Actually, Edward Holmes does not like predictions, but last year he risked breaking this rule of his. Over and over again, Holmes, an expert on viral evolution at the University of Sydney, was asked the same question: How will the SARS-CoV-2 coronavirus mutate? In May 2020, just five months after the start of the pandemic, Holmes began to accompany his speeches with a slide in which he shared his predictions. The scientist suggested that the coronavirus, in all likelihood, will evolve in order to escape the meeting with human immunity. But over time, as a result of this process, Holmes continues, the number of infected is likely to decrease, and the infectivity of the coronavirus will not change so much. In short, it turns out that the evolution of the coronavirus will not play an important role in the foreseeable future during a pandemic.
“However, a year later, all my statements were largely wrong,” says Holmes.
However, not all: the SARS-CoV-2 coronavirus, indeed, was able to evolve in order to more effectively dodge human antibodies. At the same time, the coronavirus has become more dangerous and infectious, as a result of which the number of infected has increased. And this factor had a huge impact on the entire course of the pandemic.
The currently circulating delta strain of coronavirus (as defined by the World Health Organization as one of four “worrying options”, along with four “of interest” options) is so radically different from the coronavirus that emerged in the Chinese city of Wuhan at the end of 2019, that many countries were forced to adjust the development of plans for the period of the pandemic. Governments in many countries are struggling to speed up vaccination programs by extending or even reintroducing the mask wearing regime, as well as using other sanitary and epidemiological measures. As for the achievement of herd immunity (that is, immunization of the optimal proportion of the population, as a result of which the spread of viral infection is contained), here, according to infectious disease specialist Müge Çevik from the University of St Andrews, “with the advent of delta -Variant it became clear to me that it is generally impossible to achieve this”.
And yet the most turbulent period in the evolution of SARS-CoV-2 may still be ahead, according to evolutionary biologist Aris Katzourakis from Oxford University. Now the human population has developed sufficient immunity so that competition intensifies in the course of evolution, forcing the coronavirus to adapt further. At the same time, most countries in the world are still suffering from coronavirus infection, which increases the likelihood that more and more mutations will appear as a result of the increase in the number of infected.
However, predicting where all these troubling factors will lead is as difficult today as it was a year and a half ago. “We're much better at explaining the past than predicting the future,” says evolutionary biologist Andrew Read of Pennsylvania State University at University Park. After all, the evolution of the coronavirus occurs as a result of random mutations that cannot be predicted. “It’s extremely difficult for us to predict what events should come before they actually do,” says Reed. - This is not physics for you. This does not happen on a billiard table."
Nevertheless, evolutionary biologists, based on information they know about other viruses, have received some clues to help understand in which direction the evolution of the SARS-CoV-2 coronavirus may be moving. According to Reed, judging by past outbreaks of epidemics, the coronavirus may well become even more infectious compared to the existing delta variant. "I think there is every reason to assert that the current coronavirus will be able to adapt to humans even more successfully in the future." It will not soften its deadly properties; Moreover, it can become even more deadly, like some other viruses of the past, including the influenza virus during the large-scale pandemic of 1918. And while covid-19 vaccines are doing well at the moment, history teaches us that the virus can continue to evolve to escape vaccines. True, in a recent study that studied one of the other coronaviruses, it was found that the evolution of the coronavirus can take many years; therefore, we still have time to adapt vaccines to the evolving viral threat.
Explaining the past
On January 10, 2020, Edward Holmes posted one of the first SARS-CoV-2 genomes on the Internet. Since then, more than 2 million genomes have been sequenced and published, resulting in a very detailed portrait of the changing virus. “I don’t think we have ever been able to meet such a high level of accuracy when observing evolutionary process,” says Holmes.
It is rather difficult to understand the endless stream of mutations. Each of them is a kind of only a small amendment to the instructions for preparing proteins. What mutations will eventually spread? Everything will depend on how comfortable viruses that have these altered proteins will feel in the real world.
The vast majority of mutations do not confer any benefits on the virus, and it is difficult to identify those that provide such benefits. There are obvious candidates, such as mutations that partially alter the spines located on the viral envelope that bind to human cells. However, changes elsewhere in the genome can be just as important, but more difficult to interpret. And the functions of some genes are not even clear, not to mention the properties that can arise as a result of changing the sequence of genes. The impact of any such change on the adaptability of the coronavirus also depends on other mutations that have already accumulated in it. This means the following: in order to determine which of the viral variants will be successful, scientists need to get real data. Only then will it be possible to conduct research on cell cultures and experiments on animals, which could ultimately shed light on the reasons for the success of the virus.
The SARS-CoV-2 coronavirus is capable of spreading even faster in the human population - this new property is perhaps the most incredible change that has been observed in this coronavirus so far. At some point early in the pandemic, the SARS-CoV-2 coronavirus developed a mutation called D614G, which made it even more infectious. This mutated variant of the coronavirus has spread throughout the world; almost all modern viruses originated from it. Then, at the end of 2020, scientists discovered a new variant of the coronavirus (now called Alpha) in patients in Kent County (UK), which became about 50% more transmissible. The delta variant, first discovered in India and becoming the most widespread strain in the world, turned out to be another 40-60% more transmissible compared to Alpha.
Andrew Reid argues that this situation is not surprising."The only way to prevent the growth of infection is possible only if we are faced with a coronavirus, which perfectly knows how to enter the human body, and the likelihood of this event is incredibly small," says Reed. But Edward Holmes was unpleasantly surprised. “Over the year, the current coronavirus has climbed three steps. And this fact causes me, perhaps, the greatest surprise, - says Holmes. "I never imagined how far today's coronavirus could go."
Bette Korber of Los Alamos National Laboratory and her colleagues first suggested that D614G (the very first mutation) was gaining the upper hand over the others because it promotes more efficient spread of the coronavirus. According to Corbet, in the early days of the pandemic, experts usually expressed skepticism about the ability of the coronavirus to evolve, and some scientists generally said that the obvious advantage of the D614G mutation is quite possibly just pure coincidence. "Since the exacerbation of the pandemic was recorded in the spring of 2020, there has been a strong rejection in the scientific community of the hypothesis that the current coronavirus is generally capable of evolving," says Korber.
After all, scientists have never seen a situation in which a completely new virus could spread so widely in a population and evolve. “We are used to dealing with pathogens that have existed in humanity for many centuries, and the process of their evolution has already been investigated, because these pathogenic viruses have coexisted with humans for a very long time,” says Jeremy Farrar, head of Wellcome Trust. “And perhaps this fact influenced our hypotheses and predetermined the ideas of many of us,” agrees with Farrar Aris Katsurakis.
Another difficulty, which is even more important for practice, is that the real benefits inherent in the virus cannot always be traced in cell cultures or model animals. “Nobody could have identified anything special in an alpha strain based on laboratory data alone,” says virologist Christian Drosten of the Charite University Hospital in Berlin. Drosten and others are trying to figure out the factors that gave the alpha and delta variants of the coronavirus a molecular advantage.
The alpha variant of the coronavirus appears to be able to bind more strongly to the ACE2 receptor in the human body (this receptor is the target of the coronavirus on the cell surface) due in part to a mutation in the spine protein (this mutation is called N501Y). In addition, this option can more effectively counteract interferons, that is, molecules that are one of the elements of the body's immune system. All these changes are capable of reducing the infectious dose, that is, the number of viruses required to infect a person. In the delta variant, one of the most important mutations may appear near the furin cut-off site on the spinous process, that is, where the human enzyme cleaves the protein; this is one of the key stages during which the coronavirus enters the cell. A mutation called P681R in this area makes the clipping more efficient, which allows the coronavirus to infect more cells, causing the infected person to carry more viral particles. In July of this year, Chinese scientists published a preprint of an article stating the following: as a result of infection with the delta variant (in comparison with other variants of the coronavirus), the number of viral particles in samples taken from patients can increase by a thousand times.At the same time, the accumulated evidence indicates that an infected person is able to spread the coronavirus not only more efficiently, but also faster, which, in turn, accelerates infection.
New variants of the SARS-CoV-2 coronavirus can also cause more severe forms of the disease in patients. For example, in one of the scientific studies conducted in Scotland, it was shown that when a person is infected with the delta variant, hospitalization occurs approximately twice as often as when infected with the alpha variant.
It is not the first time in the history of mankind that we observe a situation in which the contagiousness of an infection is increasing at an extremely fast pace. It is this process that appears to have been observed during the 1918-1919 influenza pandemic, says epidemiologist Lone Simonsen of the University of Roskilde, who analyzes past pandemics. “Based on the information gathered in Denmark, it can be argued that the second wave [of the Spanish] was six times more dangerous than the first,” says Lone.
There is a widespread belief that viruses evolve, as a rule, in order to decrease their infectivity over time; experts believe that this is so that the virus allows the host organism to live even longer and infect even more other living organisms. But, according to Edward Holmes, this view is too simplistic. “In general, the evolution of virulence has been challenging for evolutionary biologists,” Holmes said. "This is not an easy question."
Consider the two viruses whose evolution has been studied in most detail: the Myxoma virus and the rabbit haemorrhagic disease virus, which appeared in Australia in 1960 and 1996, respectively, and hit the European rabbit population, causing damage to cropland and the environment. At the very beginning after its appearance, the myxoma virus destroyed more than 99% of infected rabbits, but then less pathogenic strains of this virus appeared; the mitigation of pathogenicity was probably due to the fact that this virus managed to kill a sufficiently large number of rabbits before the animals had time to transmit it to other individuals. (Note that rabbits eventually became less susceptible to myxoma virus.) Conversely, the rabbit haemorrhagic disease virus has become more lethal over time; in this case, the increase in pathogenicity was probably due to the fact that the carriers of this virus were flies feeding on the corpses of rabbits, and the rapid death of rabbits only accelerated the spread of the virus.
There are other factors that increase the lethality of viruses. If, for example, a variant of a virus appears that can outstrip in its evolutionary development all other variants that have settled in the host organism, then such a virus will eventually dominate, even if, as a result of this dominance, the health of the host organism begins to deteriorate., and the likelihood of transmission will decrease. And the assumption about respiratory diseases may not always turn out to be true: for example, it is possible that a weakened virus (say, as a result of infection with which the patient is not assigned to bed rest) can contribute to the fact that an infected person will infect others. If we talk about the SARS-CoV-2 coronavirus, then in this case, infection of the general population for the most part occurs at an early stage, that is, at the moment when the coronavirus replicates in the upper respiratory tract; at the same time, the severe stage of the disease occurs later - at the moment when the coronavirus infects the lower respiratory tract. As a result, it turns out that the variant of the coronavirus, from which an infected person eventually becomes ill in a more serious form, is quite capable of spreading quickly without changing speed.
From the very beginning of the current pandemic, scientists have been worried about the appearance of a third type of mutation, in which the SARS-CoV-2 coronavirus, as a result of its evolution, will suddenly learn to bypass human immunity caused by natural infections or vaccinations - these are the mutations of the coronavirus that inspire perhaps the greatest alarm … Several variants of the coronavirus with mutated spines have already emerged, making them even more difficult for antibodies to recognize. These variants of the coronavirus have already scared many; however, despite this, the influence of these strains is still small.
Evolutionary biologist Derek Smith of the University of Cambridge has spent decades graphically figuring out how the flu virus manages to trick human immunity; for this purpose Smith used the so-called antigenic maps. The scientist asked the question: can antibodies that protect against one variant of the virus protect the body from another variant? The greater the distance on the Smith charts between two strains, the less effective antibodies, designed to protect against one particular virus strain, are able to protect the body from another strain. In a recently published preprint, a research team led by Smith and David Montefiori of Duke University used antigen maps to analyze the best known variants of the SARS-CoV-2 coronavirus.
On Smith's maps, the alpha variant of the coronavirus is very close to the Wuhan strain, which means that antibodies against one of these strains can protect against the other. However, the delta variant has departed from the Wuhan variant even further, although it also fails to completely elude human immunity. "No, he is not able to completely deceive the immune system in the sense that people usually imagine it oversimplified," says Aris Katsurakis. At the same time, the likelihood of infection of vaccinated people with the delta variant of coronavirus remains somewhat higher than the likelihood of infection with previous strains. “Thus, there may be a dangerous tendency here. And that worries me,”warns Katsurakis.
The Smith maps also show that other variants of the coronavirus, as a result of their evolution, moved a greater distance from the original strain than the delta variant. The beta variant, first discovered in South Africa, has advanced the farthest on the antigenic map, although immunity (both natural and acquired through vaccination) still protects significantly against this strain. Outsmarting human immunity will not be easy for the beta variant of the coronavirus, as it has been supplanted in every corner of the world by the delta variant. “Probably, when the coronavirus tries to escape from human immunity by means of mutations, it loses some of its other qualities,” says Derek Smith.
The antigen map shows that the coronavirus is not currently progressing in any particular direction. If the original Wuhan strain, placed on the Smith map, is likened to a city, then later, figuratively speaking, we can say that the coronavirus has spread only in the surrounding neighborhoods, traveling by suburban trains, but at the same time it has not yet reached any of the neighboring cities - yet did not arrive.
Predicting the future
It is impossible to accurately predict how the properties of the coronavirus, such as infectivity, virulence and the ability to evade recognition by the immune system, will manifest themselves in the coming months. And yet, some of the factors that inevitably affect the spread of the coronavirus are quite obvious.
One of them is immunity, which the human population is now rapidly developing. On the one hand, immunity reduces the likelihood of infection in humans and can interfere with the replication of the virus, even if the person has already become infected.“This means that if we vaccinate even more people, there will be fewer coronavirus mutations,” explains Müge Ševik. On the other hand, any variant of the coronavirus that can penetrate the immune barrier of the human body will have a huge advantage over all other strains.
In fact, according to Edward Holmes, the world has most likely passed the point of no return: given that more than two billion people have received at least one dose of the vaccine, and several hundred million more patients have recovered from covid-19, the result is, that coronavirus variants that can overcome human immunity may now have greater benefits than even the most infectious strains. “Something similar seems to have already happened in 2009, when a new H1N1 flu strain emerged that caused a pandemic,” says evolutionary biologist Katia Kölle. from Emory University. An article published in 2015 showed that mutations that the coronavirus acquired during the first two years appeared to increase its ability to spread from person to person; and at the same time, mutations that appeared after 2011 years, were mainly aimed at overcoming human immunity.
It is possible that the SARS-CoV-2 coronavirus is becoming more and more difficult to increase its infectivity. “There are some fundamental factors that limit the ability of the coronavirus to spread. At some point, SARS-CoV-2 will reach this plateau, says evolutionary biologist Jesse Bloom from the Cancer Research Center. Fred Hutchinson. "I think it's very difficult for us to say whether we are already on this plateau or just approaching it." And the evolutionary virologist Kristian Andersen from the Institute. E. B. Scripps believes that the infectiousness of the coronavirus may continue to increase. “Metaphorically speaking, the frontier in the observable viral universe is measles, which is about three times more infectious than the delta variant of the coronavirus,” says Andersen.
In addition, scientists do not know for certain how long the coronavirus is able to deceive the immune system. Smith's antigen maps indicate the space that the coronavirus has been able to cover to date. But can he go further? If the variants of the coronavirus on the antigenic map are likened to cities, then where will the natural borders of the country in which these cities are located be drawn? Where does the ocean begin? Also, where will the following coronavirus variants appear on the antigen map? The answer to the last question, according to Smith, will be one of the key clues for us. The antigenic map shows that if the beta variant began to evolve in one direction from the original coronavirus, then the delta variant evolves in a completely different direction. “It's too early to talk about it, but perhaps we are approaching a situation where two serological types of this coronavirus will coexist. And this fact must also be taken into account when creating any vaccines,”says virologist Christian Drosten.
Scientists are concerned about the ability of the coronavirus to elude immunity, as this will have to constantly update vaccines, as is already the case with the influenza virus. However, we recall that vaccines against many other diseases - for example, measles, polio and yellow fever - remained effective for decades without any updates, and even in those rare cases when viral variants appeared that managed to seep into the body, despite human immunity. According to Andrew Reed, “In 2000, there was a great deal of concern that we might have to make new vaccines for hepatitis B,” as a viral variant of hepatitis emerged that could bypass the immune system.However, this variant of hepatitis has not become widespread in the world: it is capable of infecting only the close environment of an infected person, after which it disappears. Apparently, the virus is faced with a choice: either choose the ability to transmit quickly, or choose the ability to evade immunity. A similar choice is likely facing the SARS-CoV-2 coronavirus.
In order to try to look into the future of the SARS-CoV-2 coronavirus, you can turn to those coronaviruses that have been infecting humans for a long time - much longer than the current coronavirus, for example, the acute respiratory viral infection (ARVI) virus … Some SARS viruses are known to re-infect humans, but until recently it was unclear whether this is due to a weakened immune system in recovered patients or because the virus modifies its envelope to trick the immune system. In an article published this April in the journal PLOS Pathogens, Jesse Bloom and others compared the ability of human serum taken at different times over the past decades to block a virus isolated at the same time or somewhat later. Scientists have shown that the samples can neutralize strains of coronavirus 229E isolated at about the same time, but they are not always effective against this virus after ten or more years. Obviously, the virus evolved to protect itself from meeting human immunity, but it took ten or more years.
"The ability to bypass human immunity conjures up a catastrophic immune shutdown, when in reality it is just a violation of the immune mechanism," says Jesse Bloom. "Currently, it seems that the behavior of the SARS-CoV-2 coronavirus, at least in terms of its ability to evade antibodies, is very similar to that of the 229E coronavirus."
Other scientists began to investigate the SARS-CoV-2 coronavirus itself. In a preprint published in August this year, scientists set themselves the following task: to figure out how much this coronavirus must change in order to escape from collision with antibodies that are produced in vaccinated people and in recovered patients. Scientists have established the following fact: in order for the virus to almost completely avoid collision with antibodies, twenty mutations must occur in the spine. This means that, according to one of the authors of the article, virologist Paul Bieniasz from Rockefeller University, the coronavirus still needs to work very hard to learn how to completely overcome the human immune defense. “Will it be easy for the coronavirus to do this? It's difficult for us to predict,”says Benias.
“Bypassing immunity seems to be tricky,” concludes William Hanage of the School of Public Health. Chan at Harvard University. "However, on the other hand, natural selection is also a very effective thing, and the coronavirus has only now begun to learn to overcome human immunity."
Let's not forget that the coronavirus has its own tricks. For example, a coronavirus is capable of recombining, for example, which can lead to the sudden emergence of new coronavirus variants as a result of combining the genomes (and at the same time properties) of two different variants. So, for example, in pigs, as a result of the recombination of the coronavirus [it is called "swine epidemic diarrhea virus" (PEDV)] and attenuated vaccine strains of another coronavirus, more virulent variants of PEDV have appeared. “Given the biological characteristics of these viruses, recombination may well spur the evolution of SARS-CoV-2,” says Bette Korber.
Thus, there are still many unresolved issues.With that said, it is worrying that humanity has yet to take global action to limit the spread of the SARS-CoV-2 coronavirus, said Eugene Koonin, a researcher at the US National Center for Biotechnology Information. According to him, some dangerous variants of the coronavirus can only appear if the coronavirus has some very rare winning combination of mutations. And to do this, the coronavirus may have to replicate an incredible number of times. "But such a combination may well appear, because there are millions of infected people," Kunin believes.
Indeed, adds evolutionary biologist Aris Katsurakis, the past twenty months have been a kind of warning to all of us that the evolution of the coronavirus should not be underestimated. “Many people still think the alpha and delta options are the worst,” Katsurakis said. "Although it might be more correct to view them as just the first steps on a dangerous path - the very steps that can call into question all our public health response."