Coronavirus Disease 2019 (COVID-19) Breakthrough Infection and Post-Vaccination Neutralizing Antibodies Among Healthcare Workers in a Referral Hospital in Tokyo: A Case-Control Matching Study

  1. Shohei Yamamoto
  2. Kenji Maeda
  3. Kouki Matsuda
  4. Akihito Tanaka
  5. Kumi Horii
  6. Kaori Okudera
  7. Junko S Takeuchi
  8. Tetsuya Mizoue
  9. Maki Konishi
  10. Mitsuru Ozeki
  11. Haruhito Sugiyama
  12. Nobuyoshi Aoyanagi
  13. Hiroaki Mitsuya
  14. Wataru Sugiura
  15. Norio Ohmagari

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Abstract

Background

While increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infection. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity.

Methods

We describe incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2415 fully vaccinated staff (BNT162b2) for breakthrough infection and selected 3 matched controls. We measured post-vaccination neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the 2 groups.

Results

No COVID-19 cases occurred 1–2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2–4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and participants had returned to work early. There was no measurable difference between cases and controls in post-vaccination neutralizing antibody titers against the wild-type, Alpha, Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type.

Conclusions

Post-vaccination neutralizing antibody titers were not decreased among patients with breakthrough infection relative to their controls under the Delta variant outbreak. The result points to the importance of infection-control measures in the post-vaccination era, irrespective of immunogenicity profile.

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  1. Version published to 10.1093/cid/ciab1048
  2. ScreenIT

    SciScore for 10.1101/2021.10.20.21265301: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Written informed consent was obtained from all participants, and the study procedure was approved by the NCGM ethics committee (the approved number: NCGM-G-003598).
    IRB: Written informed consent was obtained from all participants, and the study procedure was approved by the NCGM ethics committee (the approved number: NCGM-G-003598).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    BlindingThe assayers were blinded to which serum was cases or controls.
    Power AnalysisTo ensure the statistical power of the study, we applied a case-control ratio of 1:3.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The results of the first and second surveys have been reported elsewhere.12,13 In the third survey in June 2021 (within 4 months following the in-house vaccination program), we measured anti-SARS-CoV-2 spike protein antibodies, stored serum samples at -80 □ for further investigation, and collected data on COVID-19 (vaccination, occupational risk of SARS-CoV-2 infection, and infection prevention behaviors, etc.) via a questionnaire.
    anti-SARS-CoV-2 spike protein
    suggested: None
    SARS-CoV-2 antibody testing: We assessed anti-SARS-CoV-2 antibodies for all participants of the third survey and retrieved those data for the case-control subsets.
    anti-SARS-CoV-2
    suggested: None
    We quantitatively measured antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein by using the AdviseDx SARS-CoV-2 IgG II assay (Abbott) (IgG) and Elecsys Anti-SARS-CoV-2 S RUO (Roche) (predominantly IgG, also IgA and IgM).
    IgM
    suggested: None
    To examine the antibody-mediated immune response at the pre-breakthrough infection, we compared their log-transformed titers of neutralizing (wild-type, Alpha, and Delta) and anti-spike antibodies using a generalized estimating equation (GEE) with the group assignment (case or control) and robust variance estimator.
    anti-spike
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Neutralizing Antibody testing: The neutralizing activity of serum of cases and selected controls was determined by quantifying the serum-mediated suppression of the cytopathic effect (CPE) of each SARS-CoV-2 strain in VeroE6TMPRSS2 cells.
    VeroE6TMPRSS2
    suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)
    Software and Algorithms
    SentencesResources
    We also qualitatively measured antibodies against SARS-CoV-2 nucleocapsid protein using the SARS-CoV-2 IgG assay (Abbott) and Elecsys Anti-SARS-CoV-2 RUO (Roche), and used these data to exclude those with possible infection in the past.
    Abbott
    suggested: (Abbott, RRID:SCR_010477)
    Statistical analysis was performed using Stata 17.0 (StataCorp LLC), and graphics were made by GraphPad Prism 9 (GraphPad Inc).
    StataCorp
    suggested: (Stata, RRID:SCR_012763)
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    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:
    We also acknowledge study limitations. We measured antibody levels using samples obtained 5 to 10 weeks (median, 8 weeks) before the infection, which might have decreased at the time of infection due to the waning of antibodies over time. Nevertheless, we confirmed no evidence of the difference between cases and controls in the association of the duration of time between vaccination and blood sampling with neutralizing antibody titers (Supplementary Figure 1), denying faster waning of antibodies among cases than among controls. Data on virus type were available for only 5 cases (all Delta variants). However, the remaining breakthrough infections were most likely due to the Delta variant, which accounted for more than 90% of sequenced COVID-19 samples in Japan during the fifth epidemic wave.10 Conclusion: In conclusion, pre-infection neutralizing antibodies against the wild-type, Alpha, and Delta variants did not materially differ between healthcare workers who experienced breakthrough infection and those who did not under the Delta variant rampage. The result points to the importance of continued adherence to infection control measures in the post-vaccination variant-circulating era, irrespective of the level of immunogenicity.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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 10.1101/2021.10.20.21265301v1 on medRxiv