why the Omicron BA.4 and BA.5 variants win France

Forgotten by the media for several weeks, the COVID epidemic is once again being talked about with the BA.4 and BA.5 variants which are settling in France, after their breakthrough in Portugal in particular. Specialists in the epidemiology and evolution of infectious diseases within the unit “Infectious diseases and vectors: Ecology, Genetics, Evolution and Control” (University of Montpellier, CNRS, IRD), Mircea Sofonea, lecturer, and Samuel Alizon, research director, decipher the situation in France. What about these variants? Will they lead to a new wave this summer?

The Conversation: The Omicron variant, which has become the majority globally, continues to spread and evaluate. But his new avatars are now designated as BA.1, BA.2, then BA.4 and BA.5… How to find your way around?

Samuel Alizon: Indeed, there is enough to get lost in this abundance of nomenclatures! The Greek letters were issued by the World Health Organization (WHO) in 2021 with the Alpha variant. It’s probably the worst classification, because it was invented without taking evolutionary biology into account. Those of Pango or Nextclade are much more suitable. Moreover, the WHO seems to have stopped its updates and grouped under the generic term of Omicron all the variants of type BA.

We have modeled the circulation of variant lines in France in a recent work (see above) and the first Omicron wave generated by the BA.1 line emerges at the end of 2021. This was quickly supplanted by the BA.2 line , which reinforced a second hospital wave in April 2022. Now it is the BA.4 and BA.5 lines that are lagging behind.

Mircea T. Sofonea: These lines were issued in May, but they would probably have emerged during the month of December 2021 in South Africa, potentially from BA.2, the majority line in France since March 2022.

While the BA.2 variant was as different from BA.1 as the Delta variant was from the Alpha variant, the evolutionary divergence between BA.4 and BA.5 is more limited.

However, even if the number of new mutations is limited, some are challenging. Thus, the 452R mutation of the Spike protein is known to confer greater affinity with the human ACE2 receptor, used by the virus to enter our cells. The 486V mutation, still in the Spike protein, gives the virus a fairly high capacity for immune evasion.

Nevertheless, one should be careful with reasoning by analogy applied to isolated mutations. For the effect of the latter is neither absolute nor cumulative; it depends on the entire genotype, with potential synergistic and antagonistic phenomena, and includes for distant positions on the genome (we speak of epistasis).

TC: Are these mutations innovations of these variants, or do BA.4 and BA.5 “dip” into all the possibilities that were tested by their predecessors – Delta, Gamma, Beta, Alpha?

MTS: Remember that Omicron is not the descendant of the previous variants, but a distant cousin, and that the viruses do not mutate voluntarily or directed. The mutations detected in the genome of a new line appeared by chance.

The 452R mutation was not present in the BA.1 or BA.2 lines, but was found in the Delta variant. It is also one of the three mutations sought in the screening tests currently carried out on all positive PCR tests in France.

The 486V mutation is not associated with any of the circulating lineages within our species, but so-called deep mutational scanwhich consisted in producing proteins with mutations, had identified it as being potentially involved in the escape to immunity.

HER : Regarding the differences between variants, two genetic mechanisms are involved: mutations and recombination. The latter allows a mixing of entire portions of the genome when two viruses of different lineages “co-infect” the same host.

At the biological level, several hypotheses coexist to explain the emergence of variants: accumulated circulation in a population, the involvement of an animal reservoir or chronic infections in immunocompromised individuals. Indeed, the latter fail to eliminate the virus, which therefore causes longer and more lethal infections. A pre-publication (therefore to be taken with caution, as it has not yet been peer-reviewed) by a New York team thus describes the intra-patient evolution of a BA.1 virus with the accumulation of key mutations and , above all, its transmission to at least five other people.

In the case of BA.4 or BA.5, as their differences with BA.2 are quite limited, they could only be mutations fixed as the virus circulates.

TC: Why are BA.4 and BA.5 now spreading in France?

HER : One can easily estimate a growth advantage of one line over another in a population. According to our team, that of BA.5 is around 9% in France compared to BA.2.

On the other hand, it is complicated to know where this advantage comes from. Does BA.5 spread more because it is more contagious? Or because it escapes immunity better? A pre-publication by a Japanese team and a publication by a Chinese team highlight the role of immune escape, in particular via the 486V mutation.

Whatever the origin of this advantage, it can contribute to an epidemic rebound in France.

MTS: A second mechanism is also at work in France: anti-SARS-CoV-2 immunity – essentially hybrid, that is to say both post-vaccination and post-infectious – declines over time. since the last immunogenic event (whether infection or vaccination).

If the protection conferred by an Omicron infection or a third dose of vaccine remains significant after five months against a severe form, it is on the other hand very reduced against any infection. The susceptibility of the population to the virus (that is to say the pendant of collective immunity), is therefore reconstituted over time, ultimately opening up the possibility of an epidemic resumption.

In summary, BA.4 and BA.5 propagate as our immunity ages, and do so faster than BA.2, because they have a double advantage of contagiousness and immune escape. BA.4 and BA.5 therefore induce a wave sooner than BA.2 would have done.

TC: The situation in Portugal could have caused concern. But can we learn from the trends revealed in other countries?

MTS: I have reservations about intercountry comparisons: they are more and more delicate, because current circulation depends, in addition to the health measures in place, on the epidemiological and immunological history, which are increasingly differentiated according to the country.

At the level of France, it is even still difficult to quantitatively compare the relaxation of measures contributing to the recovery, and the summer context which limits it, with longer and warmer days favoring social interactions in an open environment.

HER : Portugal is one of the European countries where the BA.4/BA.5 wave is the most advanced and is accompanied by an increase in hospitalizations. It is complicated to know why it started so early, but, as with all the beginnings of epidemics, the role of random events of the “super-spread” type probably has a lot to do with it.

Globally, in South Africa, the BA.4/BA.5 wave seems to be on the decline. In the United States, on the other hand, BA.2 was first replaced by the BA.2.12 lineage, but this appears to be being replaced by BA.5.

TC: Can we anticipate the consequences of these replacements between variants on future epidemic photos?

HER : In 2021, in France, a new variant replaced the old ones, because it was more contagious. December 2021, it is rather Since immune evasion that leads the way.

This makes scenario modeling tricky. Our team’s models, such as those of the Institut Pasteur or the Pierre Louis Institute of Epidemiology and Public Health, already took into account vaccination coverage in the population and the percentage of people who had a natural infection.

On the other hand, including the time delivered since the last vaccination or natural infection is a challenge, because, after two years of pandemic, two vaccination campaigns and a huge BA.1 wave, everyone now has a different immunity!

MTS: We have developed tools to take into account this heterogeneity of immunity in populations. Given our constraints, we are currently focusing on the long term, but, in theory, it should be possible to use this framework to explore short-term prospective scenarios.

For the moment, it is difficult to say what the exact magnitude of the new epidemic wave that is beginning will be. This wave, in the genetic or virological sense, is already well advanced and BA.5 will probably become the majority by June 20. If we can count on the summer to reduce the incidence compared to the winter, it does not prevent, on its own, a wave of contamination. For the record, one of the traffic peaks in France remains August 2020, and the 4th wave (from Delta) peaked in July 2021.

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