A booster dose is immunogenic and will be needed for older adults who have completed two doses vaccination with CoronaVac: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial

  1. Minjie Li
  2. Juan Yang
  3. Lin Wang
  4. Qianhui Wu
  5. Zhiwei Wu
  6. Wen Zheng
  7. Lei Wang
  8. Wanying Lu
  9. Xiaowei Deng
  10. Cheng Peng
  11. Bihua Han
  12. Yuliang Zhao
  13. Hongjie Yu
  14. Weidong Yin

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Abstract

Importance

Whether herd immunity through mass vaccination is sufficient to curb SARS-CoV-2 transmission requires an understanding of the duration of vaccine-induced immunity, and the necessity and timing of booster doses. Objective: To evaluate immune persistence of two priming doses of CoronaVac, and immunogenicity and safety of a third dose in healthy adults ≥60 years. Design, setting, and participants: We conducted a vaccine booster study built on a single-center, randomized, double-blind phase 1/2 trial of the two-dose schedule of CoronaVac among healthy adults≥60 years in Hebei, China. We examined neutralizing antibody titres six months or more after the second dose in all participants. We provided a third dose to 303 participants recruited in phase 2 trial to assess their immune responses.

Interventions

Two formulations (3 μg, and 6 μg) were used in phase 1 trial, and an additional formulation of 1.5 μg was used in phase 2 trial. All participants were given two doses 28 days apart and followed up 6 months after the second dose. Participants in phase 2 received a third dose 8 months after the second dose.

Main outcomes and measures

Geometric mean titres (GMT) of neutralizing antibodies to live SARS-CoV-2 and adverse events were assessed at multiple time points following vaccination.

Results

Neutralizing antibody titres dropped below the seropositive cutoff of 8 at 6 months after the primary vaccination in all vaccine groups in the phase 1/2 trial. A third dose given 8 months or more after the second dose significantly increased neutralizing antibody levels. In the 3 μg group (the licensed formulation), GMT increased to 305 [95%CI 215.3-432.0] on day 7 following the third dose, an approximately 7-fold increase compared with the GMT 28 days after the second dose. All solicited adverse reactions reported within 28 days after a booster dose were of grade 1 or 2 severity.

Conclusion and relevance

Neutralizing antibody titres declined substantially six months after two doses of CoronaVac among older adults. A booster dose rapidly induces robust immune responses. This evidence could help policymakers determine the necessity and the timing of a booster dose for older adults.

Trial registration

ClinicalTrials.gov ( NCT04383574 ).

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  1. ScreenIT

    SciScore for 10.1101/2021.08.03.21261544: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Written informed consent was obtained from each participant before the third dose in the second part of the study.
    IRB: The clinical trial protocol and informed consent form were approved by the Ethics Committee of Hebei CDC (
    Sex as a biological variablenot detected.
    RandomizationStudy design and participants: Our study is a vaccine booster study built on a single-center, randomized, double-blind phase 1/2 trial of CoronaVac which was initiated in Hebei, China on May 22, 2020, among healthy elderly adults aged 60 years or above.
    BlindingAll participants, investigators, and laboratory personnel were blind to study group assignment.
    Power AnalysisAs stated in previous publication12, we did not determine the sample sizes on the basis of a statistical power calculation.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Randomization codes for phases 1 and 2 were generated using block randomization and SAS software version 9.4; codes were assigned sequentially to participants.
    SAS
    suggested: (SASqPCR, RRID:SCR_003056)

    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 has limitations. First, we only reported immune response data for healthy older adults, and did not include individuals who have underlying medical conditions. The populations are more likely to have co-morbidities placing them at higher risk of severe clinical outcomes. Second, we had only three participants 80 years of age or older, making it not possible to determine immunogenicity results for this age group. Two doses of BNT162b2 induced smaller neutralizing responses in vaccinees over 80 years of age than younger groups,20,21 but our study cannot provide evidence one way or the other. Third, high neutralizing titres are important for protection against novel circulating SARS-CoV-2 variants conferring immune escape22. We did not perform neutralization testing in vitro against variants to determine the neutralization ability of the vaccine to emerging variants of concern. Fourth, a long-term follow-up of our phase 2 trial will be needed to determine a satisfactory duration of immunity induced by the booster dose.

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

    IdentifierStatusTitle
    NCT04383574Active, not recruitingSafety and Immunogenicity Study of Inactivated Vaccine for P…

    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.

  2. Version published to 10.1101/2021.08.03.21261544v1 on medRxiv