With the horizon that vaccines will immunize most of the population against covid in the coming months, the most important obstacle to recovering a certain normality are the variants. It’s nothing that surprises scientists at this point. The virus, as it makes copies and copies to replicate in our cells, makes mistakes and generates new mutations. When any of them allow it to have some advantage to continue reproducing – because it is spread more easily or because it dodges the defenses of the immune system – that ‘new version’ of SARS-CoV-2 spreads more easily among the population.
The problem is that these changes turn the coronavirus into such a different pathogen that neither the antibodies of already infected people nor those of those vaccinated can recognize it and attack it if it knocks on the door again. Therefore, one of the most important tasks of science around covid is monitor mutations through genetic sequencing of virus samples. The Gisaid international platform It has already accumulated more than 620,000 sequences from all over the world.
In the last two months, the databases have grown more than during the rest of the pandemic, driven by the concern of the countries around three specific variants: the English (B.1.1.7), the South African (B.1.351) and the Brazilian (P.1). However, SARS-CoV-2 does not stop evolving, so they are not the only ones to monitor closely. The latest report on variants of the Ministry of Health has included four others of interest. Is the threat multiplying? What are the consequences for the pandemic?
“There are many changes, but not all have an important importance for the functioning of the virus, for example, so that it is transmitted more or so that it has a greater resistance to being neutralized by the antibodies produced by vaccines ”, virologist Rafael Delgado, head of the Microbiology Service of the 12 de Octubre University Hospital in Madrid, explains to Teknautas. The modifications of the SARS-CoV-2 genome that are of real concern are those that affect the spike protein (or protein S, from the English Spike), because it is the one that binds to human cells and the reference of vaccines, since they are thought so that the antibodies recognize it and attack the virus.
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The three known variants
The truth is “there are almost constant news”, Explains the expert, but“ even in the variants that we know best, the information is still limited ”. B.1.1.7 was found in the UK and has caused a great alarm since December when the UK reported its highest transmissibility. Later, it has even been speculated that it could be more lethal. Some data indicate that the disease it produces could be more serious in advanced ages, but it has not been confirmed.
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On the other hand, “there is no doubt that it is transmitted more easily, but we still do not know very well why,” admits Delgado. A recent Harvard University study carried out within the NBA’s follow-up strategy to its basketball teams points to a possible cause: when analyzing seven cases of the British variant, they saw that patients have a higher number of infective particles —That is, the virus replicates more in your body—, but they also found that it persists for a longer time. Both factors would contribute to increasing infections. The good news regarding this variant is that it “does not significantly compromise the protection of vaccines.”
Instead, that is the big problem with the South African and Brazilian variants, which “are very similar,” says Delgado. Both accumulate mutations in a specific area of protein S called RBD. and that serves to recognize the receptor of human cells. In particular, the E484K mutation appears to be the most relevant. “These changes make the antibodies identify the virus worse,” warns the virologist. In fact, vaccination with the AstraZeneca drug was discontinued in South Africa because initial results indicated that protection was very low against the variant that emerged in South Africa, which accounts for more than 90% of infections there.
The four new variants
Interestingly, among the four new variants of interest to which the Ministry of Health draws attention, three also include the E484K mutation. In the United Kingdom a new variant has appeared that is very similar to the already known B.1.1.7, but that adds this change. So, in theory, “allows the virus to escape neutralizing action of the antibodies generated against the previous sequences ”, comments the expert from the Hospital 12 de Octubre. At the moment, its dispersion is very limited.
Something similar happens with a new Brazilian variant, which has been called P.2, and is linked to Rio de Janeiro. There are isolated cases in some countries, all related to travel. From the point of view of genetic sequencing, again the highlight is the E484K mutation in protein S. In any case, this lineage is under study and very little is known about its impact.
The third of the new variants, called B.1.525, is somewhat more widespread, since it has been sequenced in Denmark, the United Kingdom, the Netherlands, Norway, the United States and Canada, although all cases appear to have some link to Nigeria, so it has already received the informal name of the Nigerian variant. Although it accumulates other important changes, it is not lacking the E484K either. The field of SARS-CoV-2 mutations that may become relevant “begins to acquire a certain complexity,” admits Delgado, “but if there is something in common, it is the appearance of E484K, and if it occurs,” it is because it is an advantage for the virus ”.
The field of SARS-CoV-2 mutations that may become relevant “is beginning to acquire some complexity”
The exception to the rule is a Californian variant that has been gaining weight in the rest of the United States. Its most relevant change appears to be the L425R mutation, which apparently “gives you greater transmission capacity, but we still do not have very complete information ”. Apparently, it is expanding at the same time as the British one and “there would be some competition between the two, which dominate the broadcast in California.” However, this irruption has coincided with a drastic drop in infections there and throughout the world, so its penetration is not so important in total numbers, despite the fact that it accounts for a large percentage of cases.
Despite the fact that there are so many variants that concern, from the beginning it has been known that, comparatively, SARS-CoV-2 “mutates less than other RNA viruses”, highlights Ester Lázaro, a researcher at the Center for Astrobiology (INTA-CSIC), who studies the evolution of viruses. However, “it continues to mutate more than viruses with a DNA genome or the DNA of our cells.” In fact, each infected individual contains “an immense population of viruses that differ in some mutations, although most will be irrelevant.”
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However, from time to time, one comes up that offers an advantage, for example, bind a little better to the cellular receptor and thus improve transmission. “When that happens, the viruses that have this mutation begin to be more abundant and we can speak of a new viral variant,” he says. This can happen in any patient, but there are some studies that specifically point to cases of immunosuppressed patients. In them, “the virus will be able to remain multiplying longer.” And every time a virus multiplies it mutates, thereby increasing the chances of generating one of these variants.
The ability to mutate is limited
The fact that there are changes that coincide, despite the virus having evolved independently in different places, leads experts to speak of evolutionary convergence. “It happens when a virus adapts to a new environment, which in the case of SARS-CoV-2 are human cells ”, explains the expert. “What is expected is that it has been optimized to multiply and transmit better in our species,” he adds. For this reason, “if there are mutations that are repeatedly repeated”, it is probably because they are “among the few that provide a benefit”.
This makes scientists think that the number of changes may be limited. “We have observed a number of mutations and many more may not be produced”Explains Delgado. His reasoning does not come only from epidemiological data, from the sequencing of clinical cases, but also from ‘in vitro’ studies. “When the virus is exposed to neutralizing antibodies in the laboratory, it generates the same mutations that appear in patients,” he says.
In this sense, “although we are not completely sure, it is possible that the variability may have a limit, especially in the main region of recognition of the receiver”. The RBD region of protein S is the one that interacts with the cell receptor and it is made up of “just over 100 amino acids.” The virus can change some of them, but it has to continue to recognize the receptor of cells in order to enter them and replicate. For this reason, it is likely that the capacity for variation of this small area of protein S is low.
What does it mean for vaccines
If this possibility is confirmed, we would be facing great news in the face of the neutralization of the coronavirus. In the event that any mutation or combination of mutations of the virus reduces the effectiveness of the vaccines or increases the risk of reinfections, “they will have to be taken into account in the design of new vaccines”Says Lázaro. However, if the mutations that allow the virus to elude part of the immune response are limited, “the process of updating the vaccine will be simpler than if variants were circulating that each had a particular set of mutations.” According to Delgado, “we could adapt the vaccines, but we would not have to be modifying them indefinitely”, precisely because the ability to generate new mutations by the virus has a limit.
However, as vaccination increases, the selective pressure on SARS-CoV-2 will also increase. This means that the variants that can better elude the immune response will have more advantages over the rest of the viruses that are in circulation. Nevertheless, “Although a virus mutates a lot, it cannot adapt to everything”says the researcher at the Center for Astrobiology. “Sometimes getting better at something means getting worse at something else, and the fact that the protein that the virus uses to bind to the cell receptor is the same protein towards which the immune response is directed imposes certain restrictions. For example, it can happen that the variants that are worse neutralized by the antibodies cannot interact with the receptor, with which, they could not enter our cells and would not have any long-term success ”, he explains. As mutations occur randomly, variants of this type could arise, but they would never be the majority.