Antigenic minimalism of SARS-CoV-2 is linked to surges in COVID-19 community transmission and vaccine breakthrough infections
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Abstract
The raging COVID-19 pandemic in India and reports of “vaccine breakthrough infections” globally have raised alarm mandating the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed 1.57 million SARS-CoV-2 genomes from 187 countries/territories and performed whole-genome viral sequencing from 53 COVID-19 patients, including 20 vaccine breakthrough infections. We identified 89 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-2 test positivity in any country over a three-month window. Deletions in the Spike protein N-terminal domain (NTD) are highly enriched for these ‘ surge-associated mutations ’ (Odds Ratio = 41.8, 95% CI: 6.36-1758, p-value = 7.7e-05). In the recent COVID-19 surge in India, an NTD deletion (ΔF157/R158) increased over 10-fold in prevalence from February 2021 (1.1%) to April 2021 (15%). During the recent surge in Chile, an NTD deletion (Δ246-253) increased rapidly over 30-fold in prevalence from January 2021 (0.86%) to April 2021 (33%). Strikingly, these simultaneously emerging deletions associated with surges in different parts of the world both occur at an antigenic supersite that is targeted by neutralizing antibodies. Finally, we generated clinically annotated SARS-CoV-2 whole genome sequences and identified deletions within this NTD antigenic supersite in a patient with vaccine breakthrough infection (Δ156-164) and other deletions from unvaccinated severe COVID-19 patients that could represent emerging deletion-prone regions. Overall, the expanding repertoire of Spike protein deletions throughout the pandemic and their association with case surges and vaccine breakthrough infections point to antigenic minimalism as an emerging evolutionary strategy for SARS-CoV-2 to evade immune responses. This study highlights the urgent need to sequence SARS-CoV-2 genomes at a larger scale globally and to mandate a public health policy for transparent reporting of relevant clinical annotations (e.g. vaccination status) in order to aid the development of comprehensive therapeutic strategies.
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SciScore for 10.1101/2021.05.23.21257668: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: This study was reviewed by the Mayo Clinic Institutional Review Board and determined to be exempt from human subjects research. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Structural analysis of SARS-CoV-2 Spike protein: Structural analyses and illustrations were performed in PyMOL (version 2.3.4). PyMOLsuggested: (PyMOL, RRID:SCR_000305)Viral RNA was first manually extracted and purified from these clinical specimens using MagMAX™ Viral / Pathogen Nucleic Acid Isolation Kit (Life Technologies Corp.), followed by automated reverse transcription-PCR (RT-PCR) … SciScore for 10.1101/2021.05.23.21257668: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: This study was reviewed by the Mayo Clinic Institutional Review Board and determined to be exempt from human subjects research. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Structural analysis of SARS-CoV-2 Spike protein: Structural analyses and illustrations were performed in PyMOL (version 2.3.4). PyMOLsuggested: (PyMOL, RRID:SCR_000305)Viral RNA was first manually extracted and purified from these clinical specimens using MagMAX™ Viral / Pathogen Nucleic Acid Isolation Kit (Life Technologies Corp.), followed by automated reverse transcription-PCR (RT-PCR) of viral sequences, DNA library preparation (including enzymatic shearing, adapter ligation, purification, normalization), DNA template preparation, and sequencing on the automated Genexus™ Integrated Sequencer (Life Technologies Corp.) with the Genexus™ Software version 6.2.1. Genexus™suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:There are a few limitations of this study. First, the geographic distribution of sequences deposited in the GISAID database is not representative of the global population, with a majority of the sequences coming from the United States or the United Kingdom. Future genomic epidemiology studies would be improved by expanded sequencing efforts in other countries. Second, the identification of mutations associated with surges during early months of the pandemic is complicated by the relative paucity of whole genome sequencing data deposited during that time. Third, the publicly accessible genomic data is not linked to any phenotypic information (e.g., disease severity) or relevant medical histories (e.g., comorbidities and vaccination status). Thus, while we are able to identify correlations between mutational prevalence and case surges, we cannot determine whether particular mutations are associated with more severe disease or are observed more frequently than expected by chance in vaccinated individuals. While the latter shortcoming is partially addressed by our independent whole genome sequencing of virus isolated from COVID-19 cases with accessible longitudinal records (including previously vaccinated individuals), this analysis was limited by the small size of the cohort (n = 53) and the lack of corresponding antibody titer data. We plan to address this by performing more whole genome viral sequencing of SARS-CoV-2 from COVID-19 patients. Taken together, using genomic epidem...
Results from TrialIdentifier: No clinical trial numbers were referenced.
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Results from scite Reference Check: We found no unreliable references.
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