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

Background BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 mu g or 6 mu g) 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 mu g with Algel-IMDG, 6 mu g with Algel-IMDG, or 6 mu g 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 mu g and 6 mu g 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 mu g with Algel-IMDG or 6 mu g 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 mu g with Algel-IMDG group (n=190) or 6 mu g with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT50) at day 56 were significantly higher in the 6 mu g with Algel-IMDG group (197.0 [95% CI 155.6-249.4]) than the 3 mu g 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 mu g with Algel-IMDG group and 174 (98.3% [95.1-99.6]) of 177 participants in the 6 mu g with Algel-IMDG group. GMTs (MNT50) at day 56 were 92.5 (95% CI 77.7-110.2) in the 3 mu g with Algel-IMDG group and 160.1 (135.8-188.8) in the 6 mu g 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 mu g with Algel-IMDG group and 171 (96.6% [92.8-98.8]) of 177 participants in the 6 mu g with Algel-IMDG group. The 3 mu g with Algel-IMDG and 6 mu g 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 mu g with Algel-IMDG group (38 [20.0%; 95% CI 14.7-26.5] of 190) and the 6 mu g 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 3 mu g with Algel-IMDG group, 69.5 (53.7-89.9) in the 6 mu g with Algel-IMDG group, 53.3 (40.1-71.0) in the 6 mu g 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 mu g with Algel-IMDG formulation has been selected for the phase 3 efficacy trial. Copyright (C) 2021 Elsevier Ltd. All rights reserved.