Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial

Abstract

Background: To mitigate the effects of COVID-19, a vaccine is urgently needed. BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or alum (Algel).

Methods: We did a double-blind, multicentre, randomised, controlled phase 1 trial to assess the safety and immunogenicity of BBV152 at 11 hospitals across India. Healthy adults aged 18-55 years who were deemed healthy by the investigator were eligible. Individuals with positive SARS-CoV-2 nucleic acid and/or serology tests were excluded. Participants were randomly assigned to receive either one of three vaccine formulations (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) or an Algel only control vaccine group. Block randomisation was done with a web response platform. Participants and investigators were masked to treatment group allocation. Two intramuscular doses of vaccines were administered on day 0 (the day of randomisation) and day 14. Primary outcomes were solicited local and systemic reactogenicity events at 2 h and 7 days after vaccination and throughout the full study duration, including serious adverse events. Secondary outcome was seroconversion (at least four-fold increase from baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot. The trial is registered at ClinicalTrials.gov (NCT04471519).

Findings: Between July 13 and 30, 2020, 827 participants were screened, of whom 375 were enrolled. Among the enrolled participants, 100 each were randomly assigned to the three vaccine groups, and 75 were randomly assigned to the control group (Algel only). After both doses, solicited local and systemic adverse reactions were reported by 17 (17%; 95% CI 10·5-26·1) participants in the 3 μg with Algel-IMDG group, 21 (21%; 13·8-30·5) in the 6 μg with Algel-IMDG group, 14 (14%; 8·1-22·7) in the 6 μg with Algel group, and ten (10%; 6·9-23·6) in the Algel-only group. The most common solicited adverse events were injection site pain (17 [5%] of 375 participants), headache (13 [3%]), fatigue (11 [3%]), fever (nine [2%]), and nausea or vomiting (seven [2%]). All solicited adverse events were mild (43 [69%] of 62) or moderate (19 [31%]) and were more frequent after the first dose. One serious adverse event of viral pneumonitis was reported in the 6 μg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel groups, respectively. CD4⁺ and CD8⁺ T-cell responses were detected in a subset of 16 participants from both Algel-IMDG groups.

Interpretation: BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted.

Funding: Bharat Biotech International.

Figure 1

Trial profile Due to a sudden increase in interest from potential participants, parallel enrolment at several sites, and an oversight in the trial software, 27 of the 132 people who reached target enrolment after the planned size of 375 people was reached received a first dose and 26 of them a second dose. They were not included in further safety or immunogenicity trial data, but were monitored for safety with 3 people reporting injection site pain and 1 person a tingling sensation after the first dose, and 1 person drowsiness, 2 people headache, and 1 person injection site pain after the second dose. No serious adverse events occurred. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. *Unable to contact the participant for vaccination or withdrawal of consent.

Figure 2

SARS-CoV-2 IgG titres against anti-spike protein (A), receptor-binding domain (B), and nucleocapsid IgG (C) and anti-spike protein IgG1/IgG4 ratio (D) ELISA results at baseline (day 0) and 2 weeks after the second vaccination (day 28). In A–C, error bars show 95% CIs. The cutoff for detectable antibodies was 1/500. Some samples were positive for SARS-CoV-2 in the control group, as evident by the antibody titres on day 28. Endpoint titre dilution for day 28 sera samples was established with baseline (day 0), interpolated from the absorbance of the corresponding day 0 sample. Cutoff (mean ± 3 SD) for day 0 was calculated considering the absorbance of all sera dilutions (1/500 to 1/32000) tested, except the lowest dilution (1/500). ELISA titres (endpoint titres) on day 14 were not analysed. In D, the isotyping ratio was calculated (in a randomly selected subset) as IgG1/IgG4; dots show the individual datapoints and horizontal bars show means with error bars for 95% CIs. Endpoint titre=the highest sera dilution at which the absorbance was above the cutoff. GMT=geometric mean titre. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

Figure 3

SARS-CoV-2 wild-type MNT₅₀ seroconversion rates (A) and GMT (B) and PRNT₅₀ seroconversion rates (C) and medians (D) Results at baseline (day 0), 2 weeks after the first vaccination (day 14), and 2 weeks after the second vaccination in the immunogenicity cohort. Seroconversion rates were defined by the proportion of titres achieving at least four-fold greater than baseline. In A–C, error bars show 95% CIs. In B, the human convalescent serum panel included specimens from participants with PCR-confirmed symptomatic or asymptomatic COVID-19, obtained at least 30 days after diagnosis (41 samples for MNT₅₀). In D, randomly selected serum samples from day 28 were analysed by PRNT₅₀ at the National Institute of Virology for homologous (NIV-2020-770) and heterologous (nCoV-Q11 and nCoV-Q100) assessments; dots show individual datapoints and horizontal bars show medians with error bars for IQRs. GMT=geometric mean titre. MNT₅₀=microneutralisation assay. PRNT₅₀=plaque-reduction neutralisation test. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.