Can the coronavirus mutate and become more lethal?

The word “mutation” has really disturbing connotations in the collective imagination. Marvel superheroes transform and acquire extraordinary abilities thanks to mutations, and in more than one B-series movie a mutation makes a shark or an ordinary piranha a perverse killing machine. In the movie “Burst”, which was advised by the renowned epidemiologist W. Ian Lipkin, a mutation causes Ebola to begin to be transmitted by air and become a pathogen that can only be stopped with a nuclear bomb.

The COVID-19 pandemic has outstripped the argument of any catastrophe movie. It is, according to scientists Yong-Zhen Zhang and Edward C. Holmes, “the perfect epidemiological storm.” The protagonist of this story is a tiny and insignificant virus, named SARS-CoV-2, which seems to come from bats and which evolution has allowed it to be very contagious between people and cause pneumonia. This “movie” would not have been developed if it were not for the fact that the virus appeared in the perfect place (Wuhan, China, a great city and a communications hub) and at the perfect time (before the Spring Festival). In this way, a non-living replicating entity, which does not understand borders or political rivalries, has put half a planet on the ropes in just a few weeks. As civilization recovers and prepares to strike back, it is legitimate to ask whether mutations can make this coronavirus transform and become more lethal or more elusive under a vaccine.

Mutations are copying errors
Virologist Nathan D. Grubaugh, a researcher at the Yale School of Medicine (USA), published an article in February entitled “We should not be concerned when a virus mutates into an epidemic” in the journal “Nature Microbiology”. This article explains that mutations rarely have a major effect on an epidemic and defines these changes as “An inevitable consequence of being a virus.” This is usually especially true for viruses whose genetic material is RNA (not DNA, like animals or plants), as with SARS-CoV-2.

“Mutation is a routine aspect of life for an RNA virus,” writes Grubaugh. These are especially negligent when it comes to making copies of their genetic material, an operation necessary to multiply and infect, which is why they accumulate failures, true errors in their genetic sequences, which we can also call mutations. All this happens because “they use an RNA polymerase (an enzyme that acts as a copier of genetic material) intrinsically given to making mistakes, with which their genomes will accumulate mutations in each copy cycle,” Grubaugh explains.

The clouds of mutants that infect us
These mutations have the strength of numbers on their side. While a human takes decades and a lot of effort to reproduce, a virus can multiply in a matter of hours and can also replicate thousands of times in each cell of an infected person: consequently, the same patient is not infected by a single virus, but by many different populations of viruses, each with its own mutations.

“A virus is actually a cloud of mutants,” explains Ignacio López-Goñi, professor of Micriobology at the University of Navarra and author of the Microbioblog. “So much so that we talk about viral quasi-species, instead of species, to speak of a population that shares a consensus sequence but made up of different mutants.” In fact, in the case of long-lasting infections, such as those caused by HIV, the same person can be infected by “waves” of different viruses as they evolve within their body.

Viruses don’t change that fast
It is clear that viruses have an incomparable capacity to accumulate mutations, but this does not mean that they change so much; it usually takes years for mutations to affect important features of viruses. The reasons are varied: “Most mutations have a negative impact on some function of the virus and are eliminated by natural selection,” writes Grumbaugh, which implies that they disappear from the population because acquiring them is a disadvantage. Mutations may also appear that change the virulence or transmission capacity of the virus, but according to this researcher, “they will not spread very often unless they are advantageous.”

Furthermore, many of the traits of viruses, such as the mode of transmission, depend on multiple genes, so point changes are more unlikely to have a beneficial effect. In order for benefits to appear, it is necessary for them to accumulate numerous mutations and, therefore, “it is rare to see viruses that have changed in short evolutionary times despite having high mutation rates”, in the words of Nathan D. Grubaugh.

Mutations do not usually increase lethality
For our peace of mind, these changes are unlikely to make viruses more deadly, since “High virulence can reduce virus transmissibility if the host is too ill,” according to this researcher. That is, if a virus leaves a person dying or directly deceased, it is very likely that the pathogen will leave fewer descendants capable of continuing to infect.

For this reason, “the opposite is often seen,” says José Antonio López Guerrero, a virologist and professor at the Autonomous University of Madrid. “Over time, viruses tend to adapt to the host and lose virulence, because they are not interested in destroying their host. So it was with the Spanish flu virus or the 2009 flu. A study recently uploaded to the “medRxiv” server concluded that the virus is most likely to become less severe and to become a seasonal pathogen, recurring every winter.

Therefore, the different case fatality rates that are being registered in each country “are probably not caused by the existence of more or less widowed strains,” according to López Guerrero. “This dance of numbers is artificial: it depends on the depth of the PCR and diagnostic tests (if the majority of cases are not known, only the most severe cases are counted, making the case fatality appear higher) and on social and health factors in each country ”, he continues.

Can mutations affect a vaccine?
Leaving lethality aside, as the coronavirus spreads, it continues to evolve in every cell, in every person and in every country and accumulates new mutations. So there may come a point when vaccines are no longer useful for new variants of SARS-CoV-2.

“Undoubtedly a virus that mutates a lot could give problems,” says José Antonio López. “But this does not appear to be the case for SARS-CoV-2, because it is quite stable.” In addition, as he explains, not only are there dozens of vaccine candidates (41 of them are being worked on), but they are also seeking to design them to recognize various “targets” of the viruses and to generate a prolonged immune response. Ignacio López-Goñi emphasizes that this coronavirus is less variable than the influenza virus, “a champion of variability” for which new vaccines are developed each season.

Holmes and Zhang recall that this virus has an enzyme capable of correcting errors, thus compensating for its natural tendency to negligently copy genetic material. Therefore, there is no evidence that the virus can undergo “radical changes, such as its transmissibility or virulence, since these rarely change on the scale of a single epidemic,” they write in an article published in “Cell.”

Trevor Bredford, an epidemiologist at the Fred Hutchinson Research Center and a professor at the University of Washington (USA), agrees in this regard. “My prediction is that we should see occasional mutations in the SARS-CoV-2 protein S (crucial for its ability to infect) that allow it to partially escape vaccines or group immunity, but this is a process that will surely take years and not months, ”as he wrote on Twitter.

The “virus family tree”
Although the SARS-CoV-2 mutations will not change the lethality or alter the efficacy of the vaccines, in the short term, there are many scientists collaborating and taking advantage of the mutations to study their evolution. The existence of “clusters” or groups of viruses has already been recorded in countries with different sequences and hundreds of genomes have been sequenced.

The latest update of the Nexstrain website, promoted among others by Trevor Bredford, shows the knowledge gathered about the phylogeny of the coronavirus since its departure from China: something like a family tree where you can see the history of infections. 1,495 genomes from 48 countries on six continents have already been sequenced. The latest data shows that the virus has been spreading and mixing across Europe in the past three to five weeks.

All this work allows us to study, at the molecular level, the entire history of SARS-CoV-2: what virus is it, if it is new, how is it transmitted, what is its reservoir, what factors caused its appearance, how does it evolve and how does it adapt. State-of-the-art sequencing techniques, rapid publication of articles and international collaboration of scientists, sharing data, allow very rapid advancement of knowledge about the enemy. Of course, to be fully effective, these techniques have to be combined with epidemiological studies (which measure on the ground how the epidemic is progressing) and with serological analyzes, massive surveys that track the presence of antibodies against the virus to know what the spread is really. of the virus.

What are SARS-CoV-2 mutants like?
In this record pandemic, the scientific response has also been record. Just a few days after the epidemic was detected, scientists accomplished one of the most important things in responding to these situations: taking the “robot portrait” of the enemy. On January 5, thanks to the most advanced sequencing techniques, Chinese scientists obtained the complete genome of the virus. This allowed us to find out who he was and where he came from, which is key to understanding how it is transmitted or how it infects and to design new treatments and vaccines. In fact, just two months after obtaining their sequence, vaccine candidates, such as that of the company Moderna, are already being tested in volunteer patients.

Thanks to this sequence, it is now known that SARS-CoV-2 is a coronavirus very similar to the one that caused the 2003 epidemic (now called SARS-CoV-1) and that it belongs to the genus of Betacoronaviruses. However, it has been found that, thanks to a long history of mutations and evolution, this virus has a modified envelope protein, S, which allows it to bind to the cells it is going to attack, and that the genetic sequence 28% of this is different from that of the first coronavirus. A modification in the protein S sequence has also been discovered that allows it to bind furin, an enzyme from animals. These changes, apart from others, have made SARS-CoV-2 a highly dangerous virus, due to its ability to spread between people.

The mysterious origin of the coronavirus
Analysis has also shown that SARS-CoV-2 is similar to coronaviruses that infect bats and pangolins, leading to suspicion that it comes from the former and that the latter are intermediate hosts.

The accumulation of mutations detected implies, according to what Edward C. Holmes and Yong-Zhen Zhang write in their article “Cell”, “more than 20 years of sequence evolution”. That is, the virus did not suddenly mutate, but the current pandemic was brewing for decades in various animals without being detected. Another possibility that cannot be ruled out is that the virus evolved to its current version, transmitted for years between people, without being detected until December 2019, according to Holmes and Zhang.

Furthermore, the SARS-CoV-2 genome and its mutation history are far from indicating that it comes from a laboratory, as some theory has argued. Its sequence was quickly published and has been investigated by scientists from around the world who, in addition, have been obtaining new sequences as the epidemic spread. An article published last week in “Nature Medicine” reviewed the evidence that the mutant SARS-CoV-2 has not been manufactured by humans: fundamentally, the changes it presents have nothing to do with what is predicted by the models and are not they use the known enzyme systems. “The genetic data irrefutably reveals that SARS-CoV-2 does not come from any previously used virus” chassis “,” the authors of that study write. .

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