Safety, Immunogenicity and Efficacy of the mRNA Vaccine CS-2034 as a Heterologous Booster Versus Homologous Booster with BBIBP-CorV in Adults Aged ≥18 Years: A Randomized, Partial-Blind, Phase 2b Trial

Background: Heterologous boosting is suggested to use in populations who have received inactivated COVID-19 vaccines. We assessed the safety, immunogenicity of a heterologous vaccination with mRNA vaccine CS-2034 versus BBIBP-CorV as a fourth dose, as well as the efficacy against the SARS-CoV-2 Omicron variant.Methods: We did a randomized, partial-blind, parallel-controlled study (ChiCTR2200064575) in healthy participants aged 18 years or older who had received three-dose of inactivated whole-virion vaccines at least 6 months before enrollment. Eligible participants in Cohort A were stratified by age (18-59 years and ≥ 60 years) and then randomized in a ratio of 3:1 to receive a dose of mRNA vaccine CS-2034 or inactivated vaccine (BBIBP-CorV, Sinopharm). Safety and immunogenicity against Omicron variants of the fourth dose were evaluated in Cohort A. Participants aged ≥ 60 years were involved in Cohort B for safety observation. All the participants and staff doing laboratory analyses were masked to the treatment allocations in cohort A and cohort B was an open-label cohort. The primary outcome was geometric mean titers of the neutralizing antibodies against Omicron and seroconversion rates against BA.5 variant 28 days after the boosting, and incidence of adverse reactions within 28 days. Relative efficacy of the vaccine protection against Omicron infection was estimated in participants receiving CS-2034 versus BBIBP-CorV during the high prevalence epidemic of COVID-19 in December 2022. This trial was registered at the Chinese Clinical Trial Registry Centre (ChiCTR2200064575).Findings: A total of 320 participants were in Cohort A (240 in the CS-2034, and 80 in the BBIBP-CorV groups) and 113 were in Cohort B. Adverse reactions after vaccination were more frequent in CS-2034 recipients than that in BBIBP-CorV recipients (44.76% versus 21.25%, p value=0.0001). However, the majority of the adverse reactions were mild or moderate, with grade 3 adverse reactions only reported by 2.27% of participants receiving CS-2034. Heterologous boosting with CS-2034 elicited 14.4-fold higher levels of neutralizing antibodies to SARS-CoV-2 Omicron variants BA.5 than did homologous boosting with BBIBP-CorV. The estimated relative vaccine efficacy of CS-2034 versus BBIBP-CorV was 37.9% (95% CI, 22.2 to 50.4).Interpretation: Both the administration of mRNA vaccine CS-2034 and inactivated vaccine BBIBP-CorV as a fourth dose were well-tolerated. Heterologous boosting with mRNA vaccine CS-2034 induced higher immune responses and protection against symptomatic SARS-CoV-2 Omicron infections compared with homologous boosting.Trial Registration Details: This trial was registered at the Chinese Clinical Trial Registry Centre (ChiCTR2200064575).Funding Information: This work was supported by the Science and Technology Commission of Shanghai municipality under Grant 22YJ1900700. National Natural Science Foundation of China (Grant number 82173584 and 82222062), Jiangsu Provincial Science Fund for Distinguished Young Scholars (Grant number BK20220064), and Jiangsu Provincial Key Project of Science and Technology Plan (Grant number BE2021738).Declaration of Interests: No potential conflict of interest was reported by the authors.Ethics Approval Statement: The trial protocol and informed consent form were reviewed and approved by the Research Ethics Committee of the Yixing People's Hospital, Wuxi City, Jiangsu Province, China. All the participants provided written informed consent before inclusion.