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Next-Generation Serology by Mass Spectrometry: Readout of the SARS-CoV-2 Antibody Repertoire

  • Rafael D. Melani
    Rafael D. Melani
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • Benjamin J. Des Soye
    Benjamin J. Des Soye
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
    Proteomics Center of Excellence, Evanston, Illinois 60208, United States
  • Jared O. Kafader
    Jared O. Kafader
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • Eleonora Forte
    Eleonora Forte
    Proteomics Center of Excellence, Evanston, Illinois 60208, United States
    Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States
  • Michael Hollas
    Michael Hollas
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • Voislav Blagojevic
    Voislav Blagojevic
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • Fernanda Negrão
    Fernanda Negrão
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • John P. McGee
    John P. McGee
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • Bryon Drown
    Bryon Drown
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
    More by Bryon Drown
  • Cameron Lloyd-Jones
    Cameron Lloyd-Jones
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • Henrique S. Seckler
    Henrique S. Seckler
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • Jeannie M. Camarillo
    Jeannie M. Camarillo
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • Philip D. Compton
    Philip D. Compton
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
    Integrated Protein Technologies, Evanston, Illinois 60201, United States
  • Richard D. LeDuc
    Richard D. LeDuc
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • Bryan Early
    Bryan Early
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
    More by Bryan Early
  • Ryan T. Fellers
    Ryan T. Fellers
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
  • Byoung-Kyu Cho
    Byoung-Kyu Cho
    Proteomics Center of Excellence, Evanston, Illinois 60208, United States
  • Basil Baby Mattamana
    Basil Baby Mattamana
    Proteomics Center of Excellence, Evanston, Illinois 60208, United States
  • Young Ah Goo
    Young Ah Goo
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
    Proteomics Center of Excellence, Evanston, Illinois 60208, United States
    More by Young Ah Goo
  • Paul M. Thomas
    Paul M. Thomas
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
    Proteomics Center of Excellence, Evanston, Illinois 60208, United States
  • Michelle K. Ash
    Michelle K. Ash
    Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois 60612, United States
  • Pavan P. Bhimalli
    Pavan P. Bhimalli
    Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois 60612, United States
  • Lena Al-Harthi
    Lena Al-Harthi
    Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois 60612, United States
  • Beverly E. Sha
    Beverly E. Sha
    Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois 60612, United States
  • Jeffrey R. Schneider
    Jeffrey R. Schneider
    Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois 60612, United States
  • , and 
  • Neil L. Kelleher*
    Neil L. Kelleher
    Departments of Molecular Biosciences, Chemistry, Northwestern University, Evanston, Illinois 60208, United States
    Proteomics Center of Excellence, Evanston, Illinois 60208, United States
    Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States
    *Email: [email protected]
Cite this: J. Proteome Res. 2022, 21, 1, 274–288
Publication Date (Web):December 8, 2021
https://doi.org/10.1021/acs.jproteome.1c00882
Copyright © 2021 American Chemical Society

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    Abstract

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    Methods of antibody detection are used to assess exposure or immunity to a pathogen. Here, we present Ig-MS, a novel serological readout that captures the immunoglobulin (Ig) repertoire at molecular resolution, including entire variable regions in Ig light and heavy chains. Ig-MS uses recent advances in protein mass spectrometry (MS) for multiparametric readout of antibodies, with new metrics like Ion Titer (IT) and Degree of Clonality (DoC) capturing the heterogeneity and relative abundance of individual clones without sequencing of B cells. We applied Ig-MS to plasma from subjects with severe and mild COVID-19 and immunized subjects after two vaccine doses, using the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 as the bait for antibody capture. Importantly, we report a new data type for human serology, that could use other antigens of interest to gauge immune responses to vaccination, pathogens, or autoimmune disorders.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jproteome.1c00882.

    • Additional experimental results, including I2MS spectra, charts, Western blots, and a summary table with multiple assay results. Figure S1: Expression validation of RBD region from the SARS-CoV-2 Spike protein; Figure S2: Western blot showing isotypes and IgG subclasses of the antibodies enriched with Ig-MS assay; Figure S3: Proteoform annotation of the CR3022 standard monoclonal antibody; Figure S4: Titration curve for Ig-MS to estimate the limit of detection (LOD) for NIST standard monoclonal antibody; Figure S5: Ig-MS readout of light chain region for CS1; Figure S6: Ig-MS readouts for Light and Heavy Chains; Figure S7: Ig-MS readouts of Light Chains; Figure S8: Ig-MS readouts of Heavy Chains; Figure S9: Anti-RBD antibody and neutralization titers, Figure S10: Ig-MS readouts from the vaccinated cohort; Figure S11: Ig-MS readouts of Light Chain and Fd domain; Figure S12: Comparison of ion titers between LC/HC and LC/Fd Ig-MS. Figure S13: Correlation of Ion titer (IT) and Degree of Clonality (DoC) metrics from Ig-MS with days after infection; Figure S14: Comparison of bulk IgG glycosylation profiles; Figure S15: Comparison of total glycan composition; Table S1: Correlation of Ig-MS metrics with patient metadata (PDF)

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    Cited By

    This article is cited by 11 publications.

    1. Son N. Nguyen, Si-Hung Le, Daniil G. Ivanov, Nikola Ivetic, Ishac Nazy, Igor A. Kaltashov. Structural Characterization of a Pathogenic Antibody Underlying Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT). Analytical Chemistry 2024, 96 (16) , 6209-6217. https://doi.org/10.1021/acs.analchem.3c05253
    2. Seyed Amirhossein Sadeghi, Wenrong Chen, Qianyi Wang, Qianjie Wang, Fei Fang, Xiaowen Liu, Liangliang Sun. Pilot Evaluation of the Long-Term Reproducibility of Capillary Zone Electrophoresis–Tandem Mass Spectrometry for Top-Down Proteomics of a Complex Proteome Sample. Journal of Proteome Research 2024, 23 (4) , 1399-1407. https://doi.org/10.1021/acs.jproteome.3c00872
    3. John P. McGee, Rafael D. Melani, Ben Des Soye, Derek Croote, Valerie Winton, Stephen R. Quake, Jared O. Kafader, Neil L. Kelleher. Immunocomplexed Antigen Capture and Identification by Native Top-Down Mass Spectrometry. Journal of the American Society for Mass Spectrometry 2023, 34 (10) , 2093-2097. https://doi.org/10.1021/jasms.3c00235
    4. John P. McGee, Michael W. Senko, Kevin Jooß, Benjamin J. Des Soye, Philip D. Compton, Neil L. Kelleher, Jared O. Kafader. Automated Control of Injection Times for Unattended Acquisition of Multiplexed Individual Ion Mass Spectra. Analytical Chemistry 2022, 94 (48) , 16543-16548. https://doi.org/10.1021/acs.analchem.2c03495
    5. Eleonora Forte, Benjamin J. Des Soye, Rafael D. Melani, Michael A. R. Hollas, Jared O. Kafader, Beverly E. Sha, Jeffrey R. Schneider, Neil L. Kelleher. Divergent Antibody Repertoires Found for Omicron versus Wuhan SARS-CoV-2 Strains Using Ig-MS. Journal of Proteome Research 2022, 21 (12) , 2987-2997. https://doi.org/10.1021/acs.jproteome.2c00514
    6. Marinela Contreras, Joaquín Vicente, José Joaquín Cerón, Silvia Martinez Subiela, José Miguel Urra, Francisco J. Rodríguez‐del‐Río, Elisa Ferreras‐Colino, Rita Vaz‐Rodrigues, Isabel G. de Fernández de Mera, Sandra Antunes, Ana Domingos, Christian Gortázar, José de la Fuente. Antibody isotype epitope mapping of SARS‐CoV‐2 Spike RBD protein: Targets for COVID‐19 symptomatology and disease control. European Journal of Immunology 2023, 22 , 2250206. https://doi.org/10.1002/eji.202250206
    7. Emma H. Doud, Elizabeth S. Yeh. Mass Spectrometry-Based Glycoproteomic Workflows for Cancer Biomarker Discovery. Technology in Cancer Research & Treatment 2023, 22 , 153303382211488. https://doi.org/10.1177/15330338221148811
    8. Sebastiaan C. de Graaf, Max Hoek, Sem Tamara, Albert J. R. Heck. A perspective toward mass spectrometry-based de novo sequencing of endogenous antibodies. mAbs 2022, 14 (1) https://doi.org/10.1080/19420862.2022.2079449
    9. Igor A. Kaltashov, Daniil G. Ivanov, Yang Yang. Mass spectrometry‐based methods to characterize highly heterogeneous biopharmaceuticals, vaccines, and nonbiological complex drugs at the intact‐mass level. Mass Spectrometry Reviews 2022, 82 https://doi.org/10.1002/mas.21829
    10. Michelle K. Ash, Pavan P. Bhimalli, Byoung-Kyu Cho, Basil Baby Mattamana, Stéphanie Gambut, Imad Tarhoni, Cristina L. Fhied, Anjelica F. Reyes, Samantha J. Welninski, Jaison Arivalagan, Fernanda Negrão, Renu Goel, Todd L. Beck, Thomas J. Hope, Beverly E. Sha, Young Ah Goo, Lena Al-Harthi, João I. Mamede, Jeffrey A. Borgia, Neil L. Kelleher, Jeffrey R. Schneider. Bulk IgG glycosylation predicts COVID-19 severity and vaccine antibody response. Cell Reports 2022, 41 (11) , 111799. https://doi.org/10.1016/j.celrep.2022.111799
    11. Tamas Pongracz, Gestur Vidarsson, Manfred Wuhrer. Antibody glycosylation in COVID-19. Glycoconjugate Journal 2022, 39 (3) , 335-344. https://doi.org/10.1007/s10719-022-10044-0