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

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 (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 μg and 6 μg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28.

Methods: We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12-65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 μg with Algel-IMDG or 6 μg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT₅₀) and the microneutralisation test (MNT₅₀). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov, NCT04471519.

Findings: Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 μg with Algel-IMDG group (n=190) or 6 μg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT₅₀) at day 56 were significantly higher in the 6 μg with Algel-IMDG group (197·0 [95% CI 155·6-249·4]) than the 3 μg with Algel-IMDG group (100·9 [74·1-137·4]; p=0·0041). Seroconversion based on PRNT₅₀ at day 56 was reported in 171 (92·9% [95% CI 88·2-96·2] of 184 participants in the 3 μg with Algel-IMDG group and 174 (98·3% [95·1-99·6]) of 177 participants in the 6 μg with Algel-IMDG group. GMTs (MNT₅₀) at day 56 were 92·5 (95% CI 77·7-110·2) in the 3 μg with Algel-IMDG group and 160·1 (135·8-188·8) in the 6 μg with Algel-IMDG group. Seroconversion based on MNT₅₀ at day 56 was reported in 162 (88·0% [95% CI 82·4-92·3]) of 184 participants in the 3 μg with Algel-IMDG group and 171 (96·6% [92·8-98·8]) of 177 participants in the 6 μg with Algel-IMDG group. The 3 μg with Algel-IMDG and 6 μg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 μg with Algel-IMDG group (38 [20·0%; 95% CI 14·7-26·5] of 190) and the 6 μg with Algel-IMDG group (40 [21·1%; 15·5-27·5] of 190) was observed on days 0-7 and days 28-35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT₅₀) were 39·9 (95% CI 32·0-49·9) in the 3μg with Algel-IMDG group, 69·5 (53·7-89·9) in the 6 μg with Algel-IMDG group, 53·3 (40·1-71·0) in the 6 μg with Algel group, and 20·7 (14·5-29·5) in the Algel alone group.

Interpretation: In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 μg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial.

Funding: Bharat Biotech International.

Translation: For the Hindi translation of the abstract see Supplementary Materials section.

Figure 1

Trial profile *Caused by cold chain excursions during transport of the nasopharyngeal swabs from the field site to the central laboratory. †Due to competitive recruitment, all sites were screening participants individually; therefore, there was an excess of eligible participants who were not enrolled because the recruitment target was met.

Figure 2

SARS-CoV-2 wild-type PRNT₅₀ GMTs (A), and seroconversion rates (B), and wild-type MNT₅₀ GMTs (C) and seroconversion rates (D) SARS-CoV-2 wild-type PRNT₅₀and MNT₅₀ GMTs 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) in the 3 μg with Algel-IMDG (n=190) and 6 μg (n=190) with Algel-IMDG groups are shown. Seroconversion rates were defined by the proportion of post-vaccination titres that were at least four-fold higher than baseline. In A and C, the human convalescent sera panel included specimens from participants with PCR-confirmed symptomatic and asymptomatic COVID-19 obtained at least 30–60 days after diagnosis (50 samples); dots represent individual datapoints, the horizontal bars show the GMTs, and the error bars represent the 95% CIs. In B and D, the dots represent the seroconversion rates and error bars represent 95% CIs. PRNT₅₀=plaque-reduction neutralisation test. GMT=geometric mean titre. MNT₅₀=microneutralisation assay.

Figure 3

Th1/Th2 cytokine ratios (A) and mean Th1 and Th2 cytokine levels (B) at day 42 in phase 2 participants In A and B, cell-mediated responses in blood samples from 58 participants (29 each from the 3 μg with Algel-IMDG and 6 μg with Algel-IMDG groups), with proliferative responses to vaccination at 2 weeks after the second dose (day 42), and in ten control participants (five pre-vaccination samples from each group) are shown. In A, the Th1/Th2 ratio was calculated by the sum of IFNγ plus IL-2 cytokine levels divided by the sum of IL-5 plus IL-13 cytokine levels; horizontal bars show the mean ratios and error bars show the 95% CIs. In B, mean cytokine levels in the cell culture supernatants obtained from PBMCs stimulated with SARS-CoV-2 peptides are shown; Th1 (IFNγ, IL-2, and TNFα) and Th2 (IL-5, IL-13, and IL-10) cytokines are represented by stacked bars. Th=T-helper. IFNγ=interferon-γ. TNFα=tumour necrosis factor-α. IL=interleukin.

Figure 4

SARS-CoV-2 wild-type MNT₅₀ GMTs (A) and seroconversion rates (B) in phase 1 participants, SARS-CoV-2 wild-type MNT₅₀ GMTs in phase 1 and phase 2 participants at 4 weeks after the second vaccination (C), and the proportion of CD4⁺ CD45RO⁺ (D) and CD4⁺ CD45RO⁺ CD27⁺ (E) T cells at day 104 in phase 1 participants In the phase 1 trial, the dosing schedule was day 0 for the first dose of the vaccine and day 14 for the second dose. In the phase 2 trial, the dosing schedule was day 0 for the first dose of the vaccine and day 28 for the second dose. In A, results at baseline (day 0), 2 weeks after the second vaccination (day 28), 4 weeks after the second vaccination (day 42), and 3 months after the second vaccination (day 104) for the 3 μg and 6 μg with Algel-IMDG groups, the 6 μg with Algel group, and the Algel-only control group in the phase 1 trial are shown. The human convalescent serum panel included specimens from participants with PCR-confirmed symptomatic and asymptomatic COVID-19 obtained at least at least 30 days after diagnosis (41 samples). In B, seroconversion rates were defined by the proportion of post-vaccination titres that were at least four-fold higher than baseline. In D and E, the frequencies of antigen-specific T-cell memory responses at 3 months after the second dose (day 104) in all groups from the phase 1 trial are shown; dots are individual datapoints, and horizontal bars are medians with error bars for IQRs. GMT=geometric mean titre. MNT50=microneutralisation assay.