Immunogenicity of a third dose of BNT162b2 to ancestral SARS-CoV-2 & Omicron variant in adults who received two doses of inactivated vaccine

  1. Nancy H. L. Leung
  2. Samuel M. S. Cheng
  3. Mario Martín-Sánchez
  4. Niki Y. M. Au
  5. Yvonne Y. Ng
  6. Leo L. H. Luk
  7. Karl C. K. Chan
  8. John K. C. Li
  9. Yonna W. Y. Leung
  10. Leo C. H. Tsang
  11. Sara Chaothai
  12. Kelvin K. H. Kwan
  13. Dennis K. M. Ip
  14. Leo L. M. Poon
  15. Gabriel M. Leung
  16. J. S. Malik Peiris
  17. Benjamin J. Cowling

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Abstract

Background

Limited data exist on antibody responses to mixed vaccination strategies involving inactivated COVID-19 vaccines, particularly in the context of emerging variants.

Methods

We conducted an open label trial of a third vaccine dose of an mRNA vaccine (BNT162b2, Fosun Pharma/BioNTech) in adults aged ≥30 years who had previously received two doses of inactivated COVID-19 vaccine. We collected blood samples before administering the third dose and 28 days later, and tested for antibodies to the ancestral virus using a binding assay (ELISA), a surrogate virus neutralization test (sVNT) and a live virus plaque reduction neutralization test (PRNT). We also tested for antibodies against the Omicron variant using live-virus PRNT.

Results

In 315 participants, a third dose of BNT162b2 substantially increased antibody titers on each assay. Mean ELISA levels increased from an optical density (OD) of 0.3 to 2.2 (p<0. 001), and mean sVNT levels increased from an inhibition of 17% to 96% (p<0.001). In a random subset of 20 participants, the geometric mean PRNT 50 titers rose very substantially by at least 24 fold from Day 0 to Day 28 against the ancestral virus (p<0.001) and rose by at least 11 fold against the Omicron variant (p<0.001). In daily monitoring, post-vaccination reactions subsided within 7 days for over 99% of participants.

Conclusions

A third dose of COVID-19 vaccination with an mRNA vaccine substantially improved antibody levels against the ancestral virus and the Omicron variant with well-tolerated safety profile, in adults who had received two doses of inactivated vaccine 6 months earlier.

Summary

In this open label trial of Chinese adults aged ≥30 years who received two doses of inactivated COVID-19 vaccine 6 months earlier, third-dose mRNA vaccine substantially improved antibody levels against the ancestral virus and Omicron variant with well-tolerated safety profile.

Article activity feed

  1. Version published to 10.1101/2022.01.20.22269586v2 on medRxiv
  2. Rapid Reviews Infectious Diseases

    You-Wen He, Sheng Luo

    Review 1: "BNT162b2 vaccine boosts neutralizing antibodies to ancestral SARS-CoV-2 & Omicron variant in adults received 2-dose inactivated vaccine"

    This study investigated the extent of the BNT162 third dose's protection in patients who received two doses of inactivated vaccines. The study found that the booster increased antibody levels against the ancestral strain and the Omicron VoC. Reviewers deem the claims reliable.

  3. Rapid Reviews Infectious Diseases

    Rino Rappuoli, Simone Pecetta

    Review 2: "BNT162b2 vaccine boosts neutralizing antibodies to ancestral SARS-CoV-2 & Omicron variant in adults received 2-dose inactivated vaccine"

    This study investigated the extent of the BNT162 third dose's protection in patients who received two doses of inactivated vaccines. The study found that the booster increased antibody levels against the ancestral strain and the Omicron VoC. Reviewers deem the claims reliable.

  5. ScreenIT

    SciScore for 10.1101/2022.01.20.22269586: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Ethics: Written informed consent was obtained from all participants.
    IRB: The study protocol was approved by the Institutional Review Board of the University of Hong Kong/ Hospital Authority Hong Kong West Cluster.
    Sex as a biological variableWe also excluded potential participants with diagnosed medical conditions related to their immune system, use of medication that impairs immune system in the last 6 months except topical steroids or short-term oral steroids (course lasting ≤14 days), those who had used immunoglobulins and/or any blood products within 90 days prior to enrolment, and any females who were pregnant or intending to become pregnant in the coming 3 months.
    RandomizationThis is a single-arm study with no need for randomization, and the participants and the study staff were aware of the type of vaccination received by the participants (no blinding).
    BlindingThis is a single-arm study with no need for randomization, and the participants and the study staff were aware of the type of vaccination received by the participants (no blinding).
    Power AnalysisBased on our preliminary data, assuming a GMT of 27 at Day 0 with a standard deviation of 0.85, a sample size of 300 individuals would provide 80% power to detect a mean fold rise of 1.1 or greater at the 5% significance level.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    PRNT assays were carried out using ancestral SARS-CoV-2 BetaCoV/Hong Kong/VM20001061/2020 isolated in Hong Kong in January 2020 in Vero-E6 cells (ATCC CRL-1586) and the Pango lineage B.1.1.529 Omicron variant designated hCoV-19/Hong Kong/VM21044713_WHP5047-S5/2021 was isolated in Vero-E6 TMRSS2 cells (Vero E6 cells overexpressing TMPRSS2, kindly provided by Dr S Matsuyama and colleagues), and the passage level 3 virus aliquots were used.
    Vero-E6
    suggested: None
    Vero-E6 TMRSS2
    suggested: None
    Vero E6
    suggested: RRID:CVCL_XD71)
    Software and Algorithms
    SentencesResources
    Study data were collected and managed using REDCap electronic data capture tools hosted at the School of Public Health, The University of Hong Kong (21, 22).
    REDCap
    suggested: (REDCap, RRID:SCR_003445)

    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:
    Our study had several limitations. We have only performed PRNT against ancestral strain and Omicron strain up to a dilution of 1:320. However, more than half of our study participants were positive for antibodies to the ancestral strain at this dilution indicating antibody titers ≥320, and we were therefore not able to determine exactly the GMT against ancestral strain after third dose mRNA vaccination but only confirm that it was ≥320. Similarly, Day 0 samples were typically negative even at the starting dilution of 1:10, limiting our assessment of pre-vaccination GMTs. Nevertheless, we were able to conclude that third dose of mRNA vaccination would provide substantial benefits against both ancestral and Omicron strains by comparing the lower bound of the antibody boosting with the antibody level boosted after two doses of inactivated vaccination. Our results on immunogenicity may be subjected to selection bias including volunteer bias, since in Hong Kong older adults are more inclined to receive the inactivated vaccines and younger adults to mRNA vaccines (20). Indeed, while our study aimed to enrol adults aged ≥ 30 years, over 75% of study participants were ≥ 47 years old. Individuals who have received a self-funded commercial antibody test before enrolment with identified low antibody level might also have been more inclined to join studies on third dose vaccination, although only 6% of our study participants reported this as one of the major reasons for joining our study...

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

    IdentifierStatusTitle
    NCT05057182Active, not recruitingThird Dose of mRNA Vaccination to Boost COVID-19 Immunity (m…

    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.
    • Thank you for including a protocol registration statement.

    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 10.1101/2022.01.20.22269586v1 on medRxiv