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Preprint in English | medRxiv | ID: ppmedrxiv-22268777

ABSTRACT

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.

2.
Lancet Infect Dis ; 21(7): 950-961, 2021 07.
Article in English | MEDLINE | ID: covidwho-1290388

ABSTRACT

BACKGROUND: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 µg or 6 µg) formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 µg with Algel-IMDG, 6 µg with Algel-IMDG, or 6 µg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 µg and 6 µg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28. METHODS: We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12-65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 µg with Algel-IMDG or 6 µg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT50) and the microneutralisation test (MNT50). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov, NCT04471519. FINDINGS: Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 µg with Algel-IMDG group (n=190) or 6 µg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT50) at day 56 were significantly higher in the 6 µg with Algel-IMDG group (197·0 [95% CI 155·6-249·4]) than the 3 µg with Algel-IMDG group (100·9 [74·1-137·4]; p=0·0041). Seroconversion based on PRNT50 at day 56 was reported in 171 (92·9% [95% CI 88·2-96·2] of 184 participants in the 3 µg with Algel-IMDG group and 174 (98·3% [95·1-99·6]) of 177 participants in the 6 µg with Algel-IMDG group. GMTs (MNT50) at day 56 were 92·5 (95% CI 77·7-110·2) in the 3 µg with Algel-IMDG group and 160·1 (135·8-188·8) in the 6 µg with Algel-IMDG group. Seroconversion based on MNT50 at day 56 was reported in 162 (88·0% [95% CI 82·4-92·3]) of 184 participants in the 3 µg with Algel-IMDG group and 171 (96·6% [92·8-98·8]) of 177 participants in the 6 µg with Algel-IMDG group. The 3 µg with Algel-IMDG and 6 µg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 µg with Algel-IMDG group (38 [20·0%; 95% CI 14·7-26·5] of 190) and the 6 µg with Algel-IMDG group (40 [21·1%; 15·5-27·5] of 190) was observed on days 0-7 and days 28-35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT50) were 39·9 (95% CI 32·0-49·9) in the 3µg with Algel-IMDG group, 69·5 (53·7-89·9) in the 6 µg with Algel-IMDG group, 53·3 (40·1-71·0) in the 6 µg with Algel group, and 20·7 (14·5-29·5) in the Algel alone group. INTERPRETATION: In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 µg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial. FUNDING: Bharat Biotech International. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19/immunology , Immunogenicity, Vaccine/immunology , SARS-CoV-2/immunology , Vaccines, Inactivated/adverse effects , Vaccines, Inactivated/immunology , Adolescent , Adult , Aged , Antibodies, Neutralizing/immunology , Child , Double-Blind Method , Drug-Related Side Effects and Adverse Reactions/immunology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Th1 Cells/immunology , Th2 Cells/immunology , Vaccination/adverse effects , Young Adult
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