Immunogenicity and reactogenicity of an inactivated SARS-CoV-2 vaccine (BBV152) in children aged 2-18 years: interim data from an open-label, non-randomised, age de-escalation phase 2/3 study

Abstract

Background: Despite having milder symptoms than adults, children are still susceptible to and can transmit SARS-CoV-2. Vaccination across all age groups is therefore necessary to curtail the pandemic. Among the available COVID-19 vaccine platforms, an inactivated vaccine platform has the advantage of excellent safety profile across all age groups; hence, we conducted an age de-escalation study to assess the safety, reactogenicity, and immunogenicity of an inactivated COVID-19 vaccine, BBV152 (COVAXIN; Bharat Biotech International, Hyderabad, India), in children aged 2-18 years.

Methods: In this phase 2/3 open-label, non-randomised, multicentre study done in six hospitals in India, healthy children (male or female) aged 2-18 years were eligible for inclusion into the study. Children who had positive SARS-CoV-2 nucleic acid and serology tests at baseline, or any history of previous SARS-CoV-2 infection, or with known immunosuppressive condition were excluded. Children were sequentially enrolled into one of three groups (>12 to ≤18 years [group 1], >6 to 12 years [group 2], or ≥2 to 6 years [group 3]) and administered with adult formulation of BBV152 as two 0·5 mL intramuscular doses on days 0 and 28. Co-primary endpoints were solicited adverse events for 7 days post-vaccination and neutralising antibody titres on day 56, 28 days after the second dose. Immunogenicity endpoints were compared with Biodefense and Emerging Infections, Research Resources Repository (BEI) reference serum samples and from adults who received two doses of BBV152 in the same schedule in a previously reported phase 2 study. The trial is registered with the Clinical Trials Registry, India (CTRI/2021/05/033752) and ClinicalTrials.gov (NCT04918797).

Findings: From May 27, 2021, to July 10, 2021, we enrolled 526 children sequentially into groups 1 (n=176), 2 (n=175), and 3 (n=175). Vaccination was well tolerated, with no differences in reactogenicity between the three age groups, and no serious adverse events, deaths, or withdrawals due to an adverse event. Local reactions mainly consisted of mild injection site pain in 46 (26%) of 176 participants in group 1, 61 (35%) of 175 in group 2, and 39 (22%) of 175 in group 3 after dose 1; and 39 (22%) of 176 in group 1, 43 of 175 (25%) in group 2, and 14 of 175 (8%) in group 3 after dose 2; there were no cases of severe pain and few reports of other local reactions. After dose 1, the most frequent solicited systemic adverse event was mild-to-moderate fever, reported in eight (5%) of 176 participants in group 1, 17 (10%) of 175 in group 2, and 22 (13%) of 175 in group 3. No case of severe fever was reported, and rates of all fever were all 4% or less after dose 2. Geometric mean titres (GMTs) of microneutralisation antibodies at day 56 in groups 1 (138·8 [95% CI 111·0-173·6]), 2 (137·4 [99·1-167·5]), and 3 (197·6 [176·4-221·4]) were similar to titres in vaccinated adults (160·1 [135·8-188·8]) and with BEI reference serum samples (103·3 [50·3-202·1]). Similar results were obtained using the plaque reduction neutralisation test (PRNT), in which 166 (95%) of 175 participants in group 1, 165 (98%) of 168 in group 2, and 169 (98%) of 172 in group 3 seroconverted at day 56. The GMT ratio of PRNT titres in children and adults was 1·76 (95% CI 1·32-2·33), indicating a superior response in children compared with adults.

Interpretation: BBV152 was well tolerated in children aged 2-18 years, and induced higher neutralising antibody responses than those observed in adults, in whom the efficacy (ie, the prevention or decrease in the severity of COVID-19 infection) has been demonstrated.

Funding: Bharat Biotech International.

Conflict of interest statement

Declaration of interests This work was funded by Bharat Biotech International. KMV, SRe, BG, HJ, and SPrasad, are employees of Bharat Biotech, with no stock options or incentives. Co-author, KE, is the Chairman and Managing Director of Bharat Biotech and owns equity in the company. RE and WB are independent clinical development and statistical consultants, respectively (who received fees from Bharat Biotech). NM, VNT, CS, VK, SPrasan, and SRa were principal investigators representing the study sites.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Study flow chart Chart shows the sequential enrolment of the three age groups initially in phase 2, then in phase 3, following approval by the data safety monitoring board. *After completion of participant recruitment to group 1, the study progressed to the recruitment of participants for group 2. †After completion of participant recruitment to group 2, the study progressed to the recruitment of participants for group 3. ‡More potential participants were screened than were required for the protocol numbers (the sample size had been achieved); hence, these participants were not enrolled. §After completion of 7 days post first dose for 25 participants in group 1, safety data of these participants were reviewed by data safety monitoring board, and based on their recommendation, the study progressed by enrolling an additional 151 participants to group 1. ¶After completion of 7 days post first dose for 25 participants in group 2, safety data of these participants were reviewed by data safety monitoring board, and based on their recommendation, the study progressed to enrolling an additional 150 participants to group 2.

Figure 2

Solicited reactogenicity Occurrence of solicited reaction is shown by severity in the three age groups in the 7 days after the first and second doses of BBV152 in groups 1 (>12–18 years), 2 (>6–12 years), and 3 (≥2–6 years).

Figure 3

Geometric mean titres of SARS-CoV-2 neutralising antibodies Levels of antibodies were measured by MNT50, (A) or PRNT50 (B) at baseline (day 0) and days 28 and 56 following two doses of BBV152 in group 1 (>12–18 years), group 2 (>6–12 years), and group 3 (≥2–6 years). Bars indicate 95% CIs. MNT50 GMT for 18 BEI samples are shown as a dotted line in (A) with 95% CI indicated by shading. MNT50=microneutralisation. PRNT50=plaque reduction.

Figure 4

GMT of IgG antibodies IgG antibodies were measured by ELISA against SARS-CoV-2 S-protein (A), receptor-binding domain (B), or nucleocapsid protein (C) at baseline (day 0) and days 28 and 56 after two doses of BBV152 in group 1 (>12–18 years), group 2 (>6–12 years), and group 3 (≥2–6 years). Bars indicate 95% CIs. Groups were measured at the same timepoints, but are separated laterally for clarity. GMT=geometric mean titre.