by Antonino Napoleone, Giuseppe Scarlata | January 31, 2021.

Evolution is a theory first formulated by Charles Darwin two centuries ago to explain the mechanism of natural selection that leads organisms of the same species to acquire mutations over time, for adaptive or beneficial purposes in so far as they are necessary to survive the external environment. This phenomenon arouses fascination and extreme curiosity, but it is not without its limits and perplexities, especially since it does not have homogeneous or universal characteristics but is specific and applicable individually to each organism. Researchers have already asserted for some time that this mechanism takes place at different times on both the macroscopic and microscopic scales, and the knowledge and technology available today enables us to decipher and distinguish even the slightest changes or mutations. This has constituted a vast and intricate field of research, genomics, precisely because the secret and the answer to these mutations lie at the level of the genome consisting of DNA (or RNA).

Genomic analysis of SARS-CoV-2 and the Spike protein

Genomic analysis of SARS-CoV-2 has revealed that it is a rapidly mutating microorganism, and variants of the first strain studied and sequenced in early 2020 have recently been identified (read more about the English variant of the virus). Sequencing the genome is equivalent to creating an ‘index’ or ‘list’ of every single component of the DNA (or RNA) to be analysed. The latest reading of the SARS-CoV-2 genome has shown that we are dealing with ‘lists’ with slightly different portions than the results obtained a year ago, due to genetic changes or mutations affecting mainly the virus’ Spike protein. The biological and strategic significance of this protein and the mutations that are causing its change or evolution, to return to what was mentioned above, is of central importance (Figure 1).

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Figure 1. SARS-CoV-2 variants identified to date through genomic analysis of the virus. These data are useful to understand how the virus is evolving as a result of mutations accumulated over time.

There are three perspectives to analyse:

From the perspective of the virus

The evolutionary pathway of viruses (especially RNA viruses such as the Coronavirus) is particularly dynamic and intricate, difficult for scientists to decipher and predict, and involves the accumulation of mutations that trigger structural changes over time. The virus’ Spike protein has undergone structural changes in some of its component amino acids, reflecting altered functionality. This can cause an emerging number of variants of the virus that may be associated with increased transmissibility or infectivity (Figure 2) or the opposite hypothesis cannot be excluded, i.e. that there may be a transition to harmless variants similar to other endemic human coronaviruses that cause common colds, as hypothesised in a recent study published in the well-known journal Science1.

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Figure 2. Two virus mutations (D614 and G614), both found in the English and South African variants, were examined in this experiment. Tests were carried out on human respiratory cell models to investigate whether these mutations altered the infectivity and transmissibility of the virus. The results showed that these mutations are associated with increased infectivity and transmissibility of the virus.

From the point of view of vaccination

The main strategy adopted by the pharmaceutical companies to develop an effective vaccine (see article secret ingredient mRNA vaccine), has been to use viral antigens from the Spike protein, to provide immunisation against SARS-CoV-2. Preliminary data published by the companies Pfizer and Moderna after phase 3 clinical trials showed the respective vaccines to be well tolerated and 95% effective after the second administration. Genomic analyses have shown that the highest rate of mutations is in the Spike protein of the virus, raising questions about the efficacy of the vaccination, should structural changes in the virus emerge that would compromise the efforts made so far to develop and distribute the vaccine to the population.

From the point of view of the immune system

Several studies are in progress to assess how the immune system reacts to SARS-CoV-2 infection, and especially how the response varies in infected individuals and how long the immunological memory should last (read more The way to the immunity: what happened and what is next?). In addition, microorganisms develop immune escape mechanisms as a means of going undetected and overcoming the defence barriers within the host organism. Recently, Italian immunologist Rino Rappuoli conducted a study to identify viral mutations capable of evading the immune system response. The aim was to analyse in the laboratory how the virus reacted when in contact with neutralising antibodies taken from convalescent Covid-19 patients. It was found that after only 90 days, the virus had developed 3 different mutations that made it more difficult for antibodies to eliminate. The same mutations were found in the already known English and South African variants. This suggests that the entire specific immune response against the virus, consisting of antibodies, is directed by and largely triggered by a small portion of the Spike protein. If this is the case, there are considerable implications and factors to be assessed, especially in view of the development of new therapeutic and prophylactic approaches, the possibility of re-infection in already recovered individuals, and the speed by which the virus accumulates mutations. Therefore, investigating the immunological profile is the appropriate key to resolve the numerous questions and devise an effective long-term solution.

What are the implications for the vaccine and for immunisation?

Researchers are trying to understand why the new variants identified in the UK and South Africa are spreading so rapidly, and whether they could reduce the effectiveness of the vaccine already being distributed or overcome the immune defences of cured individuals and lead to a wave of re-infections. A recent study has provided encouraging data, as the mutations found in the two English and South African variants of the virus did not alter the neutralising activity of the antibodies produced by people who received the Pfitzer/BioNTech vaccine, so the immune response triggered by the vaccine appears to maintain the levels of efficacy seen previously. Further research is underway to assess the effect of other mutations in virus variants on vaccine efficacy. It should be pointed out that the vaccine stimulates a complex immune response, which includes not only the development of neutralising antibodies against the virus (the T-lymphocyte response also plays an important role and is under evaluation), and in any case would reduce drastically the severity of symptoms and the mortality rate.
Regarding the risk of re-infection, there is still no definitive answer, but some considerations can be made on the basis of what is already known in the field of immunology. In fact, the immune system in these cases can provide protection in three ways:

  1. In the most robust way, as the neutralising immunity developed after recovery could prevent virus replication and make the host refractory to reinfection. Immune efficacy depends on the susceptibility and predisposition of individuals.
  2. Immunity does not prevent re-infection, but it may attenuate the pathology and/or reduce the transmissibility or infectivity of the virus.
  3. Re-exposure to the virus within a year of the primary infection causes re-infection, but in this case, milder symptoms occur, and recovery is faster.

In addition, the age of the primary infection should be taken into account, because the immune response in the early years of life differs from that in adults, and in the latter, re-exposure to the virus may act as a recall response for the immune system, indicating that even years later the immunological memory is not completely lost.

Conclusions

When infection rates exacerbated the situation globally, researchers responded by gathering and optimising resources and expertise, and over the past year the evolution of science has been incredible in terms of speed and results, a virtue of necessity has been made.
Virology and immunology are two sides of the same coin, and in order to find answers and technological solutions, it is essential to make progress in both areas in order to better understand the consequences of new potential virus mutations and which response mechanism will be most appropriate to provide effective protection. From an evolutionary point of view, new questions arise regarding the interaction between the virus and the human host and what dynamics will exist between immune protection and virus infectivity. Social distancing, restrictive measures and vaccine distribution are powerful tools for exerting pressure on the virus. Evolution will take place on a macroscopic and microscopic scale, and it is the immune system that will play a key role in this transition. Go and explain this to the anti-vax people.

References

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