The emergence of new variants of the virus that threaten pandemic control is an important topic in the public discourse. These new variants have been identified by the US Centers for Disease Control and Prevention as variants of interest, variants of concern, or variants of serious consequence. Currently, variants B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta), which are spreading in the United States and around the world, are variants of concern. In the context of an evolving pandemic, expectations of how SARS-CoV-2 could evolve to a form that could disrupt pandemic control or change the nature of the next endemic or combined endemic/epidemic phase need to be reassessed.
The Coronaviridae family is characterized by relatively high replication fidelity compared to other RNA viruses, which is determined by the processivity of their polymerases, as required by their extremely large genome 12 . Based on this, it has been argued that the evolution of SARS-CoV-2 will be limited, which in turn will ensure the durability of vaccines and therapeutics and support optimism that population immunity can end the pandemic. However, while on average SARS-CoV-2 evolves (perhaps 3-4 times) slower than influenza viruses 13, the virus is accumulating mutations faster than might be expected given its relative replication accuracy with approximately two mutations recorded per month 14 and much higher rates of change have been observed in some variants that are of concern. Coronaviruses also have a high rate of viral RNA recombination 15 ; thus, people infected with two SARS-CoV-2 variants may acquire multiple mutations from both variants simultaneously. We also cannot rule out possible recombination events in the future between SARS-CoV-2 and other human coronaviruses. In addition, prolonged infections of immunosuppressed individuals who cannot effectively clear the infection may create the opportunity for the accumulation of multiple mutations. Furthermore, vaccination may not be effective for immunocompromised individuals 16 .
Why do we observe the emergence of variants despite the relatively fastidious mechanism of coronavirus replication? The rate of evolution of a viral pathogen depends not only on the frequency of background mutation, but also on the time of virus generation, the duration of infection, the number of variants that develop during infection of an individual, structural and functional constraints in specific regions of viral proteins, as well as the degree and strength of natural selection acting on the virus. In addition, the greater the number of people infected with a virus, the greater the pool and diversity of mutant viruses that are produced. Although transmission events between two hosts regularly create bottlenecks that clear most low frequency mutant viruses, a large number of transmission events can facilitate the transmission of a more fit virus with the global spread of B.1.1.7 (alpha) and the current spread of B.1.617 (Delta) in India being important examples 17 , 18 , 19 , 20 .
Functional domains in viral proteins that can accept mutations without losing their overall structure and function are potentially selectable mutation sites. The region of the SARS-CoV-2 junction protein that interacts with the human ACE2 receptor shows particular structural and functional plasticity 21 , 22 . With new selection pressures created by vaccines or immunity to natural infection or the use of antiviral agents, the possibility of viruses adapting to overcome immune and/or antiviral pressures is likely to be a constant reality. There is a risk of virus diversification in the current uncontrolled or incompletely controlled pandemic in many regions of the world. In this regard, the level of knowledge about the impact of mutations outside the viral adhesion protein is in its infancy, which limits the ability to predict the evolutionary paths the virus will take in the future.
The rapid transition to the endemic phase may reduce the number of circulating variants of the virus, limiting the extensive exploration of the fitness landscape that occurs during the pandemic phase. Thus, the nature of the future equilibrium between SARS-CoV-2 and humans depends on both the speed and inclusiveness of the pandemic response in different geographic regions and cultures, as this directly affects the rate of emergence of problematic variants.
Understanding the transition to the endemic phase with potential seasonal peaks will benefit from new tools that can predict which virus variants are likely to emerge and spread. Spreading variants can be predicted to some extent by epidemiological and biological data, including ACE2 binding measured in the context of deep scan mutagenesis of the viral adhesion protein 23 . Immune escape begins to facilitate the spread of virus variants during a pandemic when high levels of vaccine- and infection-induced immunity have not yet been achieved worldwide 24 . Complete containment of the pandemic would minimize the likelihood of SARS-CoV-2 adapting to the host by reducing the length of transmission chains 25 . This seems unlikely unless very high vaccination rates can be achieved worldwide.