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. These highly mutated forms of SARS-CoV-2 had enhanced rates of transmission relative to previous variants and were termed 'variants of concern' (VOCs). 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. 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. 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. 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. 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. 

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SARS-CoV-2 variant biology: immune escape, transmission and fitness

Abstract Among the 30 nonsynonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (1) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (2) interactions of Spike with ACE2 receptors, and (3) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any virus within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and, in combination with other mutations, adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron overall previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.

Selection Analysis Identifies Clusters of Unusual Mutational Changes in Omicron Lineage BA.1 That Likely Impact Spike Function

Our understanding of the still unfolding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic would have been extremely limited without the study of the genetics and evolution of this new human coronavirus. Large-scale genome-sequencing efforts have provided close to real-time tracking of the global spread and diversification of SARS-CoV-2 since its entry into the human population in late 2019. These data have underpinned analysis of its origins, epidemiology, and adaptations to the human population: principally immune evasion and increasing transmissibility. SARS-CoV-2, despite being a new human pathogen, was highly capable of human-to-human transmission. During its rapid spread in humans, SARS-CoV-2 has evolved independent new forms, the so-called "variants of concern," that are better optimized for human-to-human transmission. The most important adaptation of the bat coronavirus progenitor of both SARS-CoV-1 and SARS-CoV-2 for human infection (and other mammals) is the use of the angiotensin-converting enzyme 2 (ACE2) receptor. Relaxed structural constraints provide plasticity to SARS-related coronavirus spike protein permitting it to accommodate significant amino acid replacements of antigenic consequence without compromising the ability to bind to ACE2. Although the bulk of research has justifiably concentrated on the viral spike protein as the main determinant of antigenic evolution and changes in transmissibility, there is accumulating evidence for the contribution of other regions of the viral proteome to virus-host interaction. Whereas levels of community transmission of recombinants compromising genetically distinct variants are at present low, when divergent variants cocirculate, recombination between SARS-CoV-2 clades is being detected, increasing the risk that viruses with new properties emerge. Applying computational and machine learning methods to genome sequence data sets to generate experimentally verifiable predictions will serve as an early warning system for novel variant surveillance and will be important in future vaccine planning. Omicron, the latest SARS-CoV-2 variant of concern, has focused attention on step change antigenic events, "shift," as opposed to incremental "drift" changes in antigenicity. Both an increase in transmissibility and antigenic shift in Omicron led to it readily causing infections in the fully vaccinated and/or previously infected. Omicron's virulence, while reduced relative to the variant of concern it replaced, Delta, is very much premised on the past immune exposure of individuals with a clear signal that boosted vaccination protects from severe disease. Currently, SARS-CoV-2 has proven itself to be a dangerous new human respiratory pathogen with an unpredictable evolutionary capacity, leading to a risk of future variants too great not to ensure all regions of the world are screened by viral genome sequencing, protected through available and affordable vaccines, and have non-punitive strategies in place for detecting and responding to novel variants of concern. 

The Evolution and Biology of SARS-CoV-2 Variants

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths and substantial morbidity worldwide. Intense scientific effort to understand the biology of SARS-CoV-2 has resulted in daunting numbers of genomic sequences. We witnessed evolutionary events that could mostly be inferred indirectly before, such as the emergence of variants with distinct phenotypes, for example transmissibility, severity and immune evasion. This Review explores the mechanisms that generate genetic variation in SARS-CoV-2, underlying the within-host and population-level processes that underpin these events. We examine the selective forces that likely drove the evolution of higher transmissibility and, in some cases, higher severity during the first year of the pandemic and the role of antigenic evolution during the second and third years, together with the implications of immune escape and reinfections, and the increasing evidence for and potential relevance of recombination. In order to understand how major lineages, such as variants of concern (VOCs), are generated, we contrast the evidence for the chronic infection model underlying the emergence of VOCs with the possibility of an animal reservoir playing a role in SARS-CoV-2 evolution, and conclude that the former is more likely. We evaluate uncertainties and outline scenarios for the possible future evolutionary trajectories of SARS-CoV-2. In this Review, Markov, Katzourakis and colleagues explore the evolution of SARS-CoV-2 at different scales, the phases of the COVID-19 pandemic, factors that drive the evolution of the virus, theories for the emergence of epidemiologically important variants and potential future evolutionary scenarios and their likely health repercussions. 

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The evolution of SARS-CoV-2

anfang dieses Jahres erreichten uns erste Meldungen über eine neue respiratorische virale Infektionskrankheit, die entsprechend den ersten Erkrankungen im Jahr 2019 als COVID-19 bezeichnet wurde. Die Weiterentwicklung zur Pandemie stellt uns sowohl medizinisch als auch gesellschaftlich und politisch vor ungeahnte Herausforderungen. War am Anfang noch von einer rein pulmonalen Erkrankung auszugehen, zeigten jedoch erste Publikationen im Frühjahr, dass auch relevante Gefäßbeteiligungen bei COVID-19-infizierten Patienten zu beobachten sind. Damit kam die Erkrankung auch in den Fokus der Gefäßmedizin und Gefäßchirurgie. Anhand der Erfahrungen in anderen europäischen Ländern, der daraus resultierenden Maßnahmen im Rahmen des Lockdowns und der entsprechend angeordneten Freihaltung von (intensiv-) medizinischen Kapazitäten in Krankenhäusern musste eine massive Einschränkung in der Versorgung von gefäßchirurgischen Patienten verzeichnet werden. Zudem erfolgte eine deutliche Umstrukturierung der Kliniken mit einem massiven Ausbau der Intensivkapazitäten. Neben der Reduktion der elektiven Eingriffe bei Gefäßpatienten und einer Veränderung der Erkrankungsschwere der im Notfall aufgenommenen Gefäßpatienten, müssen Gefäßchirurgen auch zunehmend operative Eingriffe bei COVID-19-Patienten durchführen. Auch wenn der Wissensgewinn zu COVID-19 innerhalb des ersten halben Jahresbereitsenormist, zeigt sich,dasseine stete wissenschaftliche Beschäftigung mit dieser – auch vaskulären – Erkrankung zwingend notwendig ist. Die zunehmende Beeinflussung unserer täglichenArbeit als Gefäßmediziner undGefäßchirurgen durch Covid-19 und die notwendigen Maßnahmen zum Schutz derMitarbeiter und Patienten haben uns kurzfristig bewogen, eine Ausgabe der Zeitschrift „Gefässchirurgie“ dem Thema „COVID-19“ zu widmen.

SARS-CoV-2

Wildlife reservoirs of SARS-CoV-2 may enable viral adaptation and spillback from animals to humans. In North America, there is evidence of unsustained spillover of SARS-CoV-2 from humans to white-tailed deer (Odocoileus virginianus), but no evidence of transmission from deer to humans. Through a biosurveillance program in Ontario, Canada we identified a new and highly divergent lineage of SARS-CoV-2 in white-tailed deer. This lineage is the most divergent SARS-CoV-2 lineage identified to date, with 76 consensus mutations (including 37 previously associated with non-human animal hosts) and signatures of considerable evolution and transmission within wildlife. Phylogenetic analysis also revealed an epidemiologically linked human case. Together, our findings represent the first clear evidence of sustained evolution of SARS-CoV-2 in white-tailed deer and of deer-to-human transmission.

Highly divergent white-tailed deer SARS-CoV-2 with potential deer-to-human transmission

Abstract Wildlife reservoirs of broad-host-range viruses have the potential to enable evolution of viral variants that can emerge to infect humans. In North America, there is phylogenomic evidence of continual transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to white-tailed deer ( Odocoileus virginianus ) through unknown means, but no evidence of transmission from deer to humans. We carried out an observational surveillance study in Ontario, Canada during November and December 2021 ( n = 300 deer) and identified a highly divergent lineage of SARS-CoV-2 in white-tailed deer (B.1.641). This lineage is one of the most divergent SARS-CoV-2 lineages identified so far, with 76 mutations (including 37 previously associated with non-human mammalian hosts). From a set of five complete and two partial deer-derived viral genomes we applied phylogenomic, recombination, selection and mutation spectrum analyses, which provided evidence for evolution and transmission in deer and a shared ancestry with mink-derived virus. Our analysis also revealed an epidemiologically linked human infection. Taken together, our findings provide evidence for sustained evolution of SARS-CoV-2 in white-tailed deer and of deer-to-human transmission. 

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Divergent SARS-CoV-2 variant emerges in white-tailed deer with deer-to-human transmission

The complete genome of a novel torque teno virus species (Torque teno equus virus 2 (TTEqV2) isolate Alberta/2018) was obtained by high-throughput sequencing (HTS) of nucleic acid extracted from the lung and liver tissue of a Quarter Horse gelding that died of nonsuppurative encephalitis in Alberta, Canada. The 2805 nucleotide circular genome is the first complete genome from the Mutorquevirus genus and has been approved as a new species by the International Committee on Taxonomy of Viruses. The genome contains several characteristic features of torque teno virus (TTV) genomes, including an ORF1 encoding a putative 631 aa capsid protein with an arginine-rich N-terminus, several rolling circle replication associated amino acid motifs, and a downstream polyadenylation signal. A smaller overlapping ORF2 encodes a protein with an amino acid motif (WX7HX3CXCX5H) which, in general, is highly conserved in TTVs and anelloviruses. The UTR contains two GC-rich tracts, two highly conserved 15 nucleotide sequences, and what appears to be an atypical TATA-box sequence also observed in two other TTV genera. Codon usage analysis of TTEqV2 and 11 other selected anelloviruses from five host species revealed a bias toward adenine ending (A3) codons in the anelloviruses, while in contrast, A3 codons were observed at a low frequency in horse and the four other associated host species examined. Phylogenetic analysis of TTV ORF1 sequences available to date shows TTEqV2 clusters with the only other currently reported member of the Mutorquevirus genus, Torque teno equus virus 1 (TTEqV1, KR902501). Genome-wide pairwise alignment of TTEqV2 and TTEqV1 shows the absence of several highly conserved TTV features within the UTR of TTEqV1, suggesting it is incomplete and TTEqV2 is the first complete genome within the genus Mutorquevirus. 

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Daniel Sullivan

Papers

Highly divergent white-tailed deer SARS-CoV-2 with potential deer-to-human transmission

Divergent SARS-CoV-2 variant emerges in white-tailed deer with deer-to-human transmission

Discovery and comparative genomic analysis of a novel equine anellovirus, representing the first complete Mutorquevirus genome