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Lancet ; 398(10317): 2173-2184, 2021 12 11.
Article in English | MEDLINE | ID: covidwho-1586227


BACKGROUND: We 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) in Indian adults. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre, phase 3 clinical trial in 25 Indian hospitals or medical clinics to evaluate the efficacy, safety, and immunological lot consistency of BBV152. Adults (age ≥18 years) who were healthy or had stable chronic medical conditions (not an immunocompromising condition or requiring treatment with immunosuppressive therapy) were randomised 1:1 with a computer-generated randomisation scheme (stratified for the presence or absence of chronic conditions) to receive two intramuscular doses of vaccine or placebo administered 4 weeks apart. Participants, investigators, study coordinators, study-related personnel, the sponsor, and nurses who administered the vaccines were masked to treatment group allocation; an unmasked contract research organisation and a masked expert adjudication panel assessed outcomes. The primary outcome was the efficacy of the BBV152 vaccine in preventing a first occurrence of laboratory-confirmed (RT-PCR-positive) symptomatic COVID-19 (any severity), occurring at least 14 days after the second dose in the per-protocol population. We also assessed safety and reactogenicity throughout the duration of the study in all participants who had received at least one dose of vaccine or placebo. This report contains interim results (data cutoff May 17, 2021) regarding immunogenicity and safety outcomes (captured on days 0 to 56) and efficacy results with a median of 99 days for the study population. The trial was registered on the Indian Clinical Trials Registry India, CTRI/2020/11/028976, and, NCT04641481 (active, not recruiting). FINDINGS: Between Nov 16, 2020, and Jan 7, 2021, we recruited 25 798 participants who were randomly assigned to receive BBV152 or placebo; 24 419 received two doses of BBV152 (n=12 221) or placebo (n=12 198). Efficacy analysis was dependent on having 130 cases of symptomatic COVID-19, which occurred when 16 973 initially seronegative participants had at least 14 days follow-up after the second dose. 24 (0·3%) cases occurred among 8471 vaccine recipients and 106 (1·2%) among 8502 placebo recipients, giving an overall estimated vaccine efficacy of 77·8% (95% CI 65·2-86·4). In the safety population (n=25 753), 5959 adverse events occurred in 3194 participants. BBV152 was well tolerated; the same proportion of participants reported adverse events in the vaccine group (1597 [12·4%] of 12 879) and placebo group (1597 [12·4%] of 12 874), with no clinically significant differences in the distributions of solicited, unsolicited, or serious adverse events between the groups, and no cases of anaphylaxis or vaccine-related deaths. INTERPRETATION: BBV152 was highly efficacious against laboratory-confirmed symptomatic COVID-19 disease in adults. Vaccination was well tolerated with no safety concerns raised in this interim analysis. FUNDING: Bharat Biotech International and Indian Council of Medical Research.

COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , Vaccines, Inactivated/immunology , Adjuvants, Immunologic , Adult , COVID-19 Nucleic Acid Testing , Double-Blind Method , Female , Humans , India , Male
In Silico Pharmacol ; 9(1): 40, 2021.
Article in English | MEDLINE | ID: covidwho-1286209


Recent outbreak of 2019 novel Corona virus poses serious challenge for the global health system. In lieu of paucity of experimental data, tools and the very basic understanding of host immune responses against SARS-CoV-2, well thought effective measures are needed to control COVID-19 pandemic. We have identified specific overlapping antigenic peptide epitopes (OAPE) within the 4 structural proteins of SARS-CoV-2 predictive of triggering robust CD4 and CD8 T cell responses in host using bio-informatics tools (NetMHC4.0, IEDB, and Vaxijen2.0). We speculate an early release of pro-inflammatory cytokines for protection and later release of anti-inflammatory cytokines for prevention of immunopathology in designing a vaccine for Covid-19. Therefore, the selected immunogenic OAPE were subjected to in silico tools (IL-6-Pred, IFNepitope and PIP-EL) for analyzing their pro-inflammatory response. The OAPEs found to be pro-inflammatory in nature were further subjected to prediction servers (IL-4-Pred, IL-10-Pred, Pre-AIP) to characterize them as inducers of anti-inflammatory response as well. We finally filtered out 12 OAPE which had affinity for both CD4 and CD8 T cells as well as were inducers of pro-inflammatory and anti-inflammatory cytokines. On confirmation of OAPE binding affinity for respective T cell specific MHC allele using docking studies (pepATTRACT, Hex8.0 and Discovery studio) they were found to be have more immunogenic potential than the 3 negative control peptides (NCPs) included in the study. Additionally, we constructed CTxB-adjuvanated multi-epitopic vaccine inclusive of the 12 OAPEs which was non-toxic, non-allergenic and capable of inducing both pro-inflammatory and anti-inflammatory cytokines. A successful in silico cloning and docking of modeled subunit vaccine construct with toll like receptor-2 (TLR-2) confirmed the high efficacy of our multi-epitopic vaccine which can through a balanced interplay of cytokines help in creating a steady-state immune equilibrium. In silico immune simulation studies with the vaccine using C-ImmSim server also showed higher percentage of T cells along with production of pro-inflammatory as well as some anti-inflammatory cytokines. Experimental validation of this prediction based study on Peripheral Blood Mononuclear Cells (PBMCs) of un-infected individuals, patients and recovered individuals will facilitate production of high priority effective SARS -CoV-2 vaccine candidate. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00098-7.