Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape
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Abstract
At the time of this writing, December 2021, potential emergence of vaccine escape variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a grave global concern. The interface between the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein and the host receptor (ACE2) overlap with the binding site of principal neutralizing antibodies (NAb), limiting the repertoire of viable mutations. Nonetheless, variants with multiple mutations in the RBD have rose to dominance. Non-additive, epistatic relationships among RBD mutations are apparent, and assessing the impact of such epistasis on the mutational landscape is crucial. Epistasis can substantially increase the risk of vaccine escape and cannot be completely characterized through the study of the wild type (WT) alone. We employed protein structure modeling using Rosetta to compare the effects of all single mutants at the RBD-NAb and RBD-ACE2 interfaces for the WT, Delta, Gamma, and Omicron variants. Overall, epistasis at the RBD interface appears to be limited and the effects of most multiple mutations are additive. Epistasis at the Delta variant interface weakly stabilizes NAb interaction relative to ACE2 interaction, whereas in the Gamma variant, epistasis more substantially destabilizes NAb interaction. Although a small, systematic trend towards NAb destabilization not observed for Delta or Gamma was detected for Omicron, and despite bearing significantly more RBD mutations, the epistatic landscape of the Omicron variant closely resembles that of Gamma. These results suggest that, although Omicron poses new risks not observed with Delta, structural constraints on the RBD hamper continued evolution towards more complete vaccine escape. The modest ensemble of mutations relative to the WT that are currently known to reduce vaccine efficacy is likely to comprise the majority of all possible escape mutations for future variants, predicting continued efficacy of the existing vaccines.
Significance
Emergence of vaccine escape variants of SARS-CoV-2 is arguably the most pressing problem during the COVID-19 pandemic as vaccines are distributed worldwide. We employed a computational approach to assess the risk of antibody escape resulting from mutations in the receptor-binding domain of the spike protein of the wild type SARS-CoV-2 virus as well as the Delta, Gamma, and Omicron variants. At the time of writing, December, 2021, Omicron is poised to replace Delta as the dominant variant worldwide. The efficacy of the existing vaccines against Omicron could be substantially reduced relative to the WT and the potential for vaccine escape is of grave concern. Our results suggest that although Omicron poses new evolutionary risks not observed for the Delta variant, structural constraints on the RBD make continued evolution towards more complete vaccine escape unlikely. The modest set of escape-enhancing mutations already identified for the wild type likely include the majority of all possible mutations with this effect.
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Timothy Whitehead, Irene Francino-Urdaniz
Review of "Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape"
Reviewer: Timothy Whitehead & Irene Francino-Urdaniz (University of Colorado Boulder) | 📒📒📒◻️◻️
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Timothy Whitehead, Irene Francino-Urdaniz
Review 1: "Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape"
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SciScore for 10.1101/2021.08.30.458225: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:While massively parallelizable, and in principle requiring less than 72 hours to compute, this method has practical limitations. To address this issue, we computed alternative ensembles of both variant conformations beginning with the WT ensemble (a computationally cheap approach) and demonstrated satisfactory agreement with the results obtained with the original protocol (see Extended Methods in the SI Appendix). With this modified approach, …
SciScore for 10.1101/2021.08.30.458225: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:While massively parallelizable, and in principle requiring less than 72 hours to compute, this method has practical limitations. To address this issue, we computed alternative ensembles of both variant conformations beginning with the WT ensemble (a computationally cheap approach) and demonstrated satisfactory agreement with the results obtained with the original protocol (see Extended Methods in the SI Appendix). With this modified approach, given the WT conformations reported in this work, the vaccine-escape landscape can be cheaply and rapidly established for any emergent variant of concern.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 22. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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