RESUMEN
BackgroundWe 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). MethodsWe 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. FindingsBetween 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{middle dot}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{middle dot}8% (95% CI: 65{middle dot}2-86{middle dot}4). Sixteen cases, one vaccinee and 15 placebo recipients, met the severe symptomatic COVID-19 case definition giving a vaccine efficacy of 93{middle dot}4% (57{middle dot}1-99{middle dot}8). Efficacy against asymptomatic COVID-19 was 63{middle dot}6% (29{middle dot}0-82{middle dot}4). BBV152 conferred 65{middle dot}2% (95% CI: 33{middle dot}1-83{middle dot}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. InterpretationBBV152 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. FundingThis work was supported and funded by Bharat Biotech International Limited and partly co-funded by the Indian Council of Medical Research. Clinicaltrials.gov: NCT04641481
RESUMEN
BackgroundBBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 {micro}g or 6 {micro}g) 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}g and 6 {micro}g with Algel-IMDG. MethodsWe 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}g with Algel-IMDG and 6 {micro}g 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). FindingsAmong 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{middle dot}9% (88{middle dot}2, 96{middle dot}2) and 98{middle dot}3% (95{middle dot}1, 99{middle dot}6) in the 3 {micro}g and 6 {micro}g 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{middle dot}9, 13{middle dot}2) and 10.3% (7{middle dot}4, 13{middle dot}8) in the 3 {micro}g and 6 {micro}g 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{middle dot}5% (63{middle dot}6, 81{middle dot}9), 81{middle dot}1% (71{middle dot}4, 88{middle dot}1), and 73{middle dot}1% (62{middle dot}9, 81{middle dot}8) of individuals in the 3 {micro}g with Algel-IMDG, 6 {micro}g with Algel-IMDG, and 6 {micro}g with Algel groups, respectively. InterpretationIn 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}g Algel-IMDG formulation was selected for the phase 3 efficacy trial. FundingThis work was supported and funded by Bharat Biotech International Limited. Clinicaltrials.gov: NCT04471519
