Safety and immunogenicity clinical trial of an inactivated SARS-CoV-2 vaccine, BBV152 (a phase 2, double-blind, randomised controlled trial) and the persistence of immune responses from a phase 1 follow-up report
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Abstract
Background
BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 µg or 6 µg) formulated with a Toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG). Earlier, we reported findings from a phase 1 (vaccination regimen on days 0 and 14) randomised, double-blind trial on the safety and immunogenicity of three different formulations of BBV152 and one control arm containing Algel (without antigen). Two formulations were selected for the phase 2 (days 0 and 28) study. Here, we report interim findings of a controlled, randomised, double-blind trial on the immunogenicity and safety of BBV152: 3 µg and 6 µg with Algel-IMDG.
Methods
We conducted a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152. A total of 380 healthy children and adults were randomised to receive two vaccine formulations (n=190 each) with 3 µg with Algel-IMDG and 6 µg with Algel-IMDG. Two intramuscular doses of vaccines were administered (four weeks apart). Participants, investigators, and laboratory staff were blinded to the treatment allocation. The primary outcome was seroconversion (≥4-fold above baseline) based on wild-type virus neutralisation (PRNT 50 ). Secondary outcomes were reactogenicity and safety. Cell-mediated responses were evaluated. A follow-up blood draw was collected from phase 1 participants at day 104 (three months after the second dose).
Findings
Among 921 participants screened between Sep 7-13, 2020, 380 participants were randomised to the safety and immunogenicity population. The PRNT 50 seroconversion rates of neutralising antibodies on day 56 were 92·9% (88·2, 96·2) and 98·3% (95·1, 99·6) in the 3 µg and 6 µg with Algel-IMDG groups, respectively. Higher neutralising titres (2-fold) were observed in the phase 2 study than in the phase 1 study (p<0.05). Both vaccine groups elicited more Th1 cytokines than Th2 cytokines. After two doses, the proportion (95% CI) of solicited local and systemic adverse reactions were 9.7% (6·9, 13·2) and 10.3% (7·4, 13·8) in the 3 µg and 6 µg with Algel-IMDG groups, respectively. No significant difference was observed between the groups. No serious adverse events were reported in this study. Phase 1 follow-up immunological samples at day 104 showed seroconversion in 73·5% (63·6, 81·9), 81·1% (71·4, 88·1), and 73·1% (62·9, 81·8) of individuals in the 3 µg with Algel-IMDG, 6 µg with Algel-IMDG, and 6 µg with Algel groups, respectively.
Interpretation
In the phase 1 trial, BBV152 produced high levels of neutralising antibodies that remained elevated in all participants three months after the second vaccination. In the phase 2 trial, BBV152 led to tolerable safety outcomes and enhanced humoral and cell-mediated immune responses. The safety profile of BBV152 is noticeably lower than the rates for other SARS-CoV-2 vaccine platform candidates. The 6 µg Algel-IMDG formulation was selected for the phase 3 efficacy trial.
Funding
This work was supported and funded by Bharat Biotech International Limited.
Clinicaltrials.gov : NCT04471519
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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 Statement Consent: 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.Randomization To ensure the validity of our assay, a subset of serum samples (n=50) were randomly selected and tested by PRNT50 and MNT50 at NIV. Blinding Blinding: Participants, investigators, study … 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 Statement Consent: 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.Randomization To ensure the validity of our assay, a subset of serum samples (n=50) were randomly selected and tested by PRNT50 and MNT50 at NIV. Blinding Blinding: 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 Analysis The 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 variable 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 whole-virion inactivated SARS-CoV-2 vaccine (BBV152) in healthy male and nonpregnant female volunteers across 11 hospitals. Table 2: Resources
Antibodies Sentences Resources 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 IgGsuggested: NoneSoftware and Algorithms Sentences Resources Sample size estimation was performed using PASS 13 software (Number Cruncher Statistical Systems, USA) PASSsuggested: (PASS, RRID:SCR_005490)Number Cruncher Statistical Systemssuggested: NoneResults 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:
Identifier Status Title NCT04471519 Active, not recruiting Whole-Virion Inactivated SARS-CoV-2 Vaccine (BBV152) for COV… NCT04641481 Active, not recruiting An 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.
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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 …
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.
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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 Statement 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. Randomization To ensure the validity of our assay, a subset of serum samples (n=50) were randomly selected and tested by PRNT50 and MNT50 at NIV. Blinding Participants, investigators, and laboratory staff were blinded to the treatment allocation. Power Analysis The 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 … 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 Statement 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. Randomization To ensure the validity of our assay, a subset of serum samples (n=50) were randomly selected and tested by PRNT50 and MNT50 at NIV. Blinding Participants, investigators, and laboratory staff were blinded to the treatment allocation. Power Analysis The 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 variable Methods 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 Sentences Resources 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 IgGsuggested: NoneImmune 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-IgGsuggested: NoneSARS-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 IgGsuggested: NoneFigure 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. MNT50suggested: NoneSoftware and Algorithms Sentences Resources Sample size estimation was performed using PASS 13 software (Number Cruncher Statistical Systems, USA) PASSsuggested: (PASS, RRID:SCR_005490)Number Cruncher Statistical Systemssuggested: NoneResults 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:
Identifier Status Title NCT04471519 Active, not recruiting Whole-Virion Inactivated SARS-CoV-2 Vaccine (BBV152) for COV... NCT04641481 Recruiting An 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.
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