Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein finds additional vaccine-induced epitopes beyond those for mild infection
- Fred Hutchinson Cancer Research Center, United States
- University of Washington, United States
Abstract
Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal.
Methods: The epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions we determined potential sites of escape by comparing antibody binding of peptides containing wildtype residues versus peptides containing a mutant residue.
Results: Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination.
Conclusions: The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge, they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to Spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level.
Funding: This work was supported by NIH grants AI138709 (PI Overbaugh) and AI146028 (PI Matsen). Julie Overbaugh received support as the Endowed Chair for Graduate Education (FHCRC). The research of Frederick Matsen was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685.
Data availability
We provide a fully reproducible automated workflow which ingests raw sequencing data and performs all analyses presented in the paper. The workflow defines and runs the processing steps within publicly available and static Docker software containers, including phippery and phip-flow described in the Methods section. The source code, Nextflow script, software dependencies, and instructions for re-running the analysis can be found at https://github.com/matsengrp/phage-dms-vacc-analysis.The generalized PhIP-Seq alignment and count generation pipeline script can be found at https://github.com/matsengrp/phip-flow. A template and documentation for the alignment pipeline configuration is available at https://github.com/matsengrp/phip-flow-template. Finally, we provide a python API, phippery, to query the resulting dataset post-alignment that can be found at https://github.com/matsengrp/phippery.All raw sequencing data was submitted to the NCBI SRA under PRJNA765705. Pre-processed enrichment data is available upon request. Additionally, differential selection data and more can be explored interactively using the dms-view toolkit available at https://github.com/matsengrp/vacc-dms-view-host-repo.For more information regarding code and data availability, please email jgallowa@fredhutch.org. For original data from the NIH Moderna trial please see Jackson et al32, and for information on the HAARVI cohort please contact HYC.The generalized PhIP-Seq alignment and count generation pipeline script can be found at https://github.com/matsengrp/phip-flow. A template and documentation for the alignment pipeline configuration is available at https://github.com/matsengrp/phip-flow-template. Finally, we provide a python API, phippery, to query the resulting dataset post-alignment that can be found at https://github.com/matsengrp/phippery.All raw sequencing data was submitted to the NCBI SRA. Pre-processed enrichment data is available upon request. Additionally, differential selection data and more can be explored interactively using the dms-view toolkit available at {URL redacted until publication}.For more information, please email jgallowa@fredhutch.org.
Article and author information
Author details
Frederick A Matsen IV
Funding
National Institutes of Health (5R01AI138709-04)
- Julie M Overbaugh
National Institutes of Health (1R01AI146028-01)
- Frederick A Matsen IV
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jos W Van der Meer, Radboud University Medical Centre, Netherlands
Ethics
Human subjects: Moderna Trial CohortWe obtained post-vaccination serum samples via the National Institute of Allergy and Infection Disease that were taken as part of a phase I clinical trial testing the safety and efficacy of the Moderna mRNA-1273 vaccine (NCT04283461). All samples were de-identified and thus all work was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board as nonhuman subjects research.HAARVI CohortWe obtained plasma samples from individuals enrolled in the Hospitalized or Ambulatory Adults with Respiratory Viral Infections (HAARVI) study conducted in Seattle. Individuals were either enrolled upon PCR confirmed diagnosis with SARS-CoV-2 infection or as control subjects prior to receiving vaccination with either BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna). Electronic informed consent was obtained for every individual, and the study was approved by the University of Washington Institutional Review Board.
Version history
- Received: August 31, 2021
- Preprint posted: October 7, 2021 (view preprint)
- Accepted: January 18, 2022
- Accepted Manuscript published: January 24, 2022 (version 1)
- Version of Record published: March 1, 2022 (version 2)
Copyright
© 2022, Garrett et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein finds additional vaccine-induced epitopes beyond those for mild infection
eLife 11:e73490.
https://doi.org/10.7554/eLife.73490
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