The WHO pre-qualified rotavirus vaccine, ROTAVAC®, is derived naturally from the neonatal 116E rotavirus strain, and stored at −20°C. As refrigerator storage is preferable, immunogenicity and safety of liquid formulations kept at 2–8°C, having excipients to stabilize the rotavirus, with or without buffers, were compared with ROTAVAC® in different clinical studies. Study-1, the pivotal trial for this entire product development work, was a randomized, single-blind trial with two operationally seamless phases: (i) an exploratory phase involving 675 infants in which two formulations, ROTAVAC 5C (LnHRV-1.5 mL and LnHRV-2.0 mL) containing buffer and excipients to stabilize the virus against gastric acidity and temperature, were compared with ROTAVAC®. As the immune response of ROTAVAC 5C (LnHRV-2.0 mL) was non-inferior to ROTAVAC®, it was selected for (ii) confirmatory phase, involving 1,302 infants randomized 1:1:1:1 to receive three lots of LnHRV-2.0 mL, or ROTAVAC®. Primary objectives were the evaluation of non-inferiority and lot-to-lot consistency. The secondary objectives were to assess the safety and interference with the concomitant pentavalent vaccine. As it was separately established that buffers are not required for ROTAVAC®, in Study-2, the safety and immunogenicity of ROTAVAC 5D® (with excipients) were compared with ROTAVAC® and lot-to-lot consistency was assessed in another study. All lots elicited consistent immune responses, did not interfere with UIP vaccines, and had reactogenicity similar to ROTAVAC®. ROTAVAC 5C and ROTAVAC 5D® were immunogenic and well tolerated as ROTAVAC®. ROTAVAC 5D® had comparable immunogenicity and safety profiles with ROTAVAC® and can be stored at 2–8°C, leading to WHO pre-qualification.
Background: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a TLR 7/8 agonist molecule adsorbed to alum (Algel-IMDG). Methods We 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 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg 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. Results: Reactogenicity 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-μg and 6-μg 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. Conclusions BBV152 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°C and 8°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.
Abstract Background Neutralising 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. Methods In 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 (PRNT 50 ) four weeks after the booster; safety as serious adverse events (SAE) was the key secondary outcome. Findings Four weeks after a second BBV152 vaccination geometric mean titres (GMTs) of neutralising antibodies were 197·0 PRNT 50 (95% CI: 155·6–249·4); this level declined to 23·9 PRNT 50 (14·0–40·6) six months later, with a seroconversion rate of 75·4% (95% CI: 68·4–81·6). Four weeks after booster vaccination the GMT increased on Day 243 to 746·6 PRNT 50 (514·9–1081) compared with 100·7 PRNT 50 (43·6–232·6) in the placebo group. Corresponding seroconversion rates were 98·7% (92·8–99·9) and 79·8% (69·6–87·8). 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. PRNT 50 titres against the SARS-CoV-2 variants increased—Alpha (32·6-fold), Beta (161·0-fold), Delta (264·7-fold), and Delta plus (174·2-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+ T EMRA phenotype. Reactogenicity after vaccine and placebo was minimal and comparable, and no SAEs were reported. Interpretation Six 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. Funding This work was supported and funded by Bharat Biotech International Limited.
Serum IgG anti-Vi titers attained by 327 children 6-23 months of age immunized with Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar TCV®), of whom 193/327 received a booster dose 2 years post-primary vaccination, were previously reported.Anti-Vi IgG in boosted and unboosted children 3, 5, and 7 years post-primary immunization were monitored using three different enzyme-linked immunosorbent assays (ELISAs): Vacczyme™ kit ELISA (all specimens); "Szu" ELISA (all specimens), and National Institute of Biological Standards NIBSC ELISA (subset). Endpoints analyzed included: persisting seroconversion (titer remaining ≥ 4-fold above baseline), geometric mean titer (GMT), geometric mean-fold rise post-vaccination, and percent exhibiting putative protective anti-Vi level (≥2 µgSzu/ml) using Szu method and National Institutes of Health IgG reference standard. In assessing the persistence of elevated anti-Vi titers stimulated by Typbar-TCV®, four subgroups were compared based on whether or not the initially enrolled children were boosted on day 720 and whether they provided serum on all key timepoints, or if they missed one or more timepoints: i) Among boosted participants, an "All Specimens Cohort" (ASC) comprised 86 children who provided sera on days 42, 720 (booster), 762 (42 days post-booster), 1095, 1825 and 2555, to define kinetics of the Vi antibody response in a fully compliant cohort of boosted children monitored over seven years; ii) Among non-boosted subjects, a compliant All Specimens Cohort of 25 children provided sera on days 0, 42, 720, 1095, 1825, and 2555; iii) Among boosted children, an "Any Available Specimen" (AAS) subgroup consisted of boosted children who provided sera on days 0, 42, and 720 days and also on one or more of days 762, 1095, 1825, or 2555 but not on all those time points; iv) Among the non-boosted subjects, there was also an Any Available Specimen subgroup of 47 children who provided sera on days 0 and 42, of whom 41 subsequently contributed sera on one or more of days 1095, 1825 and 2555.Vacczyme™ GMTs among boosted ASC children (N = 86) increased significantly on day 762, and remained 32-fold, 14-fold, and 10-fold over baseline at 3, 5 and 7 years; among unboosted ASC children (N = 25), GMTs remained 21-fold, 8-fold and 5-fold over baseline, respectively. Post-primary vaccination, 72% and 44% of unboosted ASC subjects (N = 25) exhibited persisting seroconversion by Vacczyme™ at 5 and 7 years, respectively; the corresponding numbers for ASC boosted subjects were 84% and 71%. Amongst the four sub-groups, boosted subjects showed higher prevalence of persisting seroconversion at most time points with the gap widening by 7th year, though not statistically significant (except 3rd year). Tested by Szu and also NIBSC ELISAs, 92-100% of unboosted ASC children showed persisting seroconversion at 7 years with 100% also exceeding the Szu protective threshold.To extend protection, administering a booster of Typbar TCV® to children ∼5 years after their primary dose, i.e., coinciding with school entry, may be advisable. Typbar TCV® is presently the only WHO pre-qualified Vi conjugate vaccine with reported efficacy, effectiveness, and long-term immunogenicity findings.
The availability of a safe and effective vaccine would be the eventual measure to deal with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) threat. Here, we have assessed the immunogenicity and protective efficacy of inactivated SARS-CoV-2 vaccine candidates BBV152A, BBV152B, and BBV152C in Syrian hamsters. Three dose vaccination regimes with vaccine candidates induced significant titers of SARS-CoV-2-specific IgG and neutralizing antibodies. BBV152A and BBV152B vaccine candidates remarkably generated a quick and robust immune response. Post-SARS-CoV-2 infection, vaccinated hamsters did not show any histopathological changes in the lungs. The protection of the hamster was evident by the rapid clearance of the virus from lower respiratory tract, reduced virus load in upper respiratory tract, absence of lung pathology, and robust humoral immune response. These findings confirm the immunogenic potential of the vaccine candidates and further protection of hamsters challenged with SARS-CoV-2. Of the three candidates, BBV152A showed the better response.
ABSTRACT 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). Methods We 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. Findings Between 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 (0·77%) 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 77·8% (95% CI: 65·2–86·4). Sixteen cases, one vaccinee and 15 placebo recipients, met the severe symptomatic COVID-19 case definition giving a vaccine efficacy of 93·4% (57·1–99·8). Efficacy against asymptomatic COVID-19 was 63·6% (29·0–82·4). BBV152 conferred 65·2% (95% CI: 33·1–83·0) 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. Interpretation BBV152 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. Funding This work was supported and funded by Bharat Biotech International Limited and partly co-funded by the Indian Council of Medical Research. Clinicaltrials.gov : NCT04641481
This study reports immunogenicity, safety, and interchangeability of a single-dose, inactivated, Vero-cell derived, JENVAC to the live-attenuated SA 14-14-2 vaccine in healthy children.This phase 4, multicenter, open-label, randomized, control trial enrolled 360 children who were equally randomized to receive a single dose of either JENVAC or SA 14-14-2. Children were followed at various time points, until 2 years (day 720) postvaccination, upon which a subset from each group was divided and allocated to a receive a booster dose or the other vaccine.At all time points, immunological measures were statistically higher in the JENVAC group. In the interchangeability study, children receiving 2 doses of JENVAC reported significantly higher response compared with 2 doses of SA 14-14-2. No difference in adverse events was observed. These corroborate with excellent seroprotection after the first dose of an earlier JENVAC study.A single-dose vaccination with JENVAC induces protective titers that persist up to 1 year. We report appreciable interchangeability between both vaccines, with JENVAC/JENVAC combination exhibiting the highest immune response. JENVAC is now licensed as a single-dose Japanese encephalitis vaccine.
ABSTRACT Background We 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. Methods This 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 ® , 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). Findings There 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 1·76 (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. Interpretation BBV152 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.
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