Spike Protein NTD mutation G142D in SARS-CoV-2 Delta VOC lineages is associated with frequent back mutations, increased viral loads, and immune evasion
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Abstract
The significantly greater infectivity of the SARS-CoV-2 Delta variants of concern (VOC) is hypothesized to be driven by key mutations that result in increased transmissibility, viral load and/or evasion of host immune response. We surveyed the mutational profiles of Delta VOC genomes between September 2020 and mid-August 2021 and identified a previously unreported mutation pattern at amino acid position 142 in the N-terminal domain (NTD) of the spike protein which demonstrated multiple rounds of mutation from G142 to D142 and back. This pattern of frequent back mutations was observed at multiple time points and across Delta VOC sub-lineages. The etiology for these recurrent mutations is unclear but raises the possibility of host-directed editing of the SARS-CoV-2 genome. Within Delta VOC this mutation is associated with higher viral load, further enhanced in the presence of another NTD mutation (T95I) which was also frequently observed in these cases. Protein modeling of both mutations predicts alterations of the surface topography of the NTD by G142D, specifically disturbance of the ‘super site’ epitope that binds NTD-directed neutralizing antibodies (NAbs). The appearance of frequent and repeated G142D followed by D142G back mutations is previously unreported in SARS-CoV-2 and may represent viral adaptation to evolving host immunity characterized by increasing frequency of spike NAbs, from both prior infection and vaccine-based immunity. The emergence of alterations of the NTD in and around the main NAb epitope is a concerning development in the ongoing evolution of SARS-CoV-2 which may contribute to increased infectivity, immune evasion and ‘breakthrough infections’ characteristic of Delta VOC. Future vaccine and therapy development may benefit by recognizing the emergence of these novel spike NTD mutations and considering their impact on antibody recognition, viral neutralization, infectivity, replication, and viral load.
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SciScore for 10.1101/2021.09.12.21263475: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Ethics approval: Study design conducted at Children’s Hospital Los Angeles was approved by the Institutional Review Board under IRB CHLA-16-00429. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar …
SciScore for 10.1101/2021.09.12.21263475: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Ethics approval: Study design conducted at Children’s Hospital Los Angeles was approved by the Institutional Review Board under IRB CHLA-16-00429. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.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 14. 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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