“It is highly probable that a new variant will find itself on the front of the stage in the coming months”

At the start of 2021, the good news was finally arriving on the pandemic of Covid-19. The first ones vaccines were available and their deployment could begin across the world, hoping that we could see the light at the end of the tunnel …

Unfortunately theeuphoria will have been short duration, With l’emergence end of 2020 from variant of concern “English” (variant of concern, B.1.1.7), later named Alpha. Its increased transmissibility raised fears of an acceleration of the pandemic.

The historical variant (Wuhan), which had locked our lives overnight, had a base reproduction number, or R₀, of 3 (each infected person could infect an average of three others). The unprecedented efforts of the population (confinement, etc.) had brought this number down below 1, indicating that each patient contaminated less than another individual, giving hope for a decrease in the number of new cases.

Unfortunately, Alpha had about 50% more transmissibility than the historical strain, with a basic reproduction number approaching 5. Then, Delta (identified in India) would appear, in basic reproduction number estimated at more than 5. Each new variant, due to its greater transmissibility, would then supplant its predecessor.

If 2020 had been the year of the epidemiology of SARS-CoV-2, 2021 will undoubtedly have been that of its evolution.

The emergence of variants, a normal phenomenon and taken into account

The virus, like any living entity, are constantly evolving. They adapt to their environment in order to maximize their propagation. But where it takes years for cash of vertebrates, viruses, like SARS-CoV-2, are infinitely faster – a million times faster than our cells, for example. It is this accelerated biological evolution but normal and expected, which the whole world has observed for a year.

The phenomenon has been widely documented in other viruses, such as influenza virus (flu). This is not without posing constraints for the control of these viruses, for which vaccines must be constantly updated.

To adapt our responses to these emergencies, it is particularly important to keep in mind that the detection of new variants in a particular locality does not mean that they appeared there or even that they are only circulating there. The example ofOmicron is particularly outrageous. Identified in South Africa, it was also detected in Hong Kong (confirmed November 15), Botswana (confirmed November 24) and, after starting to search for it, health authorities realized it had already disseminated worldwide.

The closure of air links will therefore have an extremely limited impact on its spread … but may, on the other hand, push many authorities to no longer disclose this type of information in order not to suffer the economic consequences. However, during a pandemic, the rapid sharing of information is the best weapon to prepare and adapt existing tools, in particular vaccines and diagnostics.

Another major point is that it is important to properly characterize the variants: to quantify the transmissibility, virulence and efficacy of the‘natural or vaccine immunity on the different groups of the population will be decisive in adapting a multisectoral response (restrictions, barrier gestures, vaccination, medical analysis laboratories, hospital preparation imply the coordination of different sectors and ministries).

Since the start of the emergence of variants, the world has feared three scenarios: increased transmissibility, increased lethality associated with infection or exhaust immune. So far, mainly variants with increased transmissibility have been observed.

The Omicron case

At the end of November 2021, the discovery of the Omicron variant triggered a global alert because first data suggest that this highly transmissible variant causes more re-infections than others. If this were indeed the case, it would mean that, alongside high transmission in unimmunized people, those previously infected or vaccinated would also be at risk ofbe re-infected.

With a very intense transmission and an immune escape, it is the pandemic that would restart – with its procession of restrictions. However, this variant does not seem to be associated with a gravity particular clinic and, currently, it is still the 5^e wave linked to the Delta variant which can lead to saturation of hospitals. The degree of compliance with barrier gestures and progression of booster vaccination coverage will therefore have a major impact.

On the other hand, in the short term, the very strong diffusion of Omicron in the non-immune population with risk factors could harm the health care system.

While the previous variants presented relatively “close” evolutions (a few more mutations), this variant is particularly different and has more than thirty mutations compared to Delta just for the protein Spike. A suprise…

The impact of the original population in the emergence of a virus

Although today the evolutionary history of this variant remains unknown, several hypotheses seem possible, linked to the environment in which the virus is found.

First of all, a “gradual” evolution is of course possible. The mutations observed were able to accumulate on a regular basis, without being detected for months because they did not cause major epidemiological changes – in the transmissibility, the lethality or the immunity engendered. In other words, it was only after a certain accumulation of mutations that a particular combination on the virus could represent a real turning point for our immune system (in his ability to recognize it, etc.)

This scenario is particularly found in populations with low vaccination where the virus can circulate and traverse extremely complicated “adaptive landscapes” without being too slowed down – until arriving at the famous Omicron variant. These “landscapes” are the thousands of combinations of mutations that the virus can have with each an impact on the epidemiological characteristics complicated to predict. Knowing that this virus has about 30,000 base pairs, this corresponds to more than 8.10¹⁷ possible combinations … Of course, many of these combinations will generate viruses with the same characteristics or not viable, but the range of possibilities remains huge.

Another possibility, which has come to the fore several times, is the implication of long durations of infection in immunocompromised people.

Indeed, some people affected by Covid, in particular those with a deficient immune system (for example suffering from HIV, of cancers, transplanted, etc.), can remain infected for relatively long periods (from several weeks to several months). However, if the virus evolves when it is transmitted from one individual to another, it also evolves inside infected people. Thus, patients who present with clinical forms marked by long durations of infection can allow the accumulation of mutations and thus “internally produce” a new variant different from those circulating in the general population. And who can “locally” develop specific traits adapted to their own situation, in particular an ability to escape the immune system.

Extremely complicated to test, this hypothesis is nonetheless possible biologically speaking. We know that the intra-host evolution of HIV is extremely important and affects the diversity as well as the epidemiology of viruses within the population.

Finally, the last possibility, the increase in pressures selection to which the virus is subjected. In fact, the more a population is immune to the circulating virus (naturally or by vaccination), the more a variant exhibiting a competitive advantage (such as greater transmission or immune escape) will be able to spread.

The most dangerous zone is therefore located at an intermediate level of immunization of a population: which applies selection pressures on the virus, which promote potentially more dangerous mutations, but does not constrain its circulation sufficiently to limit the virus. emergence of new variants.

It is important to note that these explanations are not exclusive: each of these three evolutionary mechanisms can contribute, to a greater or lesser extent, to the emergence of each of the variants.

What this means for the current pandemic

It is very likely that new variants will be identified in the coming months, and that one of them with a significant immune escape will find itself in the spotlight. Certain mutations (in the receptor binding domain, or RBD, 484K, K417N and L452R) are already followed in this regard. But it is also very likely that vaccines will continue to provide protection against severe forms, even if their efficiency against the infection may be reduced.

What is absolutely obvious is that, in order to evolve (and make variants emerge), a virus needs to be transmitted. In this, the extremely heterogeneous vaccination rates between the different regions of the world leave it an important space. Original vaccination strategies, adapted to the heterogeneous situations of countries with limited or unstable resources, must be designed.

It is high time to understand that this pandemic is playing out on a planetary level, and that the virus will never meet sufficiently impermeable borders.