Boosting of cross-reactive antibodies to endemic coronaviruses by SARS-CoV-2 infection but not vaccination with stabilized spike

  1. Andrew R Crowley
  2. Harini Natarajan
  3. Andrew P Hederman
  4. Carly A Bobak
  5. Joshua A Weiner
  6. Wendy Wieland-Alter
  7. Jiwon Lee
  8. Evan M Bloch
  9. Aaron AR Tobian
  10. Andrew D Redd
  11. Joel N Blankson
  12. Dana Wolf
  13. Tessa Goetghebuer
  14. Arnaud Marchant
  15. Ruth I Connor
  16. Peter F Wright
  17. Margaret E Ackerman

  • Curated by eLife

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    Evaluation Summary:

    This study is aimed to determine whether infection or vaccination affects activation of pre-existing cross-reactive memory B cells. The data are clear and have implications for further development of new-generation of vaccines.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Abstract

Preexisting antibodies to endemic coronaviruses (CoV) that cross-react with SARS-CoV-2 have the potential to influence the antibody response to COVID-19 vaccination and infection for better or worse. In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross-reactivity against endemic CoV spike (S) protein at subdomain resolution. Elevated responses, particularly to the β-CoV OC43, were observed in all natural infection cohorts tested and were correlated with the response to SARS-CoV-2. The kinetics of this response and isotypes involved suggest that infection boosts preexisting antibody lineages raised against prior endemic CoV exposure that cross-react. While further research is needed to discern whether this recalled response is desirable or detrimental, the boosted antibodies principally targeted the better-conserved S2 subdomain of the viral spike and were not associated with neutralization activity. In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity. In sum, this study provides evidence that antibodies targeting endemic CoV are robustly boosted in response to SARS-CoV-2 infection but not to vaccination with stabilized S, and that depending on conformation or other factors, the S2 subdomain of the spike protein triggers a rapidly recalled, IgG-dominated response that lacks neutralization activity.

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  1. Version published to 10.7554/elife.75228 on eLife
  2. eLife

    Evaluation Summary:

    This study is aimed to determine whether infection or vaccination affects activation of pre-existing cross-reactive memory B cells. The data are clear and have implications for further development of new-generation of vaccines.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  4. eLife

    Reviewer #1 (Public Review):

    The authors investigated the plasma antibody responses of CoV-2 infected or vaccinated against CoV-2 spike and cross-reactive endemic CoV spike. They showed the correlation of CoV2 S2 IgG responses and OC43 S2 IgG responses in convalescent plasma. To investigate cross-reactivity of plasma antibody more directly, the authors affinity-purified plasma antibody with CoV-2 spike and OC43 spike, and showed the presence of non-neutralizing S2 cross-reactive antibody in CoV2-infected individual. Finally, the authors showed stabilized CoV-2 spike-vaccinated cohort had strong IgG responses against CoV-2 but not to OC43 spike. However, their data also showed other stabilized CoV-2 spike-vaccinated cohort had milder IgG responses against OC43 spike, which need to be clarified further.

  5. eLife

    Reviewer #2 (Public Review):

    By investigating the difference of humoral memory responses generated by infection and vaccination, authors are trying to find the epitope of pre-existing antibodies cross-reactive to endemic coronaviruses. Authors believe that the broadly-reactive epitope is potentially valuable for vaccine design. A strong point of this manuscript is the detailed description of those distinct humoral responses using human serum and a series of recombinant Spike domain proteins. Pre-existing antibodies reactive to the S2 domain conserved among beta coronavirus species are unique in the convalescent group. Although the observation is suggestive of the importance of protection, as the authors also pointed out, the link between biological importance in protection and their findings from serum studies is missing. The experimental methods are fairly designed, and the results are very informative. The authors provide adequate data to reach their goal of finding epitope of cross-reactivity among species. Further authors demonstrated that infection brings those cross-reactive antibodies than trimerized recombinant Spike protein-based vaccination. This pandemic is a unique occasion to study the immune responses and their memory generation against pathogen humans haven't met before. By using precious human materials, the findings are beneficial for future vaccine research.

  6. ScreenIT

    SciScore for 10.1101/2021.10.27.21265574: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: Human subject research was approved by the Johns Hopkins University School of Medicine’s Institutional Review Board, the Dartmouth-Hitchcock Medical Center, CHU St. Pierre, Hadassah Medical Center, and BioIVT clinical site Committees for the Protection of Human Subjects as described in Table 1.
    Consent: Participants provided informed written consent.
    Sex as a biological variableTo support comparisons of natural infection and vaccination, two cohorts of pregnant women were evaluated.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Anti-isotype and subclass primary antibodies were used to quantify the total amount of each immunoglobulin isotype in a sample before (load) and after (eluate) antigen-specific antibody purification.
    Anti-isotype
    suggested: None
    Antibody isotypes and subclasses were detected using R-phycoerythrin (PE) conjugated secondary Abs as previously described55.
    R-phycoerythrin
    suggested: None
    In order to quantify the enrichment of antigen-specific antibodies, individual features (antigen-detection pair) were plotted relative to the total immunoglobulin isotype in serum across a titration range for each sample.
    antigen-specific
    suggested: None
    antigen-detection pair
    suggested: None
    total immunoglobulin
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Luciferase activity was measured using the Bright-Glo system and percent neutralization determined relative to control wells consisting of 293T-ACE2 cells infected with the pseudovirus alone.
    293T-ACE2
    suggested: None
    Software and Algorithms
    SentencesResources
    Structure Visualization and Manipulation: The sequence alignments were performed using Geneious
    Geneious
    suggested: (Geneious, RRID:SCR_010519)
    SARS-CoV-2 was structurally aligned to the other models by domain using the MatchMaker function with default parameters and visualized using Chimera version 1.1551.
    Chimera
    suggested: (Chimera, RRID:SCR_002959)
    For structural characterization of conservation among the 60 complete genomes of the Coronaviridae suborder (https://www.ncbi.nlm.nih.gov/genomes/GenomesGroup.cgi?taxid=11118), Batch Entrez was used to find 585 associated proteins, which were then further down selected to spike proteins (N=56) and aligned using Clustal Omega.
    Clustal Omega
    suggested: (Clustal Omega, RRID:SCR_001591)
    This alignment was used to render by conservation and visualized using ChimeraX version 1.252.
    ChimeraX
    suggested: (UCSF ChimeraX, RRID:SCR_015872)
    Data Analysis: Basic statistical data analysis and visualization or raw Fc Array data was performed using GraphPad Prism, with statistical tests described in each figure legend.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results 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:
    Limitations of this study include use of several small cohorts, some collected from distinct geographic locations, from subjects of varying age, who experienced differing disease severity, and who were not confirmed to lack a recent exposure to endemic CoV. While all natural infection cohorts showed evidence of boosting toward the endemic CoV OC43, it would be beneficial to survey boosting in cohorts that better span a range of disease severity and ages to examine whether those variables impact the observed boosting effect, and outcomes of infection. To the extent that question has been investigated, it appears that boosting of responses to endemic CoV may be associated with poorer responses to SARS-CoV-228. Likewise, while both vaccination cohorts showed an absence of or reduction in boosting of cross-reactive responses, whether this absence is beneficial or detrimental cannot be determined from the data presented here. While cross-reactive antibodies were non-neutralizing, neutralization is not the sole mechanism by which antibodies confer protection. Cross-reactive antibodies could interact with receptors for the Fc region of antibodies found on the surface of innate immune cells and promote protective effector function activities including antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity39-41. To this end, a subset of monoclonal antibodies isolated from SARS-CoV patients that were able to cross-react with, but not neutralize SARS-CoV-2...

    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.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  7. Version published to 10.1101/2021.10.27.21265574v1 on medRxiv