Viral variants

Content

Introduction

Viruses are simple microorganisms consisting of a nucleic acid (DNA or RNA depending on the type of virus) which contains the genetic information (genetic heritage) necessary for their multiplication and a variable number of proteins, some present on the external envelope (viral capsid). They are not autonomous and are able to live and multiply only within the cells of the organism that hosts them (for example, man).

A variant is generated when a virus, multiplying in the host organism, undergoes one or more variations (mutations) in its genetic patrimony (or genome) that make it different from the original virus.

In most cases, the mutation does not cause major changes in the structure of the virus and in the characteristics of the infection. However, in some cases the mutation, or the combination of several mutations, can give the "new" (variant) virus a greater capacity to recognize the cells to be infected and, therefore, a greater aggressiveness and speed of diffusion.

In other cases, the modified (mutated) virus may become resistant to the response of the body's defense system (immune system) that develops during natural infection or following vaccination.

More rarely, and for particular families of viruses, it may happen that the mutations present in the variant of the virus give the latter the ability to infect a host other than the usual one, passing, for example, from animal to man. SARS -CoV-2, responsible for the current pandemic, is an example of a virus that has passed from "animal to" man and continues to vary by multiplying in the human species.

How a variant is generated

At the time of infection, the virus enters the cell using one or more proteins present on its external envelope (in the case of SARS-CoV-2 mainly the protein Spike) as a key with which to force the lock (the receptors) present on the surface of the cells. Once it enters, it releases its genetic material, or genome, (consisting of DNA or RNA) containing all the information necessary to multiply in the infected cell and make the latter produce many new viruses, copies of itself, which will not only go to infect other cells of the same individual, but will also be transmitted to other people. The infected cell is therefore forced to read and decode the information contained in the genome of the virus and to produce "faithful" copies of viral RNA and all the proteins necessary to form the "child" viruses, including those of the "external envelope that they will serve to recognize the receptors to enter new cells.

During the process of multiplication (replication) of viruses, especially RNA ones such as coronaviruses or influenza viruses (Ortomixovirus), random errors (mutations) may occur, so that the copies of RNA produced are not exactly faithful copies but can present differences from the original one.Mutations in the viral genetic patrimony (genome) correspond to more or less important variations in the structure and / or function of the proteins that make up the virus and, in particular, those of the external envelope.

Since viral multiplication is an error-prone process, the appearance of "variants" of the virus that have one or more mutations in their genetic code, compared to the original or "wild" virus, is a predictable but not necessarily worrying event. In fact, in most cases, these variations of the genetic code are not reflected in substantial differences in the structure and characteristics of the virus and therefore do not have an impact on its spread, but contribute to the normal change (evolution) of the virus itself. as happens for the evolution of all living beings, including man.

However, some mutations, or combinations of several mutations, can provide the new virus (variant) with advantages such as, for example, a greater ability to spread and spread the infection. external envelope (in the case of SARS-CoV-2 the protein Spike) of the virus. In addition to recognizing the receptors present on the cells to be infected, in fact, these proteins are the ones that the host's immune system sees first and against which it triggers a stronger immune response, including the production of antibodies. Consequently, the characteristics change. of such proteins, as happens when a "dangerous" variant is generated, can give the virus the ability to infect more efficiently or to be less easily recognized by the immune system. This translates into a better ability of the virus to adapt to the " environment in which it is found, so the variant can become dominant in a short time and supplant the original virus from which it derives.In these cases, the variants become a cause for concern, and must be kept under control, especially if they simultaneously present factors that influence the clinical aspects, such as greater severity of the infection.

Factors favoring the appearance of variants

The virus variants differ from the virus from which they originate by a very small component, less than 0.1%, of the viral genetic heritage (genome). Nonetheless, some can be very different in their ability to infect and in the severity of the ailments they cause from the original virus.

As to the reasons that determine the development of a variant of a virus, several hypotheses have been advanced:

  • infection prolonged, if a person cannot recover from an infection, for example because he has a compromised immune system (immunosuppression), the virus can evolve (mutate) over time within the same person. An example is represented by the so-called "Corradino variant", which appeared in an immunosuppressed Italian woman who remained positive for infection for 5 months
  • high rate of multiplication (replication) and spread of the virus, the probability of occurrence of variations (mutations) increases with the increase in the circulation of the virus. This is the case of SARS-CoV-2 which is infecting the world population without defenses against it
  • selective pressure exerted by the immune response, from drugs or vaccines, Viruses are subjected to a strong selective pressure (the defensive response of the immune system against the virus that tries to reproduce and infect other cells) which mainly concerns the proteins of the external envelope more exposed to the attack of the immune system.Under the action of vaccines, or even drugs, which tend to reduce its multiplication, it is more likely that those random errors (mutations) that give the varied virus greater probability of resisting the attack of antibodies or the action of drugs antivirals, take over. This results in an "acceleration of the natural change (evolution) of the virus."

Variants and species jump

The change in the genetic heritage, and therefore in the proteins of the virus, is sometimes so important as to generate a varied virus (variant) with completely different characteristics from the one of origin. One example is the ability to infect cells of a different species. This new varied virus behavior is the so-called "species leap" (in English spillover), or a natural process by which a virus (or another microorganism) that normally infects animals changes (mutates) and becomes capable of infecting, reproducing and transmitting itself within the human species.

Usually, this phenomenon occurs following prolonged contact between man and the animal carrying the original virus. The more prolonged and closer the animal-human exposure, the more likely it is that random variations (mutations) in the genetic makeup of the virus can produce a "variant" capable of infecting humans.

The species jump has occurred several times over the years but only for some families of viruses that have the genetic code formed by ribonucleic acid (RNA) such as, for example, Coronaviruses. When it happened, the species jump resulted in sudden and invasive infections in the population on a global scale (pandemics). This is what happened recently with the new Coronavirus SARS-CoV-2, responsible for the disease called COVID-19, but also earlier with the Coronaviruses responsible for SARS and MERS, in 2003 and 2012 respectively.

Another example of RNA viruses for which species leaps have been described are influenza viruses (Ortomixovirus). In these viruses, simultaneous infection with remixing (reassortment) of human and animal viruses (birds or swine ) within the same host, or the direct transmission of the animal virus to man, are the mechanisms described. This jump in species has been responsible for several pandemics over the years, among which the most famous are the Spanish in 1918, the Asian in 1957, the Hong Kong flu in 1968 and the last, the "swine" in 2009. .

Variants of the SARS-CoV-2 virus

Since the beginning of the pandemic caused by the SARS-CoV-2 virus, hundreds of variations (mutations) of the virus have been identified but have not substantially altered the type and disease caused.

From September-October 2020, on the other hand, variants with clinical characteristics different from the original virus began to circulate, due to mutations in the protein. Spike, present on the external envelope. They were initially identified with the name of the country in which they were first isolated, and, more recently, with the letters of the Greek alphabet. There are currently 11 variants of SARS-CoV-2 under observation, and of these four are of greater concern (called by experts "Voc - Variants of concern”):

  • Alpha or English variant (B.1.1.7), first isolated in Great Britain in September 2020. It has demonstrated a 50% higher spreading capacity (transmissibility) than the original virus and with increased disease severity, but is well recognized from existing vaccines. It quickly spread around the world, replacing the original version of the virus and is currently the dominant variant
  • Beta or South African variant (B.1.351), isolated in South Africa in October 2020, and in Europe in late December 2020, has higher transmissibility and lower vaccine sensitivity.Its diffusion in Italy is very low
  • Gamma or Brazilian variant (P.1), isolated for the first time in January 2021 in Brazil and Japan, and soon after also in other countries, it too seems to have a greater capacity to spread and a lower sensitivity to vaccines. Furthermore, it could be responsible for new infections in people who have already had a "SARS-CoV-2 infection and have developed a" immunity. Its prevalence in Italy has declined in recent weeks
  • Delta or Indian variant (B.1.617.2), first identified in India in early 2021. It has a 50-60% higher transmission efficiency than the Alfa variant. It is currently the second-largest variant in the world and it is believed that can become the dominant virus, supplanting the Alpha variant

Then there is the Epsilon variant (B.1.427), initially isolated in California, which is currently present in 44 countries, although it is still not very widespread in Europe (only two cases recorded so far in Italy). It is currently included in the group of variants under observation (called by experts "Voi - Variants of interest”), As it has three mutations in the protein Spike which, according to a recent study, seem to make it resistant to antibodies, both those generated by the vaccine and those developed during natural infection.

The containment measures in place (social distancing), personal protective equipment (masks) and frequent hand washing are however able to limit the infection. The emergence of new variants further reinforces the importance of strictly adhering to health and behavioral control measures, even for those who have already contracted the infection or who have been vaccinated.

Variants and resistance to vaccines

The proteins present on the external envelope of the virus are those against which the immune system of the infected organism triggers a stronger response by producing, for example, antibodies capable of recognizing the virus when it enters the organism and neutralizing it.

The goal of the vaccine is precisely to simulate a natural infection by triggering the production of antibodies and other types of response to neutralize the virus as soon as it enters the body or, in any case, before it infects many cells. For this, for example, with the anti-COVID-19 vaccines currently in use, or in experimentation, introduce the protein into the human body Spike "preformed" or the instructions (for example, "messenger RNA) for making it by the human cells themselves. But vaccines built on the protein of the native" unmutated "virus may not recognize variants of the SARS-CoV- virus. 2 appeared later.

Several studies are underway to understand whether the vaccines in use are effective against the variants.

Based on the results of the first studies, a complete vaccination course (first and second dose) with the four approved vaccines is able to confer protection against the main circulating variants.

There is, at present, insufficient evidence that antiviral drugs in use or being tested for COVID-19 are always effective against variants.

An example of RNA viruses that vary rapidly during their multiplication in humans and that are able to acquire resistance against vaccines are the viruses that cause influenza (Ortomixovirus). The rapid evolution of these viruses, which determines changes in the proteins of the external envelope make them able to escape the immunity induced in people by previous infections or vaccinations.For this reason the flu can be caught several times in the course of life and every year the vaccine must be updated with the latest circulating variants.

Then there are some viruses, such as HIV-1 responsible for AIDS, which change (mutate) so rapidly that it has not been possible, until now, to develop a vaccine capable of protecting against infection.

Tests to detect variants

The scientific community and regulatory authorities carry out a careful control (monitoring) on ​​the changes that occur over time in influenza viruses and, currently, in the new Coronavirus SARS-CoV-2 and on the effectiveness of existing vaccines in protecting against any new variants of the virus. as they appear.

To be able to distinguish whether an infection is determined by a variant of a particular virus, a specific examination called “sequencing” is necessary. It consists of a very precise reading of the information contained in the genetic patrimony of the virus. Sequencing is the only test that allows to control the spread of variants but can only be performed in specialized centers. The analysis of variants of SARS-CoV-2 is carried out on specific groups of people by the laboratories of the individual regions under the coordination of the "Istituto Superiore di Sanità".

With the increase in the number of sequences to monitor the spread of viral variants it will be possible to highlight more and more new variants, not necessarily worrying or dangerous, and it will be possible to have more and more information on the evolution of the virus.

Bibliography

Sanjuán R, Domingo-Calap P. Mechanisms of viral mutation. Cellular and Molecular Life Sciences. 2016 Dec; 73: 4433-4448

In-depth link

Ministry of Health. New coronavirus

Epicenter (ISS). Influenza viruses and their changes

Epicenter (ISS). The Influenza Pandemics of the Twentieth Century

Higher Institute of Health (ISS). Special COVID-19. Variants of the virus

Mayo Clinic.COVID-19 variants: What "s the concern? (English)

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