Rapid evolution of SARS-CoV-2 challenges human defenses

There has been much discussion about the role of biodiversity impacts in facilitating the emergence of zoonoses21. However, the role of the huge globally connected human population in the mass production of virus propelling the rapid evolution of SARS-CoV-2 has not been sufficiently recognized.

Our analysis provides evidence for extraordinarily rapid evolution and selection of SARS-CoV-2, with the number of unique RBD variants doubling every 89 days, which has clearly reached full speed in the Red Queen race, risking to exceed that of human defences. The same RBD variant, or sequence-identical variant, can occur independently in different locations, as suggested by the evolutionary tree for the amino acid sequence shown by the α variant (Fig. 3a). However, the evolutionary process of SARS-CoV-2 deviates from a random process, with unbalanced branch development providing evidence for strong selection (Fig. 3a,b), consistent with observed dynamics for phylogenesis families of proteins18. Selection processes eliminate branches that are not infectious while leading to heavy branches of the most infectious strains (Fig. 3a). Indeed, the number of copies of the different RBD variants over time is not random, but is subject to selective pressure, determined in particular by the infectiousness of the new variants that have appeared, as documented for the so-called α (B.1.1 .7), RBD β (B.1.351) and γ (P.1 as well as P.2) variants of SARS-CoV-2 (Video S1, Fig. 4). The result of this process is a highly hierarchical dynamic distribution of RBD variants, with a rank-abundance structure conforming to Yule’s law20, with only 3 variants (the original one, α and γ) containing 85% of the total isolates (Fig. 2c–e). New, highly infectious variants can rapidly recruit into this dominant pool (Video S1). Increased vaccination coverage of effective vaccines should be able to alter this process by reducing the global production rate of SARS-CoV-2 and, therefore, its rate of diversification, as evidence of a change in the relationship between the total number of variants and the total number of isolates provided here suggests, which merits further and dedicated attention.

High mutation rates of RNA viruses, caused by error-prone RNA-dependent RNA polymerases22 as well as the enormous virus production mediated by the huge pool of available human hosts propel the rapid evolution of SARS-CoV-2. The presence of a large number of circulating variants within the same host population activates an additional mechanism, recombination, of viral diversification. Recombination involves the formation of chimeric molecules from parental genomes of mixed origin22, which likely contributes to the rapid diversification of SARS-CoV-2. Provided that the time of SARS-CoV-2 RBD variants is doubled by 89 days, the number of SARS-CoV-2 RBD variants will continue to grow. This rapid diversification and selection of RBD variants predicts the selection of more infectious variants becoming dominant in a highly hierarchical distribution dynamically conforming to Yule’s law. This heralds a new phase of the pandemic, beyond October 15, 2021, characterized by accelerating virus evolution rates, which will impose new challenges as new variants of concern, such as the newly detected omicron (B .1.1.529), adds to those already detected. However, viral diversification will be slowed by reduced viral replication derived from increasing immunity acquired by the global population through contact with circulating virus as well as increased coverage of effective vaccines.

Mutation and, eventually, reassortment propels SARS-CoV-2 to evolve rapidly, implying that human defense tactics must be reconsidered if we are to defeat the pandemic long before it declines to the limit of hosts available. The theory of evolution postulates that hosts develop evolutionary defenses through recombination as part of sexual reproduction allowing them to modify their genome to anticipate and prevent attacks by pathogens.2,23,24. This requires multi-generational selection and catastrophic mortality for SARS-CoV-2 morbidity to be selected. Our defense mechanisms include protections to avoid contact with the virus, as well as therapies and vaccines once SARS-CoV-2 enters our body. External defenses include social distancing, with strict lockdowns proven in many countries to be the most effective defense mechanism, however unpopular, to contain the pandemic, as well as wearing protective gear and uses emerging nanotechnology for the detection and interception of viruses.25.26. This effort should be complemented by the continued development of a diverse suite of universal immunizations, such as multivalent nanobodies27 and vaccines, eliciting variable immune defenses that can defend us against a wide range of existing and future RBD variants, as new variants that overcome the immune defenses produced by previously infected or vaccinated people emerge, such as the demonstrates our long experience in managing influenza virus drift and travel28. Indeed, recent reports indicate that convalescent sera and the BNT162b2 mRNA vaccine may not be as effective against some of the variants.29. Yet our data show, encouragingly, a slowing of the doubling time of the number of RBD variants detected as well as a gradual reduction in the number of variants detected per infected person after July 2021. A likely explanation for this change in trend, 17 months after the declaration of the pandemic, is the increase in the number of people vaccinated worldwide, a suggestion that requires dedicated analysis, as previously indicated.

Evolutionary ecology theory helps make predictions about the future behavior of SARS-CoV-2. On the other hand, the COVID-19 pandemic provides an unprecedented opportunity to test the theory of evolutionary ecology, which has largely been inferential in nature. This is important because never before has an evolutionary process been tracked in real time and with such a wealth of genomic data freely available globally. SARS-CoV-2 validates a number of evolutionary theories and laws, such as the evolutionary basis for the partially unbalanced architecture of phylogenetic trees across evolutionary scales18.19the diversification process behind the Long Yule Law20and the more focused framework of the Red Queen theory2 predict the evolutionary tactics of pathogens.

The development of the vaccine in record time, a feat made possible by unprecedented collaboration, was celebrated as the beginning of the end of the pandemic. Rather, it could be the start of a new phase, where the continued development of new, diverse and universal vaccines30 represents our main defense against the evolution of SAS-CoV-2. A universal coronavirus vaccine would ideally protect against existing and future variants of SARS-CoV-2 as well as animal-derived coronaviruses that could cause future zoonotic epidemics and pandemics30. This requires sustained global collaboration and overcomes challenges derived from the fact that SARS-CoV-2 primarily infects epithelial cells on mucosal surfaces and has limited contact with the systemic immune system, which reduces responses to intravenous vaccines. systemic30. In silico analysis of the effectiveness of current vaccines against plausible RBD variants not yet detected, and the design of new vaccines effective against these variants will allow us to overtake SARS-CoV-2 in the evolutionary race, as Reactive catch-up tactics, like the one played so far, will carry ongoing risks. Indeed, the in silico detection analysis31infectivity32 and vaccine design33 existing and future variants, represent a model for the growing use of in silico prediction as a tool for anticipating defenses in the face of the pandemic. Artificial intelligence can further help analyze the immunogenicity of all non-synonymous variations in described and predicted SARS-CoV-2 sequences to generate a blueprint for effective vaccine development.34, considering that infectivity is the primary driver of SARS-CoV-2 variant selection. However, increased vaccination and collaborative efforts in SARS-CoV-2 sequencing allowing early detection of new variants of concern17 remain essential strategies for controlling the pandemic.

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