Protective efficacy of COVAXIN(R) against Delta and Omicron variants in hamster model

The immunity acquired after natural infection or vaccinations against SARS-CoV-2 tend to wane with time. Vaccine effectiveness also varies with the variant of infection. Here, we compared the protective efficacy of COVAXIN(R) following 2 and 3 dose immunizations against the Delta variant and also studied the efficacy of COVAXIN(R) against Omicron variants in a Syrian hamster model. The antibody response, clinical observations, viral load reduction and lung disease severity after virus challenge were studied. Protective response in terms of the reduction in lung viral load and lung lesions were observed in both the 2 dose as well as 3 doses COVAXIN(R) immunized group when compared to placebo group following the Delta variant challenge. In spite of the comparable neutralizing antibody response against the homologous vaccine strain in both the 2 dose and 3 dose immunized groups, considerable reduction in the lung disease severity was observed in the 3 dose immunized group post Delta variant challenge indicating the involvement of cell mediated immune response also in protection. In the vaccine efficacy study against the Omicron variants i.e., BA.1 and BA.2, lesser virus shedding, lung viral load and lung disease severity were observed in the immunized groups in comparison to the placebo groups. The present study shows that administration of COVAXIN(R) booster dose will enhance the vaccine effectiveness against the Delta variant infection and give protection against the Omicron variants BA.1.1 and BA.2.

Persistence of immunity and impact of a third (booster) dose of an inactivated SARS-CoV-2 vaccine, BBV152; a phase 2, double-blind, randomised controlled trial

BackgroundNeutralising antibody responses to SARS-CoV-2 vaccines have been reported to decline within 6 months of vaccination, particularly against Variants of Concern (VOC). We assessed the immunogenicity and safety of a booster dose of BBV152 administered 6 months after the second of a two-dose primary vaccination series. MethodsIn an ongoing phase 2 trial (ClinicalTrials.gov: NCT04471519) the protocol was amended after six months to re-consent and randomise 184 previously vaccinated participants to receive a third dose of vaccine or placebo on Day 215. The primary outcome was to measure neutralising antibody titres by plaque-reduction neutralisation test (PRNT50) four weeks after the booster; safety as serious adverse events (SAE) was the key secondary outcome. FindingsFour weeks after a second BBV152 vaccination geometric mean titres (GMTs) of neutralising antibodies were 197{middle dot}0 PRNT50 (95% CI: 155{middle dot}6-249{middle dot}4); this level declined to 23{middle dot}9 PRNT50 (14{middle dot}0-40{middle dot}6) six months later, with a seroconversion rate of 75{middle dot}4% (95% CI: 68{middle dot}4-81{middle dot}6). Four weeks after booster vaccination the GMT increased on Day 243 to 746{middle dot}6 PRNT50 (514{middle dot}9-1081) compared with 100{middle dot}7 PRNT50 (43{middle dot}6-232{middle dot}6) in the placebo group. Corresponding seroconversion rates were 98{middle dot}7% (92{middle dot}8-99{middle dot}9) and 79{middle dot}8% (69{middle dot}6-87{middle dot}8). Increased titres in the placebo group were attributed to natural infection as the study was conducted during the second wave of COVID-19 in India. PRNT50 titres against the SARS-CoV-2 variants increased--Alpha (32{middle dot}6-fold), Beta (161{middle dot}0-fold), Delta (264{middle dot}7-fold), and Delta plus (174{middle dot}2-fold)--after the booster vaccination. We found that vaccine induces both memory B and T cells with a distinct AIM+ specific CD4+T central and effector memory phenotype, including CD8+ TEMRA phenotype. Reactogenicity after vaccine and placebo was minimal and comparable, and no SAEs were reported. InterpretationSix months after a two-dose BBV152 vaccination series cell mediated immunity and neutralising antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta and Delta plus) persisted above baseline, although the magnitude of the responses had declined. Neutralising antibodies against homologous and heterologous SARS-CoV-2 variants increased 19- to 97-fold after a third vaccination. Booster BBV152 vaccination is safe and may be necessary to ensure persistent immunity to prevent breakthrough infections. FundingThis work was supported and funded by Bharat Biotech International Limited.

Immunogenicity and safety of an inactivated SARS-CoV-2 vaccine (BBV152) in children from 2 to 18 years of age: an open-label, age-de-escalation phase 2/3 study

BackgroundWe assessed the safety, reactogenicity, and immunogenicity of BBV152 in an open-label age de-escalation study in three age cohorts of children from 18 years of age down to 2 years of age. MethodsThis was a phase 2/3 open-label, multi-centre study done across six hospitals in India. All children received two 0.5mL doses of BBV152 (Covaxin(R), Bharat Biotech International Ltd., Hyderabad, India), which is the same formulation indicated in adults. Participants were monitored for adverse events, and post-vaccination blood draws were collected to assess neutralising antibodies. A total of 526 children were enrolled into Group 1 (ages 12 through 18 years, n=176), Group 2 (ages 6 through 12 years, n=175), Group 3 (ages 2 through 6 years, n=175). FindingsThere were no serious adverse events, deaths, or withdrawals due to an adverse event during the study. Vaccination with BBV152 was generally well tolerated, with no substantial difference in reactogenicity profiles between the different age groups. Similar immune responses were measured as microneutralisation (MNT) antibody titers in all three age groups. Vaccine-induced MNT responses in all groups were comparable to BEI reference sera run in the same assay. Seroconversion (measured by Plaque Reduction Neutralization Test (PRNT)) achieved high levels (95-98%) in all three groups four weeks after the second vaccination. The PRNT GMT ratio was 1{middle dot}76 (95%CI: 1.32 - 2.33) (GMT all children subgroup / GMT in adults) had a lower limit [≥] 1, indicating superior antibodies in children when compared to adults. Vaccine responses were skewed towards a Th1 response with IgG1/IgG4 ratios above 1. InterpretationBBV152 is well tolerated and immunogenic in children from 18 years down to 2 years of age. Immunogenicity analysis (by PRNT) shows superior antibody responses were observed in children compared to adults, suggesting that BBV152 will also be efficacious in this age group.

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

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

Safety and immunogenicity trial of an inactivated SARS-CoV-2 vaccine-BBV152: a phase 1, double-blind, randomised control trial

BackgroundBBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a TLR 7/8 agonist molecule adsorbed to alum (Algel-IMDG). MethodsWe conducted a double-blind randomized controlled phase 1 clinical trial to evaluate the safety and immunogenicity of BBV152. A total of 375 participants were randomized equally to receive three vaccine formulations (n=100 each) prepared with 3 g with Algel-IMDG, 6 g with Algel-IMDG, and 6 g with Algel, and an Algel only control arm (n=75). Vaccines were administered on a two-dose intramuscular accelerated schedule on day 0 (baseline) and day 14. The primary outcomes were reactogenicity and safety. The secondary outcomes were immunogenicity based on the anti-IgG S1 response (detected with an enzyme-linked immunosorbent assay [ELISA] and wild-type virus neutralization [microneutralization and plaque reduction neutralization assays]). Cell-mediated responses were also evaluated. ResultsReactogenicity was absent in the majority of participants, with mild events. The majority of adverse events were mild and were resolved. One serious adverse event was reported, which was found to be unrelated to vaccination. All three vaccine formulations resulted in robust immune responses comparable to a panel of convalescent serum. No significant differences were observed between the 3-g and 6-g Algel-IMDG groups. Neutralizing responses to homologous and heterologous SARS-CoV-2 strains were detected in all vaccinated individuals. Cell-mediated responses were biased to a Th-1 phenotype. ConclusionsBBV152 induced binding and neutralising antibody responses and with the inclusion of the Algel-IMDG adjuvant, this is the first inactivated SARS-CoV-2 vaccine that has been reported to induce a Th1-biased response. Vaccine induced neutralizing antibody titers were reported with two divergent SARS-CoV-2 strains. BBV152 is stored between 2{degrees}C and 8{degrees}C, which is compatible with all national immunization program cold chain requirements. Both Algel-IMDG formulations were selected for the phase 2 immunogenicity trials. Further efficacy trials are underway. Clinicaltrials.gov: NCT04471519

Evaluation of Safety and Immunogenicity of an Adjuvanted, TH-1 Skewed, Whole Virion Inactivated SARS-CoV-2 Vaccine - BBV152

We report the development and evaluation of safety and immunogenicity of a whole virion inactivated SARS-COV-2 vaccine (BBV152), adjuvanted with aluminium hydroxide gel (Algel), or a novel TLR7/8 agonist adsorbed Algel. We used a well-characterized SARS-CoV-2 strain and an established vero cell platform to produce large-scale GMP grade highly purified inactivated antigen, BBV152. Product development and manufacturing were carried out in a BSL-3 facility. Immunogenicity was determined at two antigen concentrations (3g and 6g), with two different adjuvants, in mice, rats, and rabbits. Our results show that BBV152 vaccine formulations generated significantly high antigen-binding and neutralizing antibody titers, at both concentrations, in all three species with excellent safety profiles. The inactivated vaccine formulation containing TLR7/8 agonist adjuvant-induced Th1 biased antibody responses with elevated IgG2a/IgG1 ratio and increased levels of SARS-CoV-2 specific IFN-{gamma}+ CD4 T lymphocyte response. Our results support further development for Phase I/II clinical trials in humans.