Alpha, Beta, Gamma, Delta, Omicron and now XE variants of concern (VOC) in addition to other, less concerning variants have emerged during the ongoing SARS-CoV-2 pandemic. But how are new variants identified and how do we know if these new variants are cause for concern? Investigator at the Fred Hutchinson Cancer Research Center, Dr. Lue Ping Zhao orchestrated a cross-division collaboration between the Zhao, Gilbert, Geraghty and Jerome labs to characterize the mutational landscape of the Omicron variant in order to identify emerging variants. Their findings are available as a preprint in Res Sq.
A critical feature of the Omicron wave of SARS-CoV-2 infections was an increased rate of virus transmission or person-to-person virus spread. This has been attributed in part to mutations within the Spike protein, a protein on the outer surface of the virus particle. Spike is an important protein for the virus because it mediates entry of the virus into cells during infection and thus has parts of the protein that must be conserved and cannot be mutated. Additionally, the Spike protein can be recognized by antibodies that neutralize or restrict virus growth in an infected individual. Therefore, mutations to these exterior points of contact could also reduce vaccine-mediated protection and effectiveness of monoclonal antibodies or antiviral drug treatments to ebb virus-related disease. For these reasons, mutations in the Spike protein should be monitored in emerging SARS-CoV-2 variants.
Dr. Zhao led a collaborative project that determined the mutational landscape of the Alpha, Delta, and Omicron SARS-CoV-2 variants. Global sequence data for ~4,700 Alpha, ~1,000 Delta, and ~4,300 Omicron circulating variants were analyzed to generate core haplotypes or conserved genetic codes for each variant. Deviations from the core haplotypes were categorized as emerging variants. Focusing on the most recent variants Delta and Omicron, more mutations in the Spike protein were observed in the Omicron variant as compared to the Delta variant (figure). Specifically, 23 total polymutants within Spike were unique to the Omicron variant when compared to the earlier variants, Alpha and Delta. These findings indicate that over time, more mutations within the Spike protein occur. Intriguingly, some of the mutations within the Spike protein of Omicron variant sequences were not consistently present and diverged from the core haplotype. Using a non-parametric logistic regression model fit to each polymutant within the Spike protein, the researchers identified 28 core polymutants and four divergent polymutants (R346, A701, I1081, N1192) for the Omicron variant. R346, A701, I1081 mutations were observed in multiple countries, while N1192 polymutants were only observed recently in Hong Kong, United Kingdom, and Israel. Acquisition of additional Spike protein mutations may indicate the coming of another SARS-CoV-2 wave as a new variant expands in the population. But are these variants cause for concern? Dr. Zhao and his colleagues published an article earlier this year that concluded that despite the role of Spike in transmission of SARS-CoV-2, mutations within this protein were not associated with increased risk of hospitalization. That being said, mutations in the Spike protein may indicate a reduction in vaccine efficacy and therefore should be monitored to inform on virus transmission predictions and if alternative vaccines are necessary.
To provide insight into the functional outcome of mutations within the Spike protein, the researchers conducted homology modeling for each polymutant of interest. This method mapped the mutations onto the crystal structure of Spike to inform on how these mutations may alter the function of the protein. One mutation in particular, N1192S, occurred in a region of Spike that is conserved in all human coronaviruses and is important for virus-cell interaction or viral fusion. While homology modeling of N1192S suggests a potential impact of this mutation on virus infectivity, functional experiments are necessary to determine the outcome of this mutation.
Together, Dr. Zhao and his collaborators were able to identify possible emerging SARS-CoV-2 variants and provided insight into how these mutations in Spike and other viral proteins, as discussed in the research article, may alter protein function. While core haplotypes enable the identification of emerging variants for past SARS-CoV-2 waves, it is important to note that, “at the moment, the way we detect new variants is ad hoc and depends on the variant becoming dominant in a country,” said Dr. Zhao. Critically, these core haplotypes for each variant will allow Dr. Zhao to trace variant cross-continent movement to identify variant origin sites. Furthermore, Dr. Zhao offered that additional sequencing of circulating SARS-CoV-2 in combination with hospitalization risk and viral transmissibility may help prioritize which variants should be followed closely during the ongoing pandemic.
The spotlighted research was funded by the National Institutes of Health.
UW/Fred Hutch Cancer Consortium members Lue Ping Zhao, Peter Gilbert, Dan Geraghty, and Keith Jerome contributed to this work.
Zhao LP, Lybrand T, Gilbert P, Payne TH, Pyo CW, Geraghty D, Jerome K. 2022. Rapidly Identifying New Coronavirus Mutations of Potential Concern in the Omicron Variant Using an Unsupervised Learning Strategy. Res Sq. Online ahead of print.