Heterologous immunization with inactivated vaccine followed by mRNA-booster elicits strong immunity against SARS-CoV-2 Omicron variant

  1. Fanglei Zuo
  2. Hassan Abolhassani
  3. Likun Du
  4. Antonio Piralla
  5. Federico Bertoglio
  6. Leire de Campos-Mata
  7. Hui Wan
  8. Maren Schubert
  9. Irene Cassaniti
  10. Yating Wang
  11. Josè Camilla Sammartino
  12. Rui Sun
  13. Stelios Vlachiotis
  14. Federica Bergami
  15. Makiko Kumagai-Braesch
  16. Juni Andréll
  17. Zhaoxia Zhang
  18. Yintong Xue
  19. Esther Veronika Wenzel
  20. Luigi Calzolai
  21. Luca Varani
  22. Nima Rezaei
  23. Zahra Chavoshzadeh
  24. Fausto Baldanti
  25. Michael Hust
  26. Lennart Hammarström
  27. Harold Marcotte
  28. Qiang Pan-Hammarström

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

The recent emergence of the Omicron variant has raised concerns on vaccine efficacy and the urgent need to study more efficient vaccination strategies. Here we observed that an mRNA vaccine booster in individuals vaccinated with two doses of inactivated vaccine significantly increased the plasma level of specific antibodies that bind to the receptor-binding domain (RBD) or the spike (S) ectodomain (S1 + S2) of both the G614 and the Omicron variants, compared to two doses of homologous inactivated vaccine. The level of RBD- and S-specific IgG antibodies and virus neutralization titers against variants of concern in the heterologous vaccination group were similar to that in individuals receiving three doses of homologous mRNA-vaccine or a boost of mRNA vaccine after infection, but markedly higher than that in individuals receiving three doses of a homologous inactivated vaccine. This heterologous vaccination regime furthermore significantly enhanced the RBD-specific memory B cell response and S1-specific T cell response, compared to two or three doses of homologous inactivated vaccine. Our study demonstrates that mRNA vaccine booster in individuals vaccinated with inactivated vaccines can be highly beneficial, as it markedly increases the humoral and cellular immune responses against the virus, including the Omicron variant.

Article activity feed

  1. Version published to 10.1038/s41467-022-30340-5
  2. ScreenIT

    SciScore for 10.1101/2022.01.04.22268755: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Study inclusion criteria included subjects being above 18 years of age, with inactivated or mRNA vaccination schedule documented, and who were willing and able to provide written informed consent.
    IRB: The study was approved by the ethics committees in institutional review board (IRB) of Stockholm, Technische Universität Braunschweig and the Tehran University of Medical Sciences.
    Sex as a biological variableThe study includes 183 samples from 124 healthy volunteers (54.3% females, median age of 34 years) in Sweden (n=75), Germany (n=18) and Iran (n=31) during 2021.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Detection of antibodies specific to SARS-CoV-2: For assessing the anti-RBD IgG binding activity, high-binding Corning Half area plates (Corning #3690) were coated overnight at 4°C with RBD derived from WT, Beta, Delta and Omicron (1.7 μg/ml) in PBS.
    anti-RBD IgG
    suggested: None
    The ELISpot plates pre-coated with capturing monoclonal anti-human IgG antibodies were incubated with a total of 300 000 or 30 000 viable pre-stimulated cells per well for detection of RBD-specific IgG and total IgG (positive control) secreting cells, respectively.
    anti-human IgG
    suggested: None
    total IgG
    suggested: None
    A polyclonal activator for human T cells (anti-human CD3 monoclonal antibody CD3-2, #3605-1, Mabtech) was used as a positive control for cytokine secretion.
    anti-human CD3
    suggested: (MABTECH Cat# 3605-1-1000, RRID:AB_907218)
    Quantification and statistical analysis: Mann-Whitney U test was used for comparisons between groups in anti-SARS-CoV-2 antibody levels and numbers of specific memory B and T cells.
    anti-SARS-CoV-2
    suggested: None
    Software and Algorithms
    SentencesResources
    For each sample, the EC50 values were calculated using GraphPad Prism 7.04 software and expressed as relative potency towards an internal calibrant for which the Binding Antibody Unit (BAU) was calculated using the WHO International Standard 20/136 in relation to the WT RBD.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Results of ELISpot and FluoroSpot assays were evaluated using an IRIS-reader and analyzed by the IRIS software version 1.1.9 (Mabtech AB).
    IRIS
    suggested: None
    All analyses and data plotting were performed using GraphPad or R version 3.6.1.
    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:
    Limitations of this study include a rather low number of total participants, limited access to prospective sample collection and a lack of results on memory B and T cells after a third dose of the mRNA-based vaccine. Hence, our results should be confirmed in larger-scale longitudinal studies. Moreover, additional long-term studies that integrate the analysis of humoral responses with the neutralization activity of vaccine-induced antibodies against Omicron are needed.

    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 10.1101/2022.01.04.22268755v2 on medRxiv
  4. Version published to 10.1101/2022.01.04.22268755v1 on medRxiv