Humoral immunity to SARS-CoV-2 elicited by combination COVID-19 vaccination regimens

  1. Zijun Wang
  2. Frauke Muecksch
  3. Friederike Muenn
  4. Alice Cho
  5. Shuai Zong
  6. Raphael Raspe
  7. Victor Ramos
  8. Brianna Johnson
  9. Tarek Ben Tanfous
  10. Justin DaSilva
  11. Eva Bednarski
  12. Camila Guzman-Cardozo
  13. Martina Turroja
  14. Katrina G. Millard
  15. Pinkus Tober-Lau
  16. David Hillus
  17. Kai-Hui Yao
  18. Irina Shimeliovich
  19. Juan Dizon
  20. Anna Kaczynska
  21. Mila Jankovic
  22. Anna Gazumyan
  23. Thiago Y. Oliveira
  24. Marina Caskey
  25. Paul D. Bieniasz
  26. Theodora Hatziioannou
  27. Florian Kurth
  28. Leif Erik Sander
  29. Michel C. Nussenzweig
  30. Christian Gaebler

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Abstract

The SARS-CoV-2 pandemic prompted a global vaccination effort and the development of numerous COVID-19 vaccines at an unprecedented scale and pace. As a result, current COVID-19 vaccination regimens comprise diverse vaccine modalities, immunogen combinations, and dosing intervals. Here, we compare vaccine-specific antibody and memory B cell responses following two-dose mRNA, single-dose Ad26.COV.2S, and two-dose ChAdOx1, or combination ChAdOx1/mRNA vaccination. Plasma-neutralizing activity, as well as the magnitude, clonal composition, and antibody maturation of the RBD-specific memory B cell compartments, showed substantial differences between the vaccination regimens. While individual monoclonal antibodies derived from memory B cells exhibited similar binding affinities and neutralizing potency against Wuhan-Hu-1 SARS-CoV-2, there were significant differences in epitope specificity and neutralizing breadth against viral variants of concern. Although the ChAdOx1 vaccine was inferior to mRNA and Ad26.COV.2S in several respects, biochemical and structural analyses revealed enrichment in a subgroup of memory B cell neutralizing antibodies with distinct RBD-binding properties resulting in remarkable potency and breadth.

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  1. Version published to 10.1084/jem.20220826
  2. ScreenIT

    SciScore for 10.1101/2022.05.13.491823: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Study participants: Health-care workers receiving routine COVID-19 vaccination were enrolled in the EICOV and COVIM prospective observational cohort studies conducted at Charité–Universitätsmedizin Berlin (Berlin, Germany), after written informed consent was obtained.
    IRB: EICOV was approved by the ethics committee of Charité–Universitätsmedizin Berlin (EA4/245/20), and COVIM was approved by the Federal Institute for Vaccines and Biomedicines (Paul Ehrlich Institute) and by the Ethics committee of the state of Berlin (EudraCT-2021–001512–28).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Plates were washed 6 times with washing buffer and then incubated with anti-human IgG, IgM or IgA secondary antibody conjugated to horseradish peroxidase (HRP) (Jackson ImmunoResearch 109-036-088, 109-035-129, and Sigma A0295) in blocking buffer at a 1:5,000 dilution (IgM and IgG) or 1:3,000 dilution (IgA).
    anti-human IgG
    suggested: (Jackson ImmunoResearch Labs Cat# 109-036-088, RRID:AB_2337594)
    IgA
    suggested: None
    The half-maximal neutralization titers for plasma (NT50) or half-maximal and 90% inhibitory concentrations for monoclonal antibodies (IC50 and IC90) were determined using four-parameter nonlinear regression (least squares regression method without weighting; constraints: top=1, bottom=0) (GraphPad Prism).
    IC90
    suggested: None
    The enriched B cells were incubated in Flourescence-Activated Cell-sorting (FACS) buffer (1× PBS, 2% FCS, 1 mM ethylenediaminetetraacetic acid (EDTA)) with the following anti-human antibodies (all at 1:200 dilution): anti-CD20-PECy7 (BD Biosciences, 335793), anti-CD3-APC- eFluro780 (Invitrogen, 47-0037-41), anti-CD8-APC-eFluor780 (Invitrogen, 47-0086-42)
    anti-human
    suggested: (GenWay Biotech Inc. Cat# 18-202-335793-0.1 mg, RRID:AB_1981874)
    anti-CD20-PECy7
    suggested: None
    anti-CD3-APC-
    suggested: None
    anti-CD8-APC-eFluor780
    suggested: None
    The frequency distributions of human V genes in anti-SARS-CoV-2 antibodies from this study was compared to 131,284,220 IgH and IgL sequences generated by (Soto et al., 2019) and downloaded from cAb-Rep (Guo et al., 2019), a database of human shared BCR clonotypes available at https://cab-rep.c2b2.columbia.edu/.
    anti-SARS-CoV-2
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Briefly, 293T (CRL-11268) cells were obtained from ATCC, and the cells were transfected with pNL4-3 ΔEnv-nanoluc and pSARS-CoV-2-SΔ19.
    293T
    suggested: ATCC Cat# CRL-11268, RRID:CVCL_1926)
    Recombinant DNA
    SentencesResources
    Briefly, 293T (CRL-11268) cells were obtained from ATCC, and the cells were transfected with pNL4-3 ΔEnv-nanoluc and pSARS-CoV-2-SΔ19.
    pNL4-3
    suggested: None
    pSARS-CoV-2-SΔ19
    suggested: None
    Software and Algorithms
    SentencesResources
    The average of its signal was used for normalization of all the other values on the same plate with Excel software before calculating the area under the curve using Prism V9.1 (GraphPad).
    Excel
    suggested: None
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    For monoclonal antibodies, the ELISA half-maximal concentration (EC50) was determined using four-parameter nonlinear regression (GraphPad Prism V9.1).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    3,000 units/ml RNasin Ribonuclease Inhibitors (Promega, N2615)) per well using a FACS Aria III and FACSDiva software (Becton Dickinson) for acquisition and FlowJo for analysis.
    FACSDiva
    suggested: (BD FACSDiva Software, RRID:SCR_001456)
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Sequence analysis was performed using MacVector.
    MacVector
    suggested: (MacVector, RRID:SCR_015700)
    Cryo-EM data collection and processing: Single-particle cryo-EM data were collected on a Titan Krios transmission electron microscope (Thermo Fisher) equipped with a Gatan K3 direct detector, operating at 300 kV and controlled using SerialEM automated data collection software (Mastronarde, 2005).
    SerialEM
    suggested: (SerialEM, RRID:SCR_017293)
    The particles were used to generate ab initio models, which were then used for heterogeneous refinement of the entire dataset in cryoSPARC.
    cryoSPARC
    suggested: (cryoSPARC, RRID:SCR_016501)
    py implemented by Change-O v0.4.5
    Change-O
    suggested: None

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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.

  3. Version published to 10.1101/2022.05.13.491823v1 on bioRxiv