be turning a corner, colonizing a new "niche" in the upper respiratory tract.

If we approach the question from the immunological angle, this coexistence could be facilitated by the fact that immunity generated following Delta infection or vaccination extends little to the upper respiratory tract, which is poorly irrigated by the immune system. Moreover, initial results suggest that natural immunity following Omicron infection offers little protection against the other variants.

Finally, we need to be clear about the scale of coexistence. We know that two variants can coexist within the same person, as demonstrated by the existence of a recombinant virus between the Alpha variant and other lineages, or recent co-infections by Omicron and Delta in the UK.

Conversely, since the start of the epidemic, certain variants have remained in the majority in certain countries only. Here again, scientific ecology teaches us that geographical constraints facilitate the coexistence of species.

T.C.: Does the emergence of Omicron and BA.2, which crush all other variants, mark a "running out of steam" for the epidemic in terms of diversification capacity?

S.A.: From the point of view of viral evolution, it's quite the opposite. It's impressive to see that BA.2 differs from the Wuhan SARS-CoV-2 sequence by almost 80 mutations, whereas BA.1 has 70 and Delta "only" 50.

The more a virus circulates, the faster it evolves. And the Omicron variant is circulating extremely fast... Another example of this massive circulation comes from the rare monitoring of animal reservoirs: analyses of sequencing data suggest that cryptic lineages appear to be infecting New York sewage fauna.

The increase in the "biodiversity" of this virus undermines hopes that it will lead to "evolutionary dead-ends", i.e. situations where the mutations necessary for its propagation (e.g. enabling immune escape) are so costly that they cannot be propagated. Indeed, there is a high risk that one of the innumerable lineages will find a viable solution.

We must also be wary of the age-old belief that viruses become less virulent over time. As shown by this year's discovery of a more virulent HIV variant than the average circulating since the late 1990s, the opposite is true. It's true that the lethality of infections is decreasing, but this primarily reflects improvements in health response, vaccines and treatments.

One of the lessons of modeling is that we must be wary of our perceptual biases. In phases of epidemic growth, concern increases, and conversely, in phases of decline, we tend to be more optimistic... The difficulty for scientists is to stick to the facts. From this point of view, we still lack a great deal of certainty concerning the Omicron variants. What is the duration and scope of post-infectious immunity? What are the long-term effects of infections? As with the other variants, will long-lasting Covid infections occur in the coming months?

On all these essential questions, we are watching out for the results of research teams abroad, who have far more resources to work with.The Conversation

Samuel Alizon, Director of Research at CNRS, Institute of Research for Development (IRD) and Mircea T. Sofonea, Senior Lecturer in Epidemiology and Evolution of Infectious Diseases, MIVEGEC Laboratory, University of Montpellier

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