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Microfluidic Antibody Affinity Profiling Reveals the Role of Memory Reactivation and Cross-Reactivity in the Defense Against SARS-CoV-2

  • Viola Denninger
    Viola Denninger
    Fluidic Analytics, Unit A, The Paddocks Business Centre, Cherry Hinton Road, Cambridge CB1 8DH, United Kingdom
  • Catherine K. Xu
    Catherine K. Xu
    Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
  • Georg Meisl
    Georg Meisl
    Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
    More by Georg Meisl
  • Alexey S. Morgunov
    Alexey S. Morgunov
    Fluidic Analytics, Unit A, The Paddocks Business Centre, Cherry Hinton Road, Cambridge CB1 8DH, United Kingdom
    Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
  • Sebastian Fiedler
    Sebastian Fiedler
    Fluidic Analytics, Unit A, The Paddocks Business Centre, Cherry Hinton Road, Cambridge CB1 8DH, United Kingdom
  • Alison Ilsley
    Alison Ilsley
    Fluidic Analytics, Unit A, The Paddocks Business Centre, Cherry Hinton Road, Cambridge CB1 8DH, United Kingdom
  • Marc Emmenegger
    Marc Emmenegger
    Institute of Neuropathology, University of Zurich, 8091 Zurich, Switzerland
  • Anisa Y. Malik
    Anisa Y. Malik
    Fluidic Analytics, Unit A, The Paddocks Business Centre, Cherry Hinton Road, Cambridge CB1 8DH, United Kingdom
  • Monika A. Piziorska
    Monika A. Piziorska
    Fluidic Analytics, Unit A, The Paddocks Business Centre, Cherry Hinton Road, Cambridge CB1 8DH, United Kingdom
  • Matthias M. Schneider
    Matthias M. Schneider
    Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
  • Sean R. A. Devenish
    Sean R. A. Devenish
    Fluidic Analytics, Unit A, The Paddocks Business Centre, Cherry Hinton Road, Cambridge CB1 8DH, United Kingdom
  • Vasilis Kosmoliaptsis
    Vasilis Kosmoliaptsis
    Department of Surgery, University of Cambridge, Addenbrookes Hospital, Cambridge CB2 0QQ, United Kingdom
    NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Hills Road, Cambridge CB2 0QQ, United Kingdom
    NIHR Cambridge Biomedical Research Centre, Hills Road, Cambridge CB2 0QQ, United Kingdom
  • Adriano Aguzzi
    Adriano Aguzzi
    Institute of Neuropathology, University of Zurich, 8091 Zurich, Switzerland
  • Heike Fiegler
    Heike Fiegler
    Fluidic Analytics, Unit A, The Paddocks Business Centre, Cherry Hinton Road, Cambridge CB1 8DH, United Kingdom
  • , and 
  • Tuomas P. J. Knowles*
    Tuomas P. J. Knowles
    Fluidic Analytics, Unit A, The Paddocks Business Centre, Cherry Hinton Road, Cambridge CB1 8DH, United Kingdom
    Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
    Cavendish Laboratory, Department of Physics, University of Cambridge, JJ Thomson Ave, Cambridge CB3 0HE, United Kingdom
    *Email: [email protected]
Cite this: ACS Infect. Dis. 2022, 8, 4, 790–799
Publication Date (Web):March 30, 2022
https://doi.org/10.1021/acsinfecdis.1c00486
Copyright © 2022 American Chemical Society

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    Abstract

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    Recent efforts in understanding the course and severity of SARS-CoV-2 infections have highlighted both potentially beneficial and detrimental effects of cross-reactive antibodies derived from memory immunity. Specifically, due to a significant degree of sequence similarity between SARS-CoV-2 and other members of the coronavirus family, memory B-cells that emerged from previous infections with endemic human coronaviruses (HCoVs) could be reactivated upon encountering the newly emerged SARS-CoV-2, thus prompting the production of cross-reactive antibodies. Determining the affinity and concentration of these potentially cross-reactive antibodies to the new SARS-CoV-2 antigens is therefore particularly important when assessing both existing immunity against common HCoVs and adverse effects like antibody-dependent enhancement (ADE) in COVID-19. However, these two fundamental parameters cannot easily be disentangled by surface-based assays like enzyme-linked immunosorbent assays (ELISAs), which are routinely used to assess cross-reactivity. Here, we have used microfluidic antibody affinity profiling (MAAP) to quantitatively evaluate the humoral immune response in COVID-19 convalescent patients by determining both antibody affinity and concentration against spike antigens of SARS-CoV-2 directly in nine convalescent COVID-19 patient and three pre-pandemic sera that were seropositive for common HCoVs. All 12 sera contained low concentrations of high-affinity antibodies against spike antigens of HCoV-NL63 and HCoV-HKU1, indicative of past exposure to these pathogens, while the affinity against the SARS-CoV-2 spike protein was lower. These results suggest that cross-reactivity as a consequence of memory reactivation upon an acute SARS-CoV-2 infection may not be a significant factor in generating immunity against SARS-CoV-2.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.1c00486.

    • Microfluidic antibody affinity profiling against HCoV-HKU1 spike S1 and RBD reveals high-affinity antibodies at even lower concentrations than against HCoV-NL63 (Figure S1); reciprocal cross-reactivity competition assay in 4 (3) convalescent COVID-19 sera (Figure S2); best-fit values and confidence intervals for all of the MAAP measurements against the SARS-CoV-2 spike antigens RBD, S1, and S2 (Table S1); best-fit values and confidence intervals for all of the MAAP measurements against the HCoV-NL63 spike antigens RBD and S1 (Table S2); best-fit values and confidence intervals for all of the MAAP measurements against the HCoV-HKU1 spike antigens RBD and S1 (Table S3); Quality Control (QC) pipeline (Supporting Material 1) (PDF)

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    Cited By

    This article is cited by 2 publications.

    1. Peng Wang, Gege Yu, Juan Wei, Xingrui Liao, Yao Zhang, Yarong Ren, Cui Zhang, Yueqi Wang, Daohong Zhang, Jianlong Wang, Yanru Wang. A single thiolated-phage displayed nanobody-based biosensor for label-free detection of foodborne pathogen. Journal of Hazardous Materials 2023, 443 , 130157. https://doi.org/10.1016/j.jhazmat.2022.130157
    2. Hannes Ausserwöger, Matthias M. Schneider, Therese W. Herling, Paolo Arosio, Gaetano Invernizzi, Tuomas P. J. Knowles, Nikolai Lorenzen. Non-specificity as the sticky problem in therapeutic antibody development. Nature Reviews Chemistry 2022, 6 (12) , 844-861. https://doi.org/10.1038/s41570-022-00438-x

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