Breakthrough infections with the omicron and delta variants of SARS-CoV-2 result in similar re-activation of vaccine-induced immunity

  1. Arne Søraas
  2. Gunnveig Grødeland
  3. Beathe Kiland Granerud
  4. Thor Ueland
  5. Andreas Lind
  6. Børre Fevang
  7. Sarah L. Murphy
  8. Camilla Huse
  9. Anders Benteson Nygaard
  10. Anne Katrine Steffensen
  11. Huda al-Baldawi
  12. Mona Holberg-Petersen
  13. Lise Lima Andresen
  14. Camilla Ågnes
  15. Trine Ranheim
  16. Ylva Schanke
  17. Mette Istre
  18. John Arne Dahl
  19. Adity Chopra
  20. Susanne Dudman
  21. Mari Kaarbø
  22. Jan Terje Andersen
  23. Eline Benno Vaage
  24. Trung The Tran
  25. John Torgils Vaage
  26. Annika E. Michelsen
  27. Fredrik Müller
  28. Pål Aukrust
  29. Bente Halvorsen
  30. Tuva B. Dahl
  31. Jan Cato Holter
  32. Fridtjof Lund-Johansen

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Abstract

Results showing that sera from double vaccinated individuals have minimal neutralizing activity against Omicron have been interpreted as indicating the need for a third vaccine dose for protection. However, there is little information about early immune responses to Omicron infection in double vaccinated individuals.

Methods

We measured inflammatory mediators, antibodies to the SARS-CoV-2 spike and nucleocapsid proteins, and spike peptide-induced release of interferon gamma in whole blood in 51 double-vaccinated individuals infected with Omicron, in 14 infected with Delta, and in 18 healthy controls. The median time points for the first and second samples were 7 and 14 days after symptom onset, respectively.

Findings

Infection with Omicron or Delta led to a rapid and similar increase in antibodies to the receptor-binding domain (RBD) of Omicron protein and spike peptide-induced interferon gamma in whole blood. Both the Omicron- and the Delta-infected patients had a mild and transient increase in inflammatory parameters.

Interpretation

The results suggest that two vaccine doses are sufficient to mount a rapid and potent immune response upon infection in healthy individuals of with the Omicron variant.

Funding

The study was funded by the Oslo University Hospital, and by grants from The Coalition for Epidemic Preparedness Innovations, Research Council of Norway (no 312780, 324272), South-Eastern Norway Regional Health Authority (no 2019067, 2021071, 10357, 2021047, 33612, 2021087, 2017092), EU Horizon 2020 grant no 848099, a philantropic donation from Vivaldi Invest A/S, and The European Virus Archive Global.

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  1. Version published to 10.3389/fimmu.2022.964525
  2. ScreenIT

    SciScore for 10.1101/2022.01.27.22269895: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Informed consent was obtained from all individuals.
    IRB: The study was approved by the Regional Committee for Medical and Health Research Ethics in South-Eastern Norway (reference numbers 124170 and 106624).
    Sex as a biological variablenot detected.
    RandomizationWe used a linear mixed model to assess the association between virus load (log10 transformed) and symptom days with a random intercept by subject to control for repeated measures.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Blood sampling protocol: Blood for routine biochemistry, SARS-CoV-2 specific antibodies, interferon gamma (IFN-γ) release assay (IGRA), and markers of immune activation and inflammation was taken at baseline within a median of 6 days after symptom onset (Table 1), and at 1 week follow-up (4-6 days from inclusion).
    SARS-CoV-2
    suggested: None
    IFN-γ
    suggested: None
    Plasma levels of soluble (s) CD14, sCD163, sCD25, soluble T cell immunoglobulin mucin domain-3 (sTIM-3), myeoloperoxidase (MPO), lipopolysaccharide (LPS) binding protein (LBP), IFNγ-induced protein (IP-10), pentraxin-3 (PTX-3), growth differentiation factor 15 (GDF-15), matrix metallopeptidase 9 (MMP-9), and S100 calcium-binding protein A12 (S100A12) were measured in duplicate by enzyme immunoassays (EIA) using commercially available antibodies (R&D Systems, Minneapolis, MN) in a 384 format using a combination of a SELMA (Jena, Germany) pipetting robot and a BioTek (Winooski, VT) dispenser/washer.
    CD14
    suggested: (GenWay Biotech Inc. Cat# GWB-8456C7, RRID:AB_10269336)
    sCD163
    suggested: (CEDARLANE Cat# CL89175K, RRID:AB_10547358)
    immunoglobulin mucin domain-3 ( sTIM-3) , myeoloperoxidase ( MPO
    suggested: None
    LBP
    suggested: None
    IP-10
    suggested: (DSHB Cat# PDF C7, RRID:AB_760350)
    GDF-15
    suggested: None
    MMP-9
    suggested: None
    S100 calcium-binding protein
    suggested: (MyBioSource Cat# MBS608511, RRID:AB_10887090)
    S100A12
    suggested: None
    Antibody levels were measured as the R-Phycoerythrin median fluorescence intensity (MFI) of beads coupled with virus proteins divided by the signal measured for beads coupled with neutravidin only.
    R-Phycoerythrin
    suggested: None
    Plates were now incubated with horseradish peroxidase (HRP)-conjugated anti-rabbit IgG Fc antibody (cat.
    anti-rabbit IgG
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Measurement of neutralizing antibodies: Vero E6 cells were added into 96-well plates (Costar 3595,
    Vero E6
    suggested: None
    Software and Algorithms
    SentencesResources
    SSA003, Sino Biological) for 1 hour at room temperature, developed with TMB Substrate Solution (cat. N301, ThermoFisher), and read with an EnVision 2104 Multilabel Reader (Perkin Elmer).
    ThermoFisher
    suggested: (ThermoFisher; SL 8; Centrifuge, RRID:SCR_020809)

    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:
    Due to limitations in the cohort size and observation period, one cannot draw firm conclusions about the exact kinetics of virus clearance. Yet, in view of the mild symptoms and rapid clinical recovery it seems likely that the combination of circulating antibodies and recall responses in this cohort of double-vaccinated individuals was sufficient for full recovery. This interpretation is in agreement with results from a study showing that mRNA vaccines elicit highly cross-reactive antibodies to SARS-CoV-2 variants.22 The methods used here do not discriminate between primary and recall responses to the SARS-CoV-2 spike protein. Yet, results obtained for antibodies specific for the nucleocapsid protein suggest that the contribution of primary responses was modest. There was a statistically significant increase in anti-nucleocapsid antibodies over time, but except for those with a prior history of COVID-19, the levels remained near the detection limit in most individuals throughout the observation period. The levels of spike peptide-induced IFN-γ release from T-cells were higher than those observed in samples from healthy controls already at 2-10 days after symptom onset. This is well below the time range expected for a primary T-cell response. It therefore is reasonable to conclude that virus clearance was mainly mediated through recall responses. Results obtained from the single unvaccinated individual infected with Omicron should be interpreted with great caution, but they ar...

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

    IdentifierStatusTitle
    NCT04320732RecruitingRisk Factors for Community- and Workplace Transmission of CO…
    NCT04381819RecruitingNorwegian SARS-CoV-2 Study - Virological, Clinical and 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

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  3. Version published to 10.1101/2022.01.27.22269895v1 on medRxiv