Rapid evolution of SARS-CoV-2 challenges human defenses

There has been much discussion on the role of impacts on biodiversity in facilitating the arousal of zoonosis21. However, the role of the huge, globally-connected human population, in the massive production of viruses propelling the rapid evolution of SARS-CoV-2 has not been sufficiently acknowledged.

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 outpacing that of human defenses. The same RBD variant, or identical-sequence variant, may arise independently in different locations, as the evolutionary tree suggests for the amino acid sequence shown by the α variant (Fig. 3a). However, the SARS-CoV-2 evolutionary process deviates from a random process, with unbalanced branch development providing evidence of strong selection (Fig. 3a,b), consistent with the dynamics observed for the phylogenesis of protein families18. Selection processes remove branches that are not infective while leading to heavy branches of the more infective strains (Fig. 3a). Indeed, the number of copies of the different RBD variants over time is not random, but are under selective pressure, particularly determined by the infectivity of the new variants emerged, as documented for the so-called α (B.1.1.7), β (B.1.351), and γ (P.1 as well as P.2) RBD 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 just 3 variants (the original one, α and γ) containing 85% of the total isolates (Fig. 2c–e). New, highly infective variants can rapidly recruit to this dominant pool (Video S1). Increased vaccination coverage of efficient vaccines should be able to curve this process by reducing the global production rate of SARS-CoV-2 and, hence, its diversification rate, as the evidence for a change in the relationship between total number of variants and total number of isolates provided here suggests, which deserves deeper and dedicated attention.

High mutation rates of RNA viruses, caused by error-prone RNA-dependent RNA polymerases22 along with the huge 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 variants in circulation within the same host population activates an additional mechanism, recombination, for virus 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 a doubling time of SARS-CoV-2 RBD variants of 89 days, the number of SARS-CoV-2 RBD variants will continue to expand. This rapid diversification and selection of RBD variants predicts the selection of more infective variants becoming dominant in a highly hierarchical distribution dynamically conforming to Yule’s law. This heralds a new phase in the pandemic, beyond October 15, 2021, characterized by accelerating evolutionary rates of the virus, which will impose new challenges as new variants of concern, such as the newly detected omicron (B.1.1.529), add to those already detected. However, virus diversification will be slowed down by reduced viral replication derived from growing immunity acquired by the world population through contact with the circulating virus together with increased coverage of efficient vaccines.

Mutation and, possibly, reassortment propel SARS-CoV-2 to be rapidly evolving, implying that human defense tactics need to be reconsidered if we are to overcome the pandemic well before this declines upon reaching the limitation of available hosts. Evolutionary theory posits that hosts develop evolutionary defenses through recombination under sexual reproduction allowing them to modify their genome to anticipate and prevent pathogen attacks2,23,24. This requires selection across generations and catastrophic mortality for SARS-CoV-2 morbidity to be selected against. Our defense mechanisms include protections to avoid contact with the virus, and therapies and vaccines once SARS-CoV-2 enters our bodies. External defenses include social distancing, with strict lockdowns proven across many nations to be the most effective defense mechanism, whatever unpopular, to contain the pandemic, along with wearing protections and emerging uses of nanotechnology for virus detection and interception25,26. This effort must be complemented with the continuous development of a diverse suite of universal immunizations, such as multivalent nanobodies27 and vaccines, eliciting immune defenses that vary and can defend us against a wide range of RBD variants, existing and forthcoming, as new variants that overcome immune defenses produced by previously infected or vaccinated people arise, as demonstrated by our long experience in coping with the drift and shift of the influenza virus28. Indeed, recent reports indicate that the convalescent sera and BNT162b2 mRNA vaccine may not be as effective against some of the variants29. Yet, our data shows, encouragingly a slow-down of the doubling time of the number of the RBD variants detected along with a progressive reduction in the number of variants detected per infected person after July, 2021. A likely explanation for this shift in tendency, 17 months after the pandemic was declared, is the increase in the number of vaccinated people globally, a suggestion that requires a dedicated analysis, as indicated earlier.

Evolutionary ecology theory helps formulate predictions on the future behavior of SARS-CoV-2. On the other hand, the COVID-19 pandemic provides an unprecedented opportunity to test evolutionary ecology theory, which has been largely inferential in nature. This is important as never before had an evolutionary process been tracked in real time and with such wealth of openly available genomic data at a global scale. The SARS-CoV-2 validates a number of evolutionary theories and laws, such as the evolutionary underpinning of the partially imbalanced architecture of phylogenetic trees across evolutionary scales18,19, the diversification process responsible for the long-standing Yule law20, and the more targeted framework of the Red Queen theory2 predicting the evolutionary tactics of pathogens.

The development of the vaccine in record time, a feat rendered possible by unprecedented collaboration, has been celebrated as the start of the end of the pandemic. Rather, it may be the beginning of a new phase, where the continuous development of novel and diverse and universal vaccines30 represents our main defense against the evolving SAS-CoV-2. A universal coronavirus vaccine would ideally protect against existing and future SARS-CoV-2 variants as well as animal-derived coronaviruses that might cause future zoonotic outbreaks and pandemics30. This requires sustained global collaboration, and overcoming the challenges derived from the fact that SARS-CoV-2 primarily infect epithelial cells on mucosal surfaces and have limited contact with the systemic immune system, which reduce responses to systemically administered vaccines30. In silico analysis of the effectiveness of current vaccines against plausible RBD variants not yet detected, and the design of new effective vaccines against such variants will enable us to overtake SARS-CoV-2 in the evolutionary race, as a reactive, catch-up tactic, as that played to date, will carry continuous risks. Indeed, in silico analysis of detection31, infectivity32 and vaccine design33 of existing and future variants, represent a model for the growing use of in silico prediction as a tool to anticipate defenses for the pandemic. Artificial Intelligence may further help analyze the immunogenicity of all the nonsynonymous variations across described and predicted SARS-CoV-2 sequences to generate a blueprint for effective vaccine development34, considering that infectivity is the main driving force of SARS-CoV-2 variant selection. However, increased vaccination and collaborative efforts in SARS-CoV-2 sequencing enabling the early detection of new variants of concern17 remain essential strategies to control the pandemic.


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