Immunogenicity and Safety of Gamma, Omicron BA.4/5 and Bivalent SARS-CoV-2 RBD-based Protein Booster Vaccines in Adults Previously Immunized with Different Vaccine Platforms: a Phase II/III, Randomized, Clinical Trial

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Abstract Background This study (ARVAC-F2-3-002) assessed the immunogenicity, safety, and tolerability of a recombinant booster vaccine (ARVAC) containing the receptor binding domain of the SARS-CoV-2 Spike protein in three different versions: Gamma (ARVACGamma), Omicron BA.4/5 (ARVACOmicron), and Gamma/Omicron Bivalent (ARVACBivalent). Methods Randomized, double-blind, crossover, placebo-controlled, multicenter (11 centers in Argentina) Phase II/III trial including adult volunteers previously vaccinated against SARS-CoV-2 with ≤3 booster doses. Participants were randomized to receive ARVACGamma (50 µg)+placebo and vice-versa (1:1 ratio) (Phase II), and ARVACGamma (50 µg)+placebo, ARVACOmicron (50 µg)+placebo, and ARVACBivalent (Gamma/Omicron 25 µg/25 µg)+placebo and vice-versa (Phase III) (1:1:1:1:1:1 ratio) 28 days apart. The primary endpoint was the seroconversion rate of neutralizing antibodies compared to placebo. The vaccine immunogenicity was considered acceptable at >75% seroconversion rate to variants homologous to the antigen contained in the vaccine (prespecified primary endpoint). Results Participants (n=2012) (mean 48.2 years, SD 16.7; 48.1% women) were randomized and allocated to ARVACGamma (n=232 in Phase II and n=592 in Phase III), ARVACOmicron (n=594), and ARVACBivalent (n=594); 232 in Phase II and 370 in each Phase III group were included in the immunogenicity subset. Seroconversion rates to all SARS-CoV-2 variants were significantly higher after receiving any vaccine than placebo. All vaccine versions met the prespecified primary endpoint in all participants and in those 18−60 years old. In participants >60 years, the ARVACOmicron and the ARVACBivalent met the prespecified primary endpoint, whereas the ARVACGamma did not. The ARVACBivalent induced seroconversion rates were significantly higher than 75% across all tested SARS- CoV-2 variants (homologous and heterologous) and age groups. No vaccine-related serious adverse events were recorded; most local and systemic adverse events were grade 1-2. Conclusion Booster vaccination with Gamma, Omicron BA.4/5, and Bivalent protein subunit recombinant ARVAC vaccine versions elicited protective neutralizing antibody responses to several SARS-CoV-2 variants, with very low reactogenicity and a favorable safety profile. Trial registration: NCT05752201

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