![]() ![]() ![]() As we described previously 3, 11, from October 2020 onwards, novel, more heavily mutated SARS-CoV-2 variants began to emerge. A lineage defined by D614G (PANGO lineage 10 B.1) quickly became dominant in Europe, giving an early indication of the potential for SARS-CoV-2 to increase its transmissibility in humans. The first notable change, a single spike substitution (D614G), arose early in the pandemic and conferred an ~20% growth advantage relative to preceding variants 9. Once SARS-CoV-2 was in humans, the first months of SARS-CoV-2 evolution were characterized by limited adaptation and phenotypic change relative to its later evolution 8. SARS-CoV-2 has proven to be a highly capable human pathogen, but also a generalist in terms of host tropism, establishing infections in a variety of mammalian species, including infections in farmed mink 4, a stable reservoir in white-tailed deer 5, 6 and incidental infections of many other animal species 7. The success of novel genetic variants generated, although prone to stochastic sampling processes, will be very dependent on natural selection in particular, positive selection associated with mutations that are beneficial to the virus in which they occur. This, combined with the discontinuous nature of coronavirus transcription, has resulted in coronaviruses with high rates of recombination, insertions and deletions, and point mutations (although the rates are lower than for other RNA viruses due to the proofreading), as previously reviewed 3. Like other coronaviruses, SARS-CoV-2 possesses a large RNA genome, comprising ~30,000 nucleotides, whose replication is mediated by RNA-dependent RNA polymerase (RdRP) and an associated proofreading enzyme exoribonuclease (ExoN). SARS-CoV-2 (along with SARS-CoV, the cause of SARS) is a member of the species Severe acute respiratory syndrome-related coronavirus, the sole member of a subgenus of viruses, Sarbecovirus, primarily found in horseshoe bats 2. Since its initial emergence in Wuhan in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 641 million cases of COVID-19 and more than 6.6 million deaths as of December 2022 (ref. SARS-CoV-2 shows a complicated relationship among virus antigenicity, transmission and virulence, which has unpredictable implications for the future trajectory and disease burden of COVID-19. In this Review, we summarize the literature on the relative transmissibility and antigenicity of SARS-CoV-2 variants, the role of mutations at the furin spike cleavage site and of non-spike proteins, the potential importance of recombination to virus success, and SARS-CoV-2 evolution in the context of T cells, innate immunity and population immunity. The increased virus fitness associated with VOCs is the result of a complex interplay of virus biology in the context of changing human immunity due to both vaccination and prior infection. The success of each VOC relative to the previously dominant variant was enabled by altered intrinsic functional properties of the virus and, to various degrees, changes to virus antigenicity conferring the ability to evade a primed immune response. Designated Alpha, Beta, Gamma, Delta and Omicron, the VOCs emerged independently from one another, and in turn each rapidly became dominant, regionally or globally, outcompeting previous variants. These highly mutated forms of SARS-CoV-2 had enhanced rates of transmission relative to previous variants and were termed ‘variants of concern’ (VOCs). In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. ![]()
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