Systembio Distributor

Spike Variant

Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity, or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of ‘variants of concern’, that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population.

There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.

As of April 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, accounted for more than 143 million infections and more than three million deaths worldwide. Virus genomic sequences are being generated and shared at an unprecedented rate, with more than one million SARS-CoV-2 sequences available via the Global Initiative on Sharing All Influenza Data (GISAID), permitting near real-time surveillance of the unfolding pandemic. The use of pathogen genomes on this scale to track the spread of the virus internationally, study local outbreaks, and inform public health policy signifies a new age in virus genomic investigations. Further to understanding epidemiology, sequencing enables the identification of emerging SARS-CoV-2 variants and sets of mutations potentially linked to changes in viral properties.

As highly deleterious mutations are rapidly purged, most mutations observed in genomes sampled from circulating SARS-CoV-2 virions are expected to be either neutral or mildly deleterious. This is because although high-effect mutations that contribute to virus adaption and fitness do occur, they tend to be in the minority compared with tolerated low-effect or no-effect ‘neutral’ amino acid changes.

A small minority of mutations are expected to impact virus phenotype in a way that confers a fitness advantage, in at least some contexts. Such mutations may alter various aspects of virus biology, such as pathogenicity, infectivity, transmissibility, and/or antigenicity. Although care has to be taken not to confound mutations being merely present in growing lineages with mutations that change virus biology, fitness-enhancing mutations were first detected to have arisen within a few months of the evolution of SARS-CoV-2 within the human population.

For example, the spike protein amino acid change D614G was noted to be increasing in frequency in April 2020 and to have emerged several times in the global SARS-CoV-2 population, and the coding sequence exhibits a high dN/dS ratio, suggesting positive selection at the codon position 614. Subsequent studies indicated that D614G confers a moderate advantage for infectivity and transmissibility. Several other spike mutations of note have now arisen and are discussed in this review, with a particular focus on mutations affecting antigenicity.

The extent to which mutations affecting the antigenic phenotype of SARS-CoV-2 will enable variants to circumvent immunity conferred by natural infection or vaccination remains to be determined. However, there is growing evidence that mutations that change the antigenic phenotype of SARS-CoV-2 are circulating and affect immune recognition to a degree that requires immediate attention. The spike protein mediates attachment of the virus to host cell-surface receptors and fusion between virus and cell membranes (Box 1).

It is also the principal target of neutralizing antibodies generated following infection by SARS-CoV-2 and is the SARS-CoV-2 component of both mRNA and adenovirus-based vaccines licensed for use and others awaiting regulatory approval. Consequently, mutations that affect the antigenicity of the spike protein are of particular importance. In this Review, we explore the literature on these mutations and their antigenic consequences, focusing on the spike protein and antibody-mediated immunity, and discuss them in the context of observed mutation frequencies in global sequence datasets.

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