Efficacy, safety, and lot to lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): a, double-blind, randomised, controlled phase 3 trial
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Abstract
Background
We report the clinical efficacy against COVID-19 infection of BBV152, a whole-virion inactivated SARS-CoV-2 vaccine formulated with a Toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG).
Methods
We did a double-blind, randomised, multicentre, phase 3 clinical trial in 25 Indian hospitals to evaluate the efficacy, safety, and immunological lot consistency of BBV152. Healthy adults (age 18–98 years) randomised 1:1 using a computer-generated randomisation scheme received two intramuscular doses of vaccine or placebo administered four weeks apart. The primary outcome was laboratory-confirmed symptomatic COVID-19, occurring at least 14 days after the second dose. Secondary outcomes were efficacy in sub-groups for age (18–< 60 years and ≥ 60 years) and in participants with pre-existing stable medical conditions. We also evaluated safety, reactogenicity, and consistency of immune responses for three consecutive manufacturing lots.
Findings
Between November 16, 2020 and January 7, 2021 we recruited 25,798 participants who were randomised to BBV152 or placebo groups; 24,419 received two doses of BBV152 (n = 12,221) or placebo (n = 12,198). In a case-driven analysis, 130 cases of symptomatic COVID-19 were reported in 16,973 (0·77%) participants with follow-up at least two weeks after the second vaccination; 24 occurred in the vaccine group and 106 in placebo recipients giving an overall vaccine efficacy of 77·8% (95% CI: 65·2–86·4). Sixteen cases, one vaccinee and 15 placebo recipients, met the severe symptomatic COVID-19 case definition giving a vaccine efficacy of 93·4% (57·1–99·8). Efficacy against asymptomatic COVID-19 was 63·6% (29·0–82·4). BBV152 conferred 65·2% (95% CI: 33·1–83·0) protection against the SARS-CoV-2 Variant of Concern, B.1.617.2 (Delta). BBV152 was well tolerated with no clinically or statistically significant differences in the distributions of solicited, unsolicited, or serious adverse events between vaccine and placebo groups. No cases of anaphylaxis or vaccine-related deaths were reported.
Interpretation
BBV152 was immunogenic and highly efficacious against symptomatic and asymptomatic COVID-19 variant associated disease, particularly against severe disease in adults. Vaccination was well tolerated with an overall incidence of adverse events observed over a median of 146 days that was lower than that observed with other COVID-19 vaccines.
Funding
This work was supported and funded by Bharat Biotech International Limited and partly co-funded by the Indian Council of Medical Research.
Clinicaltrials.gov : NCT04641481
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SciScore for 10.1101/2021.06.30.21259439: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Field Sample Permit: The trial was approved by the National Regulatory Authority (India) and the respective Ethics Committees of each study centre and was conducted in compliance with all International Conference for Harmonization (ICH) Good Clinical Practice guidelines.
IRB: The trial was approved by the National Regulatory Authority (India) and the respective Ethics Committees of each study centre and was conducted in compliance with all International Conference for Harmonization (ICH) Good Clinical Practice guidelines.
Consent: Eligible participants provided signed and dated informed consent forms at enrolment.Sex as a biological variable All females had a urine pregnancy test. Randomization …SciScore for 10.1101/2021.06.30.21259439: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Field Sample Permit: The trial was approved by the National Regulatory Authority (India) and the respective Ethics Committees of each study centre and was conducted in compliance with all International Conference for Harmonization (ICH) Good Clinical Practice guidelines.
IRB: The trial was approved by the National Regulatory Authority (India) and the respective Ethics Committees of each study centre and was conducted in compliance with all International Conference for Harmonization (ICH) Good Clinical Practice guidelines.
Consent: Eligible participants provided signed and dated informed consent forms at enrolment.Sex as a biological variable All females had a urine pregnancy test. Randomization Study Design and Participants: We assessed the efficacy, safety and immunogenicity of two intramuscular 6 µg Algel-IMDG doses of BBV152 in a randomised, blinded, placebo-controlled, multi-centre study done in 25 centres in India. Blinding Study Design and Participants: We assessed the efficacy, safety and immunogenicity of two intramuscular 6 µg Algel-IMDG doses of BBV152 in a randomised, blinded, placebo-controlled, multi-centre study done in 25 centres in India. Power Analysis Based on a true efficacy of 60% and power of 85%, the case-driven trial was planned to accrue 130 cases. Table 2: Resources
Software and Algorithms Sentences Resources Sample size estimation was performed using PASS 13 software (NCSS, Kaysville, Utah, USA). PASSsuggested: (PASS, RRID:SCR_005490)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. Due to the low number of cases reported between doses 1 and 2, we cannot calculate vaccine efficacy after a single dose. This report contains a median safety follow-up of 146 days for all participants, so long-term safety follow-up of BBV152 is required and is currently underway. The data presented on efficacy against variants other than Delta must be considered preliminary as the numbers reported are small. Additional efforts to assess the clinical efficacy of BBV152 against VoC are being planned. The potential establishment of a correlate of protection is not feasible at the time of this report. Finally, this study population lacked ethnic and racial diversity, underscoring the importance of evaluating the efficacy of BBV152 in other populations. Although the study was designed to vaccinate and follow participants for one year after the second dose, given the nature of the pandemic in India and the emergency use authorization for BBV152, after meeting the pre-defined efficacy success criteria, the DSMB and sponsor decided to unblind those placebo participants who were eligible to receive an approved COVID-19 vaccine. Unblinding in such cohorts was planned only after the accrual of the protocol pre-specified 130 cases, in a phased manner: health care professionals, individuals ≥45 years, followed by those <45 years. Our sample estimations accounted for 20% seropositivity. As we observed baseline seropositivity rates of 30% and due to the u...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04641481 Active, not recruiting An Efficacy and Safety Clinical Trial of an Investigational … NCT04471519 Active, not recruiting Whole-Virion Inactivated SARS-CoV-2 Vaccine (BBV152) for COV… 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.
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