A Single Dose of COVID-19 mRNA Vaccine Induces Airway Immunity in COVID-19 Convalescent Patients

  1. Emanuela Martinuzzi
  2. Jonathan Benzaquen
  3. Olivier Guerin
  4. Sylvie Leroy
  5. Thomas Simon
  6. Marius Ilie
  7. Véronique Hofman
  8. Maryline Allegra
  9. Virginie Tanga
  10. Emeline Michel
  11. Jacques Boutros
  12. Charlotte Maniel
  13. Antoine Sicard
  14. Nicolas Glaichenhaus
  15. Cecil Czerkinsky
  16. Philippe Blancou
  17. Paul Hofman
  18. Charles Marquette

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Abstract

Mucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and hence virus shedding. Preclinical and clinical studies have shown that a parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior infection compared to two injections of a parenteral vaccine. We investigated whether this was also the case for a COVID-19 mRNA vaccine.

Methods

Twenty-three COVID-19 convalescent patients and 20 SARS-CoV-2-naive subjects were vaccinated with respectively one and two doses of the Pfizer-BioNTech COVID-19 RNA vaccine. Nasal Epithelial Lining Fluid (NELF) and plasma were collected before and after vaccination and assessed for Immunoglobulin (Ig)G and IgA to Spike and for their ability to inhibit the binding of Spike to its ACE-2 receptor. Blood was analyzed one week after vaccination for the number of Spike-specific Antibody Secreting Cells (ASCs) with a mucosal tropism.

Results

In COVID-19 convalescent patients, a single dose of vaccine amplified pre-existing Spike-specific IgG and IgA antibody responses in both NELF and blood against both vaccine homologous and variant strains, including delta. These responses were associated with Spike-specific IgG and IgA ASCs with a mucosal tropism in blood. Nasal IgA and IgG antibody responses were lower in magnitude in SARS-CoV-2-naive subjects after two vaccine doses

Conclusion

This study showed that a parenteral booster injection of a COVID-19 RNA vaccine promoted stronger mucosal immune responses in COVID-19 convalescent patients compared to SARS-CoV-2 naive subjects who had received a first vaccine dose.

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  1. ScreenIT

    SciScore for 10.1101/2021.12.16.21267932: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: All subjects signed an informed consent to participate in this work.
    IRB: The study was approved by the CPP Sud Méditerranée V ethics committee.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Binding inhibition assay: Plasma and nasal fluids were assessed for antibodies inhibiting the binding of a soluble angiotensin-converting enzyme 2 (ACE2) receptor to the SARS-CoV-2 RBD derived from the Wuhan strain and from its B.1.1.7 (alpha), B.1.351 (beta), B.1.526.1 (New York), B.1.617.1 (kappa), B.1.617.2 (delta), P.1 (gamma) and P.2 (zeta) variants using the multiplex V-PLEX® SARS-CoV-2 Panel 13 ACE2 Kit.
    ACE2
    suggested: None
    Human ASCs were enriched from lysed blood using a mixture (1:1) of magnetic beads (Dynabeads Pan Mouse IgG, Invitrogen) coated with monoclonal antibodies (mAbs) to either CD38 (clone HB-7, Biolegend) or β7 integrin (clone FIB504, BD Bioscience) followed by application of a magnetic field.
    CD38
    suggested: None
    Next, a mixture of appropriately diluted goat antibodies to human IgA and IgG, respectively labelled with alkaline phosphatase and horseradish peroxidase (Southern Biotech) was added to the wells.
    appropriately diluted goat antibodies to human IgA
    suggested: None
    Zones of solid phase-bound secreted IgA and IgG antibodies were visualized by stepwise incubation with corresponding enzyme chromogen substrates.
    IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    Standard Dressing, ref 400400, Medtronic, Minneapolis, MN, US), were inserted between the nasal septum and the inferior turbinate (17), left in place for 3 to 6 minutes until they swelled, gently retrieved and placed in a 50 ml Falcon tube (Dustcher, Bernolsheim, France) containing 2 ml of saline solution.
    Medtronic
    suggested: (Medtronic, RRID:SCR_003988)
    Statistical analyses were performed using GraphPad Prism 9·0 (
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad Software, Inc.
    GraphPad
    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:
    The present study has some limitations. Firstly, our study sample consisted of a small cohort of COVID-19 convalescent patients and SARS-CoV-2-naive subjects. Therefore, our results need to be validated with a larger and independent cohort of patients. Further, only 11 Covid- subjects were sampled after the second vaccine dose therefore limiting the statistical power. Secondly, the results showing the impact of vaccination on inhibition of binding by NELF antibodies should be taken with caution because of the high inter-individual variability in the levels of total IgG and IgA in NELF possibly resulting from differences in the production of mucus. Thirdly, COVID-19 convalescent patients were sampled three weeks after vaccination but not at later time points. Therefore, it is possible that the levels of SARS-CoV-2-specific IgA in NELF may have dropped after three weeks. Finally, while mucosal IgA have been demonstrated to prevent virus shedding and transmission in other infectious diseases, this has not been demonstrated in COVID-19 patients or vaccinated SARS-CoV-2 naive subjects. To our knowledge, this is the first study that documents the induction of mucosal immune responses in the upper airway mucosa, the main site of infection by SARS CoV-2 and as such a major site of person-to-person transmission. Given the exceptionally potent SARS-CoV-2 neutralizing properties of secretory antibodies and particularly secretory IgA (19) the most abundant class of Ig in human secretions...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04418206RecruitingValidating an ELISpot for Early Detection of an Active Immun…

    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.

  2. Version published to 10.1101/2021.12.16.21267932v1 on medRxiv