What is delta plus, the variant of the coronavirus that you should not know

What is delta plus, the variant of the coronavirus that you should not know

"I shouldn't know what a variant is," assured a frustrated Twitter user during the months when each new SARS-CoV-2 lineage generated unflattering news. Today the headlines no longer speak of variants, but of a division of these: the one baptized as 'delta plus' is actually a sub-lineage of the original delta variant. In other words, a 'subvariant'. But does the population need to know in such a level of detail how the coronavirus mutates? What about the epidemiologists and public health experts who must handle the pandemic?

Several researchers consulted by elDiario.es consider that too much is being done zoom on the coronavirus genome, a magnifying glass that they define as "ridiculous" and "absurd".

"For epidemiological purposes what we are doing does not make sense because every time we subdivide more and more", assures the bioinformatics of the Biomedical Research Center of La Rioja María de Toro. This "obsession" with subdividing, he adds, "then is useless." He believes that it is not advisable to give so many details to the general public, and that this can be counterproductive if one day a variant emerges that is truly worrisome.

"It is true that there are some changes and you can classify them however you want, but we are making such a fine classification that it seems little manageable at the public health level," says the Carlos III Health Institute researcher María Iglesias.

"The virus is dynamic and we strive to compartmentalize everything very much. That makes epidemiology difficult because now we are losing focus on delta and focusing it on sublineages that we still do not know what they do," says De Toro. As a result, the work of many people is complicated.

"When you try to collect all your data, it will not help you because what a month ago was 1.617.2 is now AY.2, AY.3.5 or AY.4.", Laments Iglesias. "Do we have to update the sequences every week? It doesn't make sense." If Spain separates its delta sequences into sublineages "it will not be used for any study and they will have to regroup as delta. So why do we want so many?", The virologist wonders.

The director of the Public Health Observatory of Cantabria Adrián Aginagalde is one of the people who lives these changes from the trench. "It is possible that more genomic information is being generated than there is time to find out its impact." He believes that these types of findings are useful, but that their implications should always be evaluated by looking at possible immunity leaks, increases in virulence and transmissibility. "The speed of new information is such that the genomic information arrives long before there is time to contrast it with the epidemiological information and carry out the risk assessment", adds Aginagalde.

Iglesias explains that genomic surveillance is done with the spicule (the crown that gives the virus its name), which in many lineages is identical. "Epidemiologists rightly ask you why the spicule of AY.33 is the same as that of AY.32: the reason is that the lineages are assigned by whole genome, something that for traditional surveillance is sometimes quite incomprehensible ".

"The definition of a variant has somewhat diffuse limits, it is based on the phylogeny and on mutations called markers", clarifies De Toro. It is often they copy mutations among themselves: "The virus is not tight, it is a constellation of mutations and we are focusing a lot on very specific positions when we should assess that constellation, which is not closed."

Where does delta plus come from?

But where did delta plus come from? Is there anything in your genome that deserves our attention? Who decides which delta will have daughters? In autumn 2020, a new lineage of the SARS-CoV-2 coronavirus was discovered: B.1.617, the first sequence of which dates from October 5. In the following months it was divided into three sublineages: B.1.617.1, B.1.617.2 and B.1.617.3. Of these, only the second brother was successful: B.1.617.2 is what we call today the delta variant that dominates most of the world.

This did not end there: towards the summer of 2021, delta was divided into AY.1, AY.2 and AY.3, which contained the K417N mutation and therefore received the name "delta plus" (from English, delta plus K417N).

So the British joined the party: in July 2021 they identified the AY.4.2 sublineage. This subvariant is today known as the delta plus that the United Kingdom classified last week as a variant of interest and that has already been detected in Spain. Actually, it was already there: "The laboratories that do monitoring reported the subvariants of delta as delta until 15 days ago, but for practical purposes it is still delta," says De Toro.

"AY.4.2 [delta plus] it is a sub-lineage: they have added a sub-variant to the delta lineage because two changes in the spicule are not enough to give it a lineage entity ", clarifies Iglesias, who understands that the public can get lost in the face of such technical distinctions.

This also does not help the media and popularizers, who see how naming new versions of the coronavirus is increasingly difficult despite the system suggested by the WHO based on the Greek alphabet. Ironically, the subvariant AY.4.2 is not the original delta plus, although it is being called that outside of scientific circles.

What's new about delta plus?

What today we call delta plus has two mutations that stand out: A222V and Y145H. "Y145H are structural changes not exposed to antibodies, so I don't think they have any impact on the vaccine," Iglesias explains. There is speculation as to whether this mutation may act as a sensor that would be charged when the pH was lowered and, consequently, would cause a repulsion that would favor spike transmission. But, as the virologist recalls, "all this remains to be demonstrated."

The A222V mutation is an old acquaintance. "It is what they say originated in Spain, which was present in B.1 and became the B.1.177 lineage, which was dominant until the arrival of alpha," says Iglesias. "It is very relevant because it is thought that the change is closely related to creating a stability that favors its transmission."

So is it more transmittable? What about vaccines?

One of the lessons that alpha left is that initial observational studies of a lineage give a distorted picture of reality due to lack of data and abundance of biases. Initial estimates of this variant gave an increase in transmission of 74% or even 90%, which months later decreased to 29%. As De Toro recalls, the behavior of the variants depends a lot on the measures taken and the behavior of the population.

"Population observation studies are always much more exaggerated than when more complete studies are made and the transmission potential and how the neutralizing antibodies against the spicule act are well characterized", adds Iglesias, who assures that there are many studies to be done with the variants circulating today.

Delta plus has attracted attention in the United Kingdom not because of its mutations, but because of the increase in the number of cases since it was detected in July 2021. If at the end of September it represented 3.8% of the samples, at the beginning of October the percentage was close to 6%.

However, its advantage over the original delta does not seem great, to the point that researchers are still not clear that it even exists. The latest British estimates conclude that delta plus would be between 8 and 16% more transmittable than the original version. As with alpha, many researchers do not rule out that much of what is observed is due to the behavior of a population that has lived without measures since last July 19.

"We are always talking about improving transmission a little bit, but always maintaining protection from the vaccine", reassures Iglesias. "This is of interest to those of us who study it because of what may happen, and I would not worry as an ordinary citizen beyond the fact that it is necessary to monitor and observe what happens."

Who decides what a variant is and names them?

B.1.117, B.1.617.2, AY.4.2… We could think that this system of classifying a virus as it evolves is something old. Researchers have been turning to genomic sequencing to study these parasites for decades, but the level of detail seen with SARS-CoV-2 has never been achieved.

The person in charge is a software called Pangolin, which uses a nomenclature proposed by evolutionary biologist at the University of Edinburgh (Scotland) Andrew Rambaut in April 2020, called Pango. His goal was to bring order to the chaos of mutations that any virus represents. They succeeded, but some researchers wonder if it hasn't gotten out of hand. It is no coincidence that the country that has established this system and is a leader in genomic surveillance seems to find all the variants in its territory.

"As the data has grown, some cracks have started to appear around the edges. [de Pangolin]", says an article published in the magazine MIT Technology Review which tells the story of this program and the researchers who made it possible.

The GISAID genomic database has more than 4.5 million shared coronavirus sequences, which the Rambaut system has divided into thousands of variants. Of these, the WHO only considers four as variants of concern (alpha, beta, gamma and delta) and two of interest (lambda and mu).

Pango's numbers may seem large, but keep in mind that SARS-CoV-2 barely mutates compared to other viruses. "[El coronavirus] It hardly changes and has thousands of lineages, of which 90% do not circulate. What would we have done with HIV? Put numbers like a phone? If we focus on each change in SARS-CoV-2, I don't know what will happen if we do the same with the flu, there would be updates eight times a day, "criticized Iglesias.

Maybe that will cause the cracks in Pangolin. "With so much to process, the software is starting to fail. Things are being mislabeled. Many variants are alike, because the virus evolves the most advantageous mutations over and over again, "explained the article by MIT Technology Review already in July.

De Toro thinks we should focus more on what the studies say in vitro when classifying. "We are going very crazy with the Pangolin classification and with subdividing, and it is confusing: when I make the determinations I use three different methods and sometimes they do not coincide, even if it is the same lineage. You give epidemiologists that number, but we are not helping them nothing to understand what is happening, and the population either ".

Rambaut, for his part, defended the usefulness of his ranking on Twitter last August. "All AY.x lineages are the delta variant, but they are epidemiologically distinct. […] Lineages are used for epidemiological tracking, in particular to allow connections [entre brotes]".

The difficulty of defining a variant at a genome stroke

The problem is that defining a new variant (or subvariant) is not as easy as discovering a new species of bird. "People believe that a lineage is something totally closed and strict with walls that separate it," explains De Toro. Reality, he says, looks more like a "constellation" of mutations. "A million delta sequences are not equal to one hundred percent, but there are practically fixed mutations and others that dance."

"When new lineages and strains are considered, there has been an antigenic change [que dificulta el reconocimiento del virus por parte del sistema inmunitario], and this has not happened yet with the new coronavirus, "recalls Iglesias.

That is why he considers it "absolutely absurd" to do so much zoom about SARS-CoV-2: "[Los cambios de delta plus] they do not carry antigenic change, we cannot assemble a lineage every four non-defining changes in a 30 kilobase genome [unidad de longitud que denota el tamaño de un genoma]".

It is something that virologists like the researcher at the National Institute for Agrarian and Food Research and Technology, Miguel Ángel Jiménez, support. Not only does he consider that the virus is repeating itself in its mutations, but the changes observed in subvariants such as delta plus are not enough to generate a new serotype, a variant that is distinguishable by specific antibodies. In fact, he considers that it is very difficult for SARS-CoV-2 to form them.


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