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Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial.
Lancet Infect Dis. 2021 07; 21(7):950-961.LI

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.

Authors+Show Affiliations

Bharat Biotech, Hyderabad, India.Bharat Biotech, Hyderabad, India.Bharat Biotech, Hyderabad, India.Bharat Biotech, Hyderabad, India.Bharat Biotech, Hyderabad, India.Bharat Biotech, Hyderabad, India.Bharat Biotech, Hyderabad, India.Bharat Biotech, Hyderabad, India.Bharat Biotech, Hyderabad, India.Indian Council of Medical Research-National Institute of Virology, Pune, India.Indian Council of Medical Research-National Institute of Virology, Pune, India.Nizams Institute of Medical Sciences, Hyderabad, India.Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, India.All India Institute of Medical Sciences, Patna, India.Redkar Hospital, Dargalim, India.Gillurkar Hospital, Nagpur, India.Prakhar Hospital, Kanpur, India.SRM Hospital and Research Centre, Kattankulathur, India.Jeevan Rekha Hospital, Belgaum, India.All India Institute of Medical Sciences, New Delhi, India.Indian Council of Medical Research, New Delhi, India.Indian Council of Medical Research-National Institute of Virology, Pune, India.Indian Council of Medical Research, New Delhi, India.Bharat Biotech, Hyderabad, India.Indian Council of Medical Research, New Delhi, India.Bharat Biotech, Hyderabad, India. Electronic address: kmohan@bharatbiotech.com.

Pub Type(s)

Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33705727

Citation

Ella, Raches, et al. "Safety and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine, BBV152: Interim Results From a Double-blind, Randomised, Multicentre, Phase 2 Trial, and 3-month Follow-up of a Double-blind, Randomised Phase 1 Trial." The Lancet. Infectious Diseases, vol. 21, no. 7, 2021, pp. 950-961.
Ella R, Reddy S, Jogdand H, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial. Lancet Infect Dis. 2021;21(7):950-961.
Ella, R., Reddy, S., Jogdand, H., Sarangi, V., Ganneru, B., Prasad, S., Das, D., Raju, D., Praturi, U., Sapkal, G., Yadav, P., Reddy, P., Verma, S., Singh, C., Redkar, S. V., Gillurkar, C. S., Kushwaha, J. S., Mohapatra, S., Bhate, A., ... Vadrevu, K. M. (2021). Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial. The Lancet. Infectious Diseases, 21(7), 950-961. https://doi.org/10.1016/S1473-3099(21)00070-0
Ella R, et al. Safety and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine, BBV152: Interim Results From a Double-blind, Randomised, Multicentre, Phase 2 Trial, and 3-month Follow-up of a Double-blind, Randomised Phase 1 Trial. Lancet Infect Dis. 2021;21(7):950-961. PubMed PMID: 33705727.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial. AU - Ella,Raches, AU - Reddy,Siddharth, AU - Jogdand,Harsh, AU - Sarangi,Vamshi, AU - Ganneru,Brunda, AU - Prasad,Sai, AU - Das,Dipankar, AU - Raju,Dugyala, AU - Praturi,Usha, AU - Sapkal,Gajanan, AU - Yadav,Pragya, AU - Reddy,Prabhakar, AU - Verma,Savita, AU - Singh,Chandramani, AU - Redkar,Sagar Vivek, AU - Gillurkar,Chandra Sekhar, AU - Kushwaha,Jitendra Singh, AU - Mohapatra,Satyajit, AU - Bhate,Amit, AU - Rai,Sanjay, AU - Panda,Samiran, AU - Abraham,Priya, AU - Gupta,Nivedita, AU - Ella,Krishna, AU - Bhargava,Balram, AU - Vadrevu,Krishna Mohan, Y1 - 2021/03/08/ PY - 2020/12/21/received PY - 2021/01/29/revised PY - 2021/02/01/accepted PY - 2021/3/12/pubmed PY - 2021/7/2/medline PY - 2021/3/11/entrez SP - 950 EP - 961 JF - The Lancet. Infectious diseases JO - Lancet Infect Dis VL - 21 IS - 7 N2 - 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. SN - 1474-4457 UR - https://www.unboundmedicine.com/medline/citation/33705727/Safety_and_immunogenicity_of_an_inactivated_SARS_CoV_2_vaccine_BBV152:_interim_results_from_a_double_blind_randomised_multicentre_phase_2_trial_and_3_month_follow_up_of_a_double_blind_randomised_phase_1_trial_ DB - PRIME DP - Unbound Medicine ER -