Well before the arrival of the infectious agents that cause Sars and MERS it was already known that there are four other coronaviruses circulating in the human population, giving colds that are not worrying at all. The question is: when and how did they arrive? Have they always been relatively harmless, or have they traveled a path that began with serious infections and then reached, over time, a pact of non-belligerence with the host, that is us, and thus guaranteeing a smooth replication? The answer is crucial, because it could help glimpse what will happen with Sars-CoV 2, and provide suggestions on how to beat it on time.
A woman, June Almeida, discovered the coronavirus (born Hart), a Scottish expert in electron microscopy, to the point that other important first descriptions are due to her, such as that of the rubella and hepatitis B viruses. In 1966 her colleague David Tyrrel sent her a sample of a boy chilled in which there is something that escapes all scrutiny, because it is none of the known viruses and bacteria. The organism, called B814, is identified by Almeida: it is a large rounded virus, which has a sort of corona similar to the solar one. The name she has chosen can only be: coronavirus. And until Sars nobody cares too much about a family that, in the meantime, continues to grow (more than 3,000 coronaviruses are classified).
Longform
Covid: the origin of the pandemic
by Davide Michielin
The history of those viruses today helps predict that of Sars-CoV 2. A difficult task, because the average life span was much shorter then, and respiratory infections afflicted the population much more than today: among the many that have occurred, there may also have been a pandemic of a coronavirus which then evolved towards harmless forms or almost. But we still try to deduce the crucial elements of the family.
Graziano Pesole, professor of Molecular Biology at the University of Bari and coordinator of the Italian branch of the international sequencing project Elixir, which brings together 23 centers throughout the country, explains: “The primary purpose of viruses is to live and proliferate undisturbed and, consequently, be as infectious as possible and, at the same time, not very pathogenic (virtually not at all): a successful virus is a virus that camouflages and integrates with the host without causing any discomfort. To achieve this goal, it changes continuously “. The variants that worry so much, therefore, are not a recent phenomenon, quite the contrary. “The first evidence of coronavirus variants dates back to autumn 2019 and more than 60,000 have been observed since then,” Pesole confirms. “It is a statistical fact: the greater the circulation of the virus, the greater the number of variants. The real point is to know them, to act immediately and effectively on the dangerous ones, and to follow their progress over time. For this reason it is urgent to organize the sequencing , which today is still carried out too unevenly and in totally insufficient quantities “.
Most of the variants (more than 99.9%) are “neutral”, ie they do not modify the properties of the virus. But a small part may be the result of an adaptive evolution, that is, a response to specific environmental situations. These “adapted” variants actually modify the characteristics of the virus and, Pesole clarifies, are generated more frequently when the virus is under attack due to vaccines and the increase in the number of naturally immunized people. “Is called immune escape, that is, literally, ‘escape from the immune system’, and it is, for the virus, a push to mutate further, to become less recognizable to antibodies: for this reason it must be beaten on time, and vaccinated as many people as possible before it act a winning strategy “.
To complicate the existence of Sars-CoV 2 there is also the coexistence – which is sometimes ruthless competition – with other viruses that have the same targets. In short, the world of Sars-CoV 2 is very dynamic and constantly looking for a balance.
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For this reason, making predictions is an exercise with a high risk of error: many variables come into play. However, as a panel of experts interviewed by “Nature” pointed out, it is expected that Sars-CoV 2, after such a turbulent onset, caused by the fact that it infected humans for the first time, will become much more meek, and become part of the already large group of respiratory viruses. In short, it could become a seasonal virus (the other coronaviruses are), present every year with different variants, against which it may be necessary to reformulate the vaccines periodically, if not every year. A virus no longer capable of killing the host and, with it, itself.
How the vaccinations will go and how our body will react
Sars-CoV 2, therefore, is here to stay, that is, to become an endemic virus and of little concern, like his four close relatives who cause normal colds, or will his parable be a dazzling parable, but doomed to run out? To answer this question, Nature consulted about a hundred immunologists, virologists and experts of various kinds: almost two thirds said they were optimistic, despite numerous distinctions and “ifs” referring to as many variables. Because if a certain type of trend can be expected, it is also true that this is a still little known virus, which has already baffled those who study it. And what happens is not just up to him. Much, in fact, depends on the host. The progress of the vaccination campaigns but, above all, the many unanswered questions about the reactions of the human organism will influence its behavior, and will direct it towards a certain specific evolutionary destiny.
To better understand the weight of each of the variables relating to the host, we consulted Luca Guidotti, deputy scientific director of the San Raffaele Hospital in Milan, a great virus expert and head of one of the most complete research laboratories on Sars-CoV present in Italy, the only one to have Covid-19 animal models. Who explained to us that there are two main areas to pay attention to: that of vaccines and drugs and that of the immune response to a virus with which man has had to learn to deal with for the first time in his history.
Longform
Variants and mutations, the virus strategy to fool our immune system
by Daniele Banfi
One of the concepts that has become more familiar is that of herd immunity, which should ensure the containment of the virus for lack of people susceptible to infection. In reality, no one today can say what percentage of the population needs to be vaccinated to reach it: estimates range from 70 to 90%, depending on the variants that will prevail and on the possible updating of vaccines against them, which in any case takes time.
It also remains to be seen whether the coverage should be included the infant population which, due to its characteristics (high percentage of asymptomatic and high transmission capacity), risks being the element that compromises vaccination efforts. For now it has been ruled out, but Pfizer, Moderna and AstraZeneca are conducting the necessary studies and should have the first data by the summer: decisions will be made on the basis of what emerges. Another decisive question is that of the ability of vaccines to significantly reduce transmission: even if there are no certainties, from what is happening in Israel and in Great Britain it seems that this is the case, and this could help a lot, especially if measures are maintained. precautions such as spacing and use of masks.
Looking at longer times, in general, Guidotti explains: “It must be remembered that the vaccination effort, given the drama of the moment, was directed towards the most obvious target, the spike protein. Current vaccines not only induce B lymphocytes. to produce antibodies that can block the virus from entering cells, but they also stimulate T lymphocytes to recognize and kill cells that have already become infected. We do not yet know if future spike mutations will allow the virus to evade antibody responses and those T lymphocytes, but it is obvious that this risk will decrease when vaccines capable of stimulating a protective immune reaction against other viral proteins arrive. Let’s not forget that Sars-CoV 2 contains, in addition to the spike, another thirty proteins of which we know still little “.
Another area that could make a difference is that of antivirals, which so far has given many disappointments, because the focus has been mainly on drugs imagined for other viruses. But there may be surprises in the coming years. In fact, several new generation antivirals are being studied, including some viral enzyme inhibitors – proteases – on which Guidotti himself is working together with colleagues from the universities of Milan and Naples. These drugs should be effective against all coronaviruses and be taken at the first suspicions of the disease, in order to prevent serious forms and hospitalizations and thus manage Covid in a very different way from what has happened so far. It still takes time, and a lot of money, because developing antivirals is more complex than developing vaccines, but there are indications that allow us to hope.
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In addition to the questions about vaccines and drugs, many questions concern the reactions of our organism, which are starting to be clearer, but which are still far from being fully understood. “We focused on antibodies, whose production is however extremely variable and destined to disappear after a few months”. We also know, from the history of Sars, that antibodies against the first strains, over time, have become less and less effective against the variants that have gradually appeared, and the same is beginning to be seen also with Sars-CoV 2. In short, we must change strategy, and first of all to better understand how memory B and T lymphocytes behave. This will make it possible to predict, for example, how long protective immunity lasts, or what happens if a variant arrives, both for vaccine-induced and natural immunity. It appears that this virus leaves a robust memory at the level of T lymphocytes, but only time will provide definitive responses. And when we know more, we can also think of vaccines or innovative drugs, which selectively enhance that type of response. For now, one of the ways is to thoroughly analyze people who, despite having been exposed to certain sources of contagion, did not get sick, and then verify everything in animal models.
The question is: what makes them resistant? “One of the main steps forward in HIV studies has been done in this way”: Guidotti refers to the story of Stephen Crohn, a man whose partner died in 1978 of AIDS, but who never fell ill. By analyzing his immune system, which had a specific mutation present in only 1% of the population, which prevents the virus from binding to the host’s cells, discoveries were made that led to the antiviral maraviroc, still fundamental today.
In the case of Sars-Cov 2, it has been understood that those who become more seriously ill often have defects in the production of interferon, a kind of natural antiviral, or autoantibodies against it, and this is considered a good place to start. For some, Neanderthal genes also play a role, which would make the excess response that causes the most serious problems more likely, just as blood type 0 with Rh negative seems to play a protective role.
But a great deal remains to be understood: the fact of being able to predict, before realizing it in the facts, depends on that basic knowledge, if and when Sars-CoV 2 will become endemic.
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