Three-dose vaccination-induced immune responses protect against SARS-CoV-2 Omicron BA.2

  1. Runhong Zhou
  2. Na Liu
  3. Xin Li
  4. Qiaoli Peng
  5. Cheuk-Kwan Yiu
  6. Haode Huang
  7. Dawei Yang
  8. Zhenglong Du
  9. Hau-Yee Kwok
  10. Ka-Kit Au
  11. Jian-Piao Cai
  12. Ivan Fan-Ngai Hung
  13. Kelvin Kai-Wang To
  14. Xiaoning Xu
  15. Kwok-Yung Yuen
  16. Zhiwei Chen

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Abstract

Background

The ongoing outbreak of SARS-CoV-2 Omicron BA.2 infections in Hong Kong, the model city of universal masking of the world, has resulted in a major public health crisis. Although the third vaccination resulted in strong boosting of neutralization antibody, vaccine efficacy and corelates of immune protection against the major circulating Omicron BA.2 remains to be investigated.

Methods

We investigated the vaccine efficacy against the Omicron BA.2 breakthrough infection among 470 public servants who had received different SARS-CoV-2 vaccine regimens including two-dose BNT162b2 (2×BNT, n=169), three-dose BNT162b2 (3×BNT, n=170), two-dose CoronaVac (2×CorV, n=34), three-dose CoronaVac (3×CorV, n=67) and third-dose BNT162b2 following 2×CorV (2×CorV+1BNT, n=32). Humoral and cellular immune responses after three-dose vaccination were further characterized and correlated with clinical characteristics of BA.2 infection.

Findings

During the BA.2 outbreak, 27.7% vaccinees were infected. The timely third-dose vaccination provided significant protection with lower incidence rates of breakthrough infections (2×BNT 49.2% vs 3×BNT 13.1%, p <0.0001; 2×CorV 44.1% vs 3×CoV 19.4%, p=0.003). Investigation of immune response on blood samples derived from 92 subjects in three-dose vaccination cohorts collected before the BA.2 outbreak revealed that the third-dose vaccination activated spike (S)-specific memory B cells and Omicron cross-reactive T cell responses, which correlated with reduced frequencies of breakthrough infections and disease severity rather than with types of vaccines. Moreover, the frequency of S-specific activated memory B cells was significantly lower in infected vaccinees than uninfected vaccinees before vaccine-breakthrough infection whereas IFN-γ + CD4 T cells were negatively associated with age and viral clearance time. Critically, BA.2 breakthrough infection boosted cross-reactive memory B cells with enhanced cross-neutralizing antibodies to Omicron sublineages, including BA.2.12.1 and BA.4/5, in all vaccinees tested.

Interpretation

Our results imply that the timely third vaccination and immune responses are likely required for vaccine-mediated protection against Omicron BA.2 pandemic. Although BA.2 conferred the highest neutralization resistance compared with variants of concern tested before the emergence of BA.2.12.1 and BA.4/5, the third dose vaccination-activated S-specific memory B cells and Omicron cross-reactive T cell responses contributed to reduced frequencies of breakthrough infection and disease severity. Neutralizing antibody potency enhanced by BA. 2 breakthrough infection with previous 3 doses of vaccines (CoronaVac or BNT162b2) may reduce the risk for infection of ongoing BA.2.12.1 and BA.4/5.

Funding

Hong Kong Research Grants Council Collaborative Research Fund, Health and Medical Research Fund, Wellcome Trust, Shenzhen Science and Technology Program, the Health@InnoHK, Innovation and Technology Commission of Hong Kong, China, National Program on Key Research Project, Emergency Key Program of Guangzhou Laboratory, donations from the Friends of Hope Education Fund and the Hong Kong Theme-Based Research Scheme.

Article activity feed

  1. Version published to 10.1101/2022.05.09.491254v2 on bioRxiv
  2. Rapid Reviews Infectious Diseases

    Cássia Terrassani Silveira

    Review 2: "Three-dose vaccination-induced immune responses protect against SARS-CoV-2 Omicron-BA.2"

    This preprint investigates the efficacy of 2/3 dose regimes of vaccines against Omicron BA.2 infection. Reviewers overall find this study informative, but highlight technical issues, and stylistic issues of results, that impact the conclusions drawn from the presented data.

  3. Rapid Reviews Infectious Diseases

    Claudio Acuña

    Review 1: "Three-dose vaccination-induced immune responses protect against SARS-CoV-2 Omicron-BA.2"

    This preprint investigates the efficacy of 2/3 dose regimes of vaccines against Omicron BA.2 infection. Reviewers overall find this study informative, but highlight technical issues, and stylistic issues of results, that impact the conclusions drawn from the presented data.

  5. ScreenIT

    SciScore for 10.1101/2022.05.09.491254: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: EXPERIMENTAL MODELS AND SUBJECT DETAILS: MATERIALS AND METHODS: Human subjects: This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (Ref No. UW 21-452).
    Consent: Written informed consent and questionnaire of vaccination and infection were obtained from these subjects.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Antigen-specific B cells: To characterize the SARS-CoV-2 Spike-specific B cells, PBMCs from each vaccinee were first stained with an antibody cocktail contained dead cell dye (Zombie aquae), CD3-Pacific Blue, CD14-Pacific Blue, CD56-Pacific Blue, CD19-BV785, IgD-BV605, IgG-PE, CD27-BV711, CD21-PE/Cy7, CD38-Percp/Cy5.5, CD11C-APC/Fire750 and His-tag Spike protein.
    IgD-BV605, IgG-PE
    suggested: None
    CD38-Percp/Cy5.5
    suggested: None
    CD11C-APC/Fire750
    suggested: None
    His-tag Spike protein.
    suggested: None
    Cells were then washed with FACS buffer (PBS with 2% FBS) and further stained with the secondary antibodies including APC anti-His and DyLight 488 anti-his antibodies.
    anti-His
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    In brief, different SARS-CoV-2 pseudotyped viruses were generated through co-transfection of 293T cells with 2 plasmids, pSARS-CoV-2 S and pNL4-3Luc_Env_Vpr, carrying the optimized SARS-CoV-2 S gene and a human immunodeficiency virus type 1 backbone, respectively.
    293T
    suggested: None
    The plasma-virus mixtures were then added into pre-seeded HEK293T-hACE2 cells.
    HEK293T-hACE2
    suggested: RRID:CVCL_A7UK)
    Recombinant DNA
    SentencesResources
    In brief, different SARS-CoV-2 pseudotyped viruses were generated through co-transfection of 293T cells with 2 plasmids, pSARS-CoV-2 S and pNL4-3Luc_Env_Vpr, carrying the optimized SARS-CoV-2 S gene and a human immunodeficiency virus type 1 backbone, respectively.
    pNL4-3Luc_Env_Vpr
    suggested: None
    Software and Algorithms
    SentencesResources
    For intracellular staining, cells were fixed and permeabilized with BD Cytofix/Cytoperm (BD Biosciences) prior to staining with the mAbs against IFN-γ-PE, TNF-α-AF488 and IL-2-PE-Cy7.
    BD Cytofix/Cytoperm
    suggested: None
    Stained cells were acquired by FACSAriaIII Flow Cytometer (BD Biosciences) and analyzed with FlowJo software (v10.6) (BD Bioscience).
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Correlation plots and heatmap visualizations: Correlograms plotting the Spearman rank correlation coefficient (r), between all parameter pairs were generated with the corrplot package (v0.84) (Wei and Sikmo, 2017) running under R (v3.6.1) in Rstudio (1.1.456).
    Rstudio
    suggested: (RStudio, RRID:SCR_000432)
    Spearman rank two-tailed P values were calculated using corr.test (psych v1.8.12) and graphed (ggplot2 v3.1.1) based on *p<0.05, **p<0.01, ***p<0.001.
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)
    Statistical analysis: Statistical analysis was performed using PRISM 8.0.
    PRISM
    suggested: (PRISM, RRID:SCR_005375)

    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 the study: There are some limitations in our study. First, we were unable to obtain blood samples from our subjects after they became infected and quarantined. We, therefore, could not determine the B and T cell activation post BA.2 infection. Nevertheless, vaccine breakthrough infections often recall rapid NAbs and T responses against various VOCs, including Omicron (Collier et al., 2022; Suntronwong et al., 2022; Zhou et al., 2022). Second, most of our infected vaccinees were confirmed infection by self-RAT, thus the effect of different vaccine regimens on controlling viral loads was not determined. It remains necessary to compare the dynamics and magnitudes of recalled immune responses among vaccinees with BA.2 breakthrough infection patients in the future. In summary, we report that 3×BNT and 3×CorV provided better protection against SARS-COV-2 BA.2 than 2×BNT and 2×CorV. High frequencies of S-specific activated memory B cells and cross-reactive T cell responses induced by the third vaccination are critical for protection and illness reduction during the Omicron BA.2 breakthrough infection.

    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.

  6. Version published to 10.1101/2022.05.09.491254v1 on bioRxiv