Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial

  1. Raches Ella
  2. Siddharth Reddy
  3. Harsh Jogdand
  4. Vamshi Sarangi
  5. Brunda Ganneru
  6. Sai Prasad
  7. Dipankar Das
  8. Dugyala Raju
  9. Usha Praturi
  10. Gajanan Sapkal
  11. Pragya Yadav
  12. Prabhakar Reddy
  13. Savita Verma
  14. Chandramani Singh
  15. Sagar Vivek Redkar
  16. Chandra Sekhar Gillurkar
  17. Jitendra Singh Kushwaha
  18. Satyajit Mohapatra
  19. Amit Bhate
  20. Sanjay Rai
  21. Samiran Panda
  22. Priya Abraham
  23. Nivedita Gupta
  24. Krishna Ella
  25. Balram Bhargava
  26. Krishna Mohan Vadrevu

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Abstract

No abstract available

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  1. Version published to 10.1016/s1473-3099(21)00070-0
  2. ScreenIT

    SciScore for 10.1101/2020.12.21.20248643: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: Participants were screened for eligibility based on their health status, including their medical history, vital signs, and physical examination results and were enrolled after providing signed and dated informed consent forms.
    IRB: The trial was approved by the National Regulatory Authority (India) and the respective Ethics Committees and was conducted in compliance with all International Council for Harmonization (ICH) Good Clinical Practice guidelines.
    RandomizationTo ensure the validity of our assay, a subset of serum samples (n=50) were randomly selected and tested by PRNT50 and MNT50 at NIV.
    BlindingBlinding: Participants, investigators, study coordinators, study-related personnel, and the sponsor were blinded to the treatment group allocation (excluding an unblinded CRO that was tasked with the dispatch and labelling of vaccine vials and the generation of the master randomisation code).
    Power AnalysisThe required sample size for 90% power to find a significant difference (between vaccine formulations differing in the GMT by a ratio of 2) in a trial with a 1:1 allocation using a two-sample z-test at the two-sided 5% significance level was 171 per group.
    Sex as a biological variableTrial Design and Participants: This was a randomised, double-blind, multicentre phase 1 trial that was seamlessly followed by a phase 2 trial to evaluate the safety, reactogenicity, tolerability, and immunogenicity of a whole-virion inactivated SARS-CoV-2 vaccine (BBV152) in healthy male and nonpregnant female volunteers across 11 hospitals.

    Table 2: Resources

    Antibodies
    SentencesResources
    After antigen stimulation of day 104 PBMCs, culture supernatant was collected on day 3, to assess cytokines and secreted SARS-CoV-2 IgG antibodies (by ELISA) on day 6.
    SARS-CoV-2 IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    Sample size estimation was performed using PASS 13 software (Number Cruncher Statistical Systems, USA)
    PASS
    suggested: (PASS, RRID:SCR_005490)
    Number Cruncher Statistical Systems
    suggested: None

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

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

    IdentifierStatusTitle
    NCT04471519Active, not recruitingWhole-Virion Inactivated SARS-CoV-2 Vaccine (BBV152) for COV…
    NCT04641481Active, not recruitingAn Efficacy and Safety Clinical Trial of an Investigational …

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 32. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

    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. NCRC

    Our take

    The best hope for overcoming COVID-19 epidemic is the development of efficient vaccines. This study, available as a preprint and thus not yet peer reviewed, showed that this whole inactivated SARS-CoV-2 virion vaccine (manufactured by Bharat Biotech) is safe and can induce significant immune responses against the virus. In addition, the data showed that this vaccine induces immune response against multiple viral components including the spike protein, the primary target for the vaccines currently approved for emergency use. However, a phase 3 clinical trial is needed to test the efficiency of this vaccine in preventing COVID-19.

    Study design

    randomized-controlled-trial

    Study population and setting

    This is data from the phase 2 clinical trial for the SARS-CoV-2 vaccine BBV152, a whole inactivated virion formulated with an adjuvant to enhance the immune response (manufactured by Bharat Biotech). The study included 380 healthy volunteers between ages 12- 65 years recruited from 11 centers across India. The participants were screened for previous SARS-CoV-2 infection and were randomly assigned to receive one of two vaccine formulations at days 0 and 28. Side effects of the vaccine were monitored for one week after vaccination and immune response was assessed for four weeks after the second dose of the tested vaccine. The study also included the assessment of the vaccine immunogenicity in 198 participants who were included in the phase 1 clinical trial, along with their controls.

    Summary of main findings

    The study found that the vaccine induced minor side effects including fever, chills, aches, malaise and weakness in about 10% of the participant. No severe or life-threatening adverse reactions were reported. The vaccine induced antibodies that can bind to the SARS-CoV-2 virus in over 98% and 92% of the participants receiving the high and low doses, respectively. The authors showed also that the whole inactivated virion induced immune memory cells, suggesting possible longer-term protection of this experimental vaccine.

    Study strengths

    The current study has the advantage of including a relatively large number of participants for a phase 2 clinical trial across many centers in India and simultaneously testing two different formulations. The study also included children and teens 12 years and older, compared to Pfizer and Moderna vaccines that are approved for adults above 16 and 18 years respectively. Most of the front runner vaccines focus on targeting SARS-CoV-2 spike protein. The current study tested a vaccine prepared from a whole inactivated virion and showed some evidence of inducing immune response toward the other viral proteins as well. However, it is not clear if targeting other viral proteins can provide any further protection against SARS-CoV-2 infection.

    Limitations

    This is a phase2 clinical trial so does not present any data on vaccine efficacy. In addition, the study was conducted solely in India and there is no data about ethnic backgrounds of the participants.

    Value added

    The study showed a whole inactivated virion vaccine against SARS-CoV-2 is safe and induces an immune response. While this is not the first inactivated vaccine that was tested, considering the wide spread of COVID-19 in the world and current vaccine shortage, any effective vaccine can help mitigate the consequences of this disease world-wide.

  4. ScreenIT

    SciScore for 10.1101/2020.12.21.20248643: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementParticipants were screened for eligibility based on their health status, including their medical history, vital signs, and physical examination results and were enrolled after providing signed and dated informed consent forms.RandomizationTo ensure the validity of our assay, a subset of serum samples (n=50) were randomly selected and tested by PRNT50 and MNT50 at NIV.BlindingParticipants, investigators, and laboratory staff were blinded to the treatment allocation.Power AnalysisThe required sample size for 90% power to find a significant difference (between vaccine formulations differing in the GMT by a ratio of 2) in a trial with a 1:1 allocation using a twosample z-test at the two-sided 5% significance level was 171 per group.Sex as a biological variableMethods Trial Design and Participants This was a randomised, double-blind, multicentre phase 1 trial that was seamlessly followed by a phase 2 trial to evaluate the safety, reactogenicity, tolerability, and immunogenicity of a wholevirion inactivated SARS-CoV-2 vaccine (BBV152) in healthy male and nonpregnant female volunteers across 11 hospitals.

    Table 2: Resources

    Antibodies
    SentencesResources
    After antigen stimulation of day 104 PBMCs, culture supernatant was collected on day 3, to assess cytokines and secreted SARS-CoV-2 IgG antibodies (by ELISA) on day 6.
    SARS-CoV-2 IgG
    suggested: None
    Immune Responses Phase 2: Binding Antibody Titres Binding antibody Anti-IgG titres (GMTs) to all epitopes (S1 protein, RBD, and N protein) increased rapidly after the administration of both doses.
    Anti-IgG
    suggested: None
    SARS-CoV-2 Binding Antibody Responses (Anti-S1, -RBD, and -N IgG) ELISA (Anti-S1, -RBD, and -N IgG) Day 0 S1Protein Day 28 Day 42 Day 56 Day 0 GMT (95% CI) RBDProtein
    -N IgG
    suggested: None
    Figure 2: SARS-CoV-2 Neutralising Antibody Responses Titres of the wild-type SARS-CoV-2 neutralisation assay (PRNT50 and MNT50) at baseline (day 0), 4 weeks after the first vaccination (day 28), 2 weeks after the second vaccination (day 42), and 4 weeks after the second vaccination (day 56) for the 3 µg (n=190) and 6 µg (n=190) with Algel-IMDG groups are shown.
    MNT50
    suggested: None
    Software and Algorithms
    SentencesResources
    Sample size estimation was performed using PASS 13 software (Number Cruncher Statistical Systems, USA)
    PASS
    suggested: (PASS, RRID:SCR_005490)
    Number Cruncher Statistical Systems
    suggested: None

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

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

    IdentifierStatusTitle
    NCT04471519Active, not recruitingWhole-Virion Inactivated SARS-CoV-2 Vaccine (BBV152) for COV...
    NCT04641481RecruitingAn Efficacy and Safety Clinical Trial of an Investigational ...

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap used on page 32. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

  5. Version published to 10.1101/2020.12.21.20248643v1 on medRxiv