Safety and immunogenicity of booster doses of an XBB.1.5 RBD subunit COVID-19 vaccine among individuals aged 5-80 years in India: a phase 3, single-blind, randomised controlled trial

Abstract

Background: The SARS-CoV-2 virus continues to evolve with recent variants such as the omicron sub-variants potentially exhibiting increased transmissibility. Of note, the XBB.1.5 variant has been associated with vaccine-breakthrough cases. We utilised the same platform previously used to develop CORBEVAX™, an ancestral Wuhan strain COVID-19 RBD subunit vaccine, to now develop an XBB.1.5 RBD subunit vaccine. We evaluated the safety and immunogenicity of the new XBB.1.5 RBD subunit vaccine compared to an ancestral Wuhan strain RBD subunit vaccine.

Methods: This prospective, single-blind, phase 3 randomised controlled trial was conducted in participants aged 5-80 years. Participants who had not received any other approved COVID-19 vaccine within the last 6 months were enrolled and randomised in a 2:1 ratio to receive two booster doses of either the test vaccine or the control vaccine. The vaccines were administered on Day 0 and Day 28 with immunogenicity assessments on Day 0, Day 28, and Day 42. Safety assessments included the collection of solicited and unsolicited adverse events (AEs) up to Day 56. The primary objective of the study was to demonstrate immunogenic superiority of the test vaccine booster series compared to the control vaccine series. This superiority objective was to be met if the lower limit of the two-sided 95% CI of the anti-XBB.1.5.RBD neutralising antibody (nAb) geometric mean titre (GMT) ratio of test: control was >1.0 on either Day 28 or Day 42. Given the emergence of JN.1 as the prevalent SARS-CoV-2 strain during the conduct of this study, Day 42 anti-JN.1 nAb levels were measured in a post hoc immunogenicity assessment. In addition, anti-XBB.1.5 RBD protein IgG concentrations were also measured by ELISA on Day 0, Day 28, and Day 42. The trial was registered at Clinical Trials Registry-India as CTRI/2024/01/061423.

Findings: A total of 360 participants (32.8% female) were enrolled and randomised across seven sites in India. The nAb GMT ratio of test: control participants was 2.08 (95% CI 1.64-2.63) on Day 28 and 2.91 (95% CI 2.38-3.56) on Day 42. The geometric mean fold rise (GMFR) of neutralising antibodies (nAb) was 7.637 (95% CI 6.090-9.578) on Day 28 and 17.02 (95% CI 13.79-21.01) on Day 42 in the test booster series arm. The nAb GMFRs in the control booster series arm at the same time points were 3.033 (95% CI 2.340-3.932) and 4.824 (95% CI 3.731-6.236), respectively. Post hoc analyses revealed an nAb GMT ratio of 1.90 (95% CI 1.56-2.31) for test: control against the JN.1 SARS-CoV-2 strain. The safety profile of the new XBB.1.5 RBD subunit vaccine was found to be very similar to that of the ancestral strain vaccine with 59 AEs (about 1 AE for every 8 doses administered) and 27 AEs (a little less than 1 AE for every 8 doses administered) respectively during the study. No serious AEs or AEs of special interest were reported in either the test or control arm of the study. Two cases of pyrexia required medical attention, one in each arm.

Interpretation: The new XBB.1.5 RBD subunit vaccine was found to be both safe and robustly immunogenic when administered as a two-dose booster series in individuals aged 5-80 years. In particular, the vaccine induced a significant rise in neutralising antibodies against the XBB.1.5 strain as well as cross-protective neutralising antibodies against the JN.1 SARS-CoV-2 strain. These data are in line with studies of other XBB.1.5 monovalent vaccines and support a positive risk-benefit profile. Real-world studies may provide additional evidence about the effectiveness of this new updated vaccine.

Funding: Biological E Limited, India.

Keywords: Booster; COVID-19; Randomised controlled trial; Subunit vaccine; XBB.1.5 variant.

Fig. 1

Trial profile.

Fig. 2

A) Geometric mean titres. B) Geometric mean titre ratio of XBB.1.5 neutralising antibodies. C) Geometric mean concentration anti-XBB.1.5 IgG antibodies (“XBB.1.5” represents the XBB.1.5 RBD subunit test vaccine and “Ancestral” represents CORBEVAX™, the Ancestral SARS-CoV-2 strain RBD subunit control vaccine). D) Geometric mean titres of neutralising antibodies measured by PSVNT 50 induced against the JN.1 and XBB.1.5 strains of SARS-CoV-2 14 days after the two-dose booster series. PSVNT: Pseudo-Virus Neutralization Titer50.