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

Ella, R.; Reddy, S.; Jogdand, H.; Sarangi, V.; Ganneru, B.; Prasad, S.; Das, D.; Raju, D.; Praturi, U.; Sapkal, G.; Yadav, P.; Reddy, P.; Verma, S.; Singh, C.; Redkar, S. V.; Gillurkar, C. S.; Kushwaha, J. S.; Mohapatra, S.; Rai, S. K.; Bhate, A.; Panda, S.; Abraham, P.; Gupta, N.; Ella, K.; Bhargava, B.; Vadrevu, K. M.

Background BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3{micro} or 6{micro}) 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{micro} and 6{micro} 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{micro} with Algel-IMDG and 6{micro} 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 (PRNT50). 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 PRNT50 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{micro} and 6{micro} 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{micro} and 6{micro} 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{micro} with Algel-IMDG, 6{micro} with Algel-IMDG, and 6{micro} 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{micro} Algel-IMDG formulation was selected for the phase 3 efficacy trial.