Safety and immunogenicity of heterologous boost immunization with an adenovirus type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001): A randomized, observer-blinded, placebo-controlled trial

  1. Pengfei Jin
  2. Xiling Guo
  3. Wei Chen
  4. Shihua Ma
  5. Hongxing Pan
  6. Lianpan Dai
  7. Pan Du
  8. Lili Wang
  9. Lairun Jin
  10. Yin Chen
  11. Fengjuan Shi
  12. Jingxian Liu
  13. Xiaoyu Xu
  14. Yanan Zhang
  15. George F. Gao
  16. Cancan Chen
  17. Jialu Feng
  18. Jingxin Li
  19. Fengcai Zhu

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Abstract

Heterologous boost vaccination has been proposed as an option to elicit stronger and broader, or longer-lasting immunity. We assessed the safety and immunogenicity of heterologous immunization with a recombinant adenovirus type-5-vectored Coronavirus Disease 2019 (COVID-19) vaccine (Convidecia, hereafter referred to as CV) and a protein-subunit-based COVID-19 vaccine (ZF2001, hereafter referred to as ZF).

Methods and findings

We conducted a randomized, observer-blinded, placebo-controlled trial, in which healthy adults aged 18 years or older, who have received 1 dose of Convidecia, with no history of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, were recruited in Jiangsu, China. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or placebo control (trivalent inactivated influenza vaccine (TIV)) administered at 28 days after priming, and received the third injection with ZF2001 at 5 months, referred to as CV/ZF/ZF (D0-D28-M5) and CV/ZF (D0-M5) regimen, respectively. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or TIV administered at 56 days after priming, and received the third injection with ZF2001 at 6 months, referred to as CV/ZF/ZF (D0-D56-M6) and CV/ZF (D0-M6) regimen, respectively. Participants and investigators were masked to the vaccine received but not to the boosting interval. Primary endpoints were the geometric mean titer (GMT) of neutralizing antibodies against wild-type SARS-CoV-2 and 7-day solicited adverse reactions. The primary analysis was done in the intention-to-treat population. Between April 7, 2021 and May 6, 2021, 120 eligible participants were randomly assigned to receive ZF2001/ZF2001 ( n = 40) or TIV/ZF2001 ( n = 20) 28 days and 5 months post priming, and receive ZF2001/ZF2001 ( n = 40) or TIV/ZF2001 ( n = 20) 56 days and 6 months post priming. Of them, 7 participants did not receive the third injection with ZF2001. A total of 26 participants (21.7%) reported solicited adverse reactions within 7 days post boost vaccinations, and all the reported adverse reactions were mild, with 13 (32.5%) in CV/ZF/ZF (D0-D28-M5) regimen, 7 (35.0%) in CV/ZF (D0- M5) regimen, 4 (10.0%) in CV/ZF/ZF (D0-D56-M6) regimen, and 2 (10.0%) in CV/ZF (D0-M6) regimen, respectively. At 14 days post first boost, GMTs of neutralizing antibodies in recipients receiving ZF2001 at 28 days and 56 days post priming were 18.7 (95% CI 13.7 to 25.5) and 25.9 (17.0 to 39.3), respectively, with geometric mean ratios of 2.0 (1.2 to 3.5) and 3.4 (1.8 to 6.4) compared to TIV. GMTs at 14 days after second boost of neutralizing antibodies increased to 107.2 (73.7 to 155.8) in CV/ZF/ZF (D0-D28-M5) regimen and 141.2 (83.4 to 238.8) in CV/ZF/ZF (D0-D56-M6) regimen. Two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6) induced antibody levels comparable with that elicited by 3-dose schedules, with GMTs of 90.5 (45.6, 179.8) and 94.1 (44.0, 200.9), respectively. Study limitations include the absence of vaccine effectiveness in a real-world setting and current lack of immune persistence data.

Conclusions

Heterologous boosting with ZF2001 following primary vaccination with Convidecia is more immunogenic than a single dose of Convidecia and is not associated with safety concerns. These results support flexibility in cooperating viral vectored and recombinant protein vaccines.

Trial registration

Study on Heterologous Prime-boost of Recombinant COVID-19 Vaccine (Ad5 Vector) and RBD-based Protein Subunit Vaccine; ClinicalTrial.gov NCT04833101 .

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  1. Version published to 10.1371/journal.pmed.1003953
  2. ScreenIT

    SciScore for 10.1101/2022.02.24.22271445: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The trial protocol was reviewed and approved by the institutional review board of the Jiangsu Provincial Center of Disease Control and Prevention (approval number: JSJK2021-A005-02).
    Consent: All participants provided written informed consent before enrollment.
    Sex as a biological variableWomen with positive urine pregnancy test were also excluded from this study.
    RandomizationStudy design and participants: This study was designed as a randomized, observer-blinded, placebo-controlled trial to access the safety and immunogenicity of a heterologous prime-boost immunization with Convidecia and ZF2001 in Guanyun County, Jiangsu Province, China.
    Blindingnot detected.
    Power AnalysisAssuming a standard deviation of 4, 40 and 20 participants receiving vaccine and placebo control in each regimen group, respectively, was estimated to provide 81·6% power for declaring the superiority.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Binding antibodies against receptor-binding domain (RBD) and spike protein were detected by an indirect ELISA assay with a cutoff titer of 1:10.
    receptor-binding domain ( RBD )
    suggested: None
    Briefly, serum samples were serially diluted (anti-RBD antibody detection, 1:10 to 1:1280; anti-Spike antibody detection, 1:10 to 1:21870) with sample diluent and tested in 96-well plates costed with a recombinant RBD or Spike antigen.
    anti-RBD
    suggested: None
    anti-Spike
    suggested: None
    IgG was detected using an anti-human IgG monoclonal antibody conjugated to horseradish peroxidase (HRP) diluted for each ELISA assay and TMB substrate.
    anti-human IgG
    suggested: None
    The antibodies against SARS-CoV-2 were presented as GMTs, GMFIs and seroconversion with 95% CIs, and the cellular responses were shown as the average number of positive cells per PBMCs.
    SARS-CoV-2
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    neutralizing antibody titer in serum was determined using a cytopathic effect (CPE)-based microneutralization assay with the SARS-CoV-2 virus strain in Vero-E6 cells (wild-type SARS-CoV-2: BetaCoV/Jiangsu/JS02/2020 (EPI_ISL_411952); delta variant B.1.617.2: hCoV-19/China/JS07/2021(EPI_ISL_4515846)), as described previously(21).
    Vero-E6
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical analyses were done by a statistician using SAS (version 9·4) or GraphPad Prism 8.0.1.
    GraphPad Prism
    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:
    This study has several limitations. First, it is the absence of a randomized control group completing the homologous Convidecia scheme. Although we select two extend controls receiving homologous immunization of Convidecia following a 0-56 days regimen and 0-6 months regimen, which are both comparable with the cohorts receiving heterologous immunization between Convidecia and ZF001 in baseline characteristics, there may be some potential bias. As an immunogenicity and reactogenicity study, we do not know whether the immune responses observed in our study will result in better effectiveness, and it is needed to be confirmed in real-world studies. Additionally, we are unable, at this point, to determine whether higher antibody titers measured at 14 days post boost immunization will result in a more sustained elevation of antibodies, and this will be assessed at 6 moths post 2nd boost vaccination. Lastly, the recently emerged SARS-CoV-2 Omicron variants of concern is quickly rising in worldwide and raised concerns about the effectiveness of available vaccines due to multiple amino acid mutations in the spike protein(31). Preliminary studies indicated that the neutralizing activity of plasma from individuals receiving prime COVID-19 vaccination from different platforms is severely reduced against Omicron variant(32, 33). In this study, the neutralizing activity of heterologous immunization with Convidecia and ZF001 against Omicron is not tested. In conclusion, our study shows tha...

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

    IdentifierStatusTitle
    NCT04833101Active, not recruitingStudy on Heterologous Prime-boost of Recombinant COVID-19 Va…

    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 10.1101/2022.02.24.22271445 on medRxiv