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.

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 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. 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.