Why is it unlikely that the coronavirus will lose its virulence?

 Viruses would lose their virulence over time ... What about this "vision" shared and hoped for by many individuals? Answer with the explanations of two researchers, authors of this article, who follow the evolution of SARS-CoV-2.

Article by Samuel Alizon, Director of Research at CNRS, Institut de recherche pour le développement ( IRD ) and Mircea T. Sofonea, lecturer in epidemiology and evolution of infectious diseases, Mivegec laboratory, University of Montpellier, published in The Conversation on the 5th September 2021.

Since the start of the Covid-19 pandemic, strong opinions have been regularly issued on the evolution of the virulence of SARS-CoV-2. For many, it should inevitably decrease since “of all times” viruses, bacteria, and other parasites would have lost their virulence while adapting to their hosts.

Unfortunately, this "intuition" does not stand up to analysis, because it requires seeing the human immunodeficiency virus ( HIV ), the tuberculosis bacillus, the hematozoa of malaria or the flu as exceptions. In fact, no matter how hard you look, it's difficult to find "parasites" (to use an evolutionary biology term) that conform to this axiom, baptized "  law of decreasing virulence  " at the beginning of the 20th century.

Why then does this vision persist? What do recent findings in evolutionary biology tell us about virulence? And what to expect in the case of SARS-CoV-2?

Do not confuse lethality and virulence

The logic underlying the theory of systematic evolution of parasites towards a state devoid of virulence ( avirulent ) is childishly simple: for the parasite, to kill its host is to kill the goose that lays the golden eggs. In other words, the strains (or “variants” to use a more fashionable qualifier) ​​which kill their host quickly should be less successful than the others and therefore disappear.

One explanation for the fact that this century-old theory is still so pervasive is the confusion between the notions of lethality and virulence. Lethality is the proportion of infected individuals who die as a result of infection with a given parasite, in a given location, at a given time. Many elements contribute to reducing the apparent lethality: treatments, vaccination, quality of clinical management, etc. Virulence corresponds to the parasite's propensity to harm its host. It is quantified in the absence of specific care.

In other words, the same viral variant will have a different lethality from one country to another depending, for example, on the quality of the hospital system. On the other hand, its virulence will be unchanged.

In the case of SARS-CoV-2, there has been a decline in the case fatality since the start of the epidemic in many countries, largely due to vaccination. On the other hand, the virulence increased. Alpha variant infections more often cause deaths than those involving ancestral lines that circulated in early 2020. As for the Delta variant, the first results seem to indicate that it is more virulent than the Alpha variant because it would lead to more hospitalizations. in unvaccinated people. Preliminary results point in the same direction for the beta variant.

Recognize that this is counterintuitive. But it is also the illustration that the biology of evolution is a discipline in its own right, and that it is risky to proclaim oneself an expert. However, many consider it more as a kind of "hobby", which one would practice after having acquired enough experience on more proximal subjects, such as the mechanisms of development or the physiology of organisms. This is probably another reason for the persistence of received ideas on the evolution of virulence.

Does the biology of evolution really have more to contribute than the intuitions of "old sages"? Obviously, this area of ​​research suffers from the fact that one cannot reproduce an epidemic identically. However, the analysis of epidemics prior to the one we are currently experiencing (in particular that of HIV ) and so-called “experimental” evolutionary studies, carried out on other parasites, are rich in lessons.

Two kinds of virulence

To begin with, we must distinguish two categories among the damage inflicted by a parasite on its host, depending on whether or not they influence the propagation of said parasite: non-adaptive virulence and adaptive virulence.

Nonadaptive virulence benefits neither party. In the case of SARS-CoV-2, it can include particularly severe manifestations of the infection, such as cytokine storms. The second category of virulence is called “adaptive” because it is associated with better propagation of the parasite, directly or indirectly.

A human T lymphocyte (blue) attacked by HIV (yellow), the virus that causes AIDS. The virus specifically targets T cells, which play an essential role in the body's immune response against invaders such as bacteria and viruses. Seth Pincus, Elizabeth Fischer and Austin Athman, National Institute of Allergy and Infectious Diseases / NIH
A human T lymphocyte (blue) is attacked by HIV (yellow), the virus that causes AIDS. The virus specifically targets T cells, which play an essential role in the body's immune response against invaders such as bacteria and viruses. Seth Pincus, Elizabeth Fischer, and Austin Athman, National Institute of Allergy and Infectious Diseases / NIH 

In the case of HIV, for example, it has been shown that the more virulent variants - those which produce the most viral particles by exploiting the cells of their host more efficiently or escaping the immune response better - have also been shown to be more contagious, because the likelihood of transmission is related to the amount of virus in the blood.

Distinguishing the non-adaptive and adaptive components of virulence allows us to better reason on the evolution of this trait. Nonadaptive virulence is generally expected to decrease since it is associated only with costs. However, it is not that simple, because you have to take into account the life cycle of the parasite.

In the case of SARS-CoV-2, the symptoms severe usually appear after 2 weeks of infection, or more than 95% of transmissions occur before the 11 th day. In other words, from the point of view of this coronavirus, late pathological manifestations (in particular inflammatory) of virulence do not constitute a loss of transmission opportunities. Therefore, it is unfortunately unlikely that natural selection will favor variants less often causing such immunopathological manifestations.

At the level of the adaptive component of virulence, predictions are even less straightforward. It all depends on the relationship between the costs (virulence) and the benefits for the spread of the virus (rate of transmission, duration of infection). In the case of HIV again, it has been shown that an intermediate level of virulence maximizes the selective value of the virus, that is to say, the number of infections caused by a person carrying the virus.

One thing that might lead us to think that there is such a correlation between virulence and transmission in the case of SARS-CoV-2 is that the more transmissible variants are also more virulent.

Our team has, for example, shown that in France the Alpha variant had a clear advantage in transmission over ancestral lines. Our British colleagues, for their part, concluded that its virulence had increased by 50%. Likewise, in June 2021, we showed that the Delta variant was more contagious than the Alpha variant. According to this logic, a more transmissible variant could therefore be even more virulent.

What can we expect?

The fact that the more contagious variants are more virulent suggests that the adaptive component of virulence is not zero.

The difficulty in anticipating viral evolution is that we have to know how well the virus, and therefore the Delta variant, is now adapted to us. Does this coronavirus still have room to exploit its human host more efficiently (in other words, for this level of contagiousness, could it be less virulent)? Or on the contrary, would any drop in virulence also result in a drop in contagiousness?

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