COVID-19 vaccines dampen genomic diversity of SARS-CoV-2: Unvaccinated patients exhibit more antigenic mutational variance
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Abstract
Variants of SARS-CoV-2 are evolving under a combination of immune selective pressure in infected hosts and natural genetic drift, raising a global alarm regarding the durability of COVID-19 vaccines. Here, we conducted longitudinal analysis over 1.8 million SARS-CoV-2 genomes from 183 countries or territories to capture vaccination-associated viral evolutionary patterns. To augment this macroscale analysis, we performed viral genome sequencing in 23 vaccine breakthrough COVID-19 patients and 30 unvaccinated COVID-19 patients for whom we also conducted machine-augmented curation of the electronic health records (EHRs). Strikingly, we find the diversity of the SARS-CoV-2 lineages is declining at the country-level with increased rate of mass vaccination (n = 25 countries, mean correlation coefficient = −0.72, S.D. = 0.20). Given that the COVID-19 vaccines leverage B-cell and T-cell epitopes, analysis of mutation rates shows neutralizing B-cell epitopes to be particularly more mutated than comparable amino acid clusters (4.3-fold, p < 0.001). Prospective validation of these macroscale evolutionary patterns using clinically annotated SARS-CoV-2 whole genome sequences confirms that vaccine breakthrough patients indeed harbor viruses with significantly lower diversity in known B cell epitopes compared to unvaccinated COVID-19 patients (2.3-fold, 95% C.I. 1.4-3.7). Incidentally, in these study cohorts, vaccinated breakthrough patients also displayed fewer COVID-associated complications and pre-existing conditions relative to unvaccinated COVID-19 patients. This study presents the first known evidence that COVID-19 vaccines are fundamentally restricting the evolutionary and antigenic escape pathways accessible to SARS-CoV-2. The societal benefit of mass vaccination may consequently go far beyond the widely reported mitigation of SARS-CoV-2 infection risk and amelioration of community transmission, to include stemming of rampant viral evolution.
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SciScore for 10.1101/2021.07.01.21259833: (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
Software and Algorithms Sentences Resources Controls restraint to surface residues were generated by calculating the solvent accessible surface area of each residue within the Spike protein (using the Biopython SASA module). Biopythonsuggested: (Biopython, RRID:SCR_007173)/ 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 … SciScore for 10.1101/2021.07.01.21259833: (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
Software and Algorithms Sentences Resources Controls restraint to surface residues were generated by calculating the solvent accessible surface area of each residue within the Spike protein (using the Biopython SASA module). Biopythonsuggested: (Biopython, RRID:SCR_007173)/ 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:Our study has a number of key limitations. First, the list of B cell and T cell epitopes in the Spike (S) glycoprotein antigen studied here may not be exhaustive as they are based on curation of studies deposited in the immune epitope database (IEDB) as of June 10, 2021 (https://www.iedb.org/). The immunologic analysis presented in this study consequently has to be updated regularly as more evidence emerges regarding the exhaustive T cell and B cell epitopes presented by the SARS-CoV-2 pathogen and their neutralization potential in the human population. Similarly, the SARS-CoV-2 genomes analyzed herein were deposited in the global initiative on sharing avian influenza data (GISAID) initiative as of June 10, 2021 (https://www.gisaid.org/). Despite having over 1 million SARS-CoV-2 genomes at the time of this analysis, GISAID still represents less than 0.60% of the 175 million COVID-19 cases reported worldwide as of June 10, 2021, thus providing only a partial representation of the genomic evolution of SARS-CoV-2. Finally, we consider any mutation away from the wild-type genomic sequence of known immunogenic epitopes as deleterious to their immunogenicity. While it is possible that mutations in the Spike protein sequence result in new immunogenic epitopes, a scan of 469,649 unique mutated peptides identified from the SARS-CoV-2 genomes reveals that only 8 of these peptides match a previously defined T cell epitopes (from IEDB), from within the SARS-CoV and SARS-CoV-2 genomes (Ta...
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: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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