Safety and efficacy of the two doses conjugated protein-based SOBERANA-02 COVID-19 vaccine and of a heterologous three-dose combination with SOBERANA-Plus: a double-blind, randomised, placebo-controlled phase 3 clinical trial.

Background: SOBERANA-02 is a COVID-19 conjugate vaccine (recombinant RBD conjugated to tetanus toxoid). Phases 1/2 clinical trials demonstrated high immunogenicity, promoting neutralising IgG and specific T-cell response. A third heterologous dose of SOBERANA-Plus (RBD-dimer) further increased neutralising antibodies. The aim of this study is to evaluate the safety and efficacy of two immunisation regimes: two doses of SOBERANA-02 and a heterologous three-dose combination with SOBERANA-Plus added to it. Methods: From March 8th to June 24th, 2021 we conducted in Havana, Cuba a multicentre randomised, double-blind, placebo-controlled, phase-3 trial evaluating a two doses SOBERANA-02 scheme and a heterologous scheme with one dose SOBERANA-Plus added to it (RPCEC00000354). Participants 19-80 years were randomly assigned to receiving 28 days apart either the two or three dose scheme or placebo. The main endpoint was vaccine efficacy in preventing the occurrence of RT-PCR confirmed symptomatic COVID-19 at least 14 days after the second or third dose in the per-protocol population. We also assessed efficacy against severe disease and, in all participants receiving at least one vaccine/placebo dose, safety for 28 days after each dose. Findings: We included 44,031 participants (52.0% female, 48.0% male; median age 50 years, range 19-80 years; 7.0% black, 24.0% mixed-race, 59.0% white) in a context of initial Beta VOC predominance, with this variant being partially replaced by Delta near the trial's end. Vaccine efficacy in the heterologous combination was 92.0% (95%CI 80.4-96.7) against symptomatic disease. There were no severe COVID-19 cases in the vaccine group against 6 in the placebo group. Two doses of SOBERANA-02 was 69.7% (95%CI 56.5-78.9) and 74.9% (95%CI 33.7-90.5) efficacious against symptomatic and severe COVID-19, respectively. The occurrence of serious and severe adverse events (AE) was very rare and equally distributed between placebo and vaccine groups. Solicited AEs were slightly more frequent in the vaccine group but predominantly local and mostly mild and transient. Interpretation: Our results indicate that the straightforward to manufacture SOBERANA vaccines are efficacious in a context of Beta and Delta VOC circulation, have a favourable safety profile, and may represent an attractive option for use in COVID-19 vaccination programmes. Funding: This study received funds from the National Fund for Science and Technology (FONCI-CITMA-Cuba, contract 2020-20) of the Ministry of Science, Technology and Environment of Cuba.

Safety and immunogenicity of anti-SARS-CoV-2 heterologous scheme with SOBERANA 02 and SOBERANA Plus vaccines: Phase IIb clinical trial in adults.

BACKGROUND: SOBERANA 02 has been evaluated in phase I and IIa studies comparing homologous versus heterologous schedule (this one, including SOBERANA Plus). Here, we report results of immunogenicity, safety, and reactogenicity of SOBERANA 02 in a two- or three-dose heterologous scheme in adults. METHOD: Phase IIb was a parallel, multicenter, adaptive, double-blind, randomized, and placebo-controlled trial. Subjects (n = 810) aged 19-80 years were randomized to receive two doses of SARS-CoV-2 RBD conjugated to tetanus toxoid (SOBERANA 02) and a third dose of dimeric RBD (SOBERANA Plus) 28 days apart; two production batches of active ingredients of SOBERANA 02 were evaluated. Primary outcome was the percentage of seroconverted subjects with ≥4-fold the anti-RBD immunoglobulin G (IgG) concentration. Secondary outcomes were safety, reactogenicity, and neutralizing antibodies. FINDINGS: Seroconversion rate in vaccinees was 76.3% after two doses and 96.8% after the third dose of SOBERANA Plus (7.3% in the placebo group). Neutralizing IgG antibodies were detected against D614G and variants of concern (VOCs) Alpha, Beta, Delta, and Omicron. Specific, functional antibodies were detected 7-8 months after the third dose. The frequency of serious adverse events (AEs) associated with vaccination was very low (0.1%). Local pain was the most frequent AE. CONCLUSIONS: Two doses of SOBERANA 02 were safe and immunogenic in adults. The heterologous combination with SOBERANA Plus increased neutralizing antibodies, detectable 7-8 months after the third dose. TRIAL REGISTRY: https://rpcec.sld.cu/trials/RPCEC00000347 FUNDING: This work was supported by Finlay Vaccine Institute, BioCubaFarma, and the Fondo Nacional de Ciencia y Técnica (FONCI-CITMA-Cuba, contract 2020-20).

Safety and immunogenicity of anti-SARS CoV-2 vaccine SOBERANA 02 in homologous or heterologous scheme: Open label phase I and phase IIa clinical trials.

BACKGROUND: SOBERANA 02 is a COVID-19 vaccine based on SARS-CoV-2 recombinant RBD conjugated to tetanus toxoid (TT). SOBERANA Plus antigen is dimeric-RBD. Here we report safety and immunogenicity from phase I and IIa clinical trials using two-doses of SOBERANA 02 and three-doses (homologous) or heterologous (with SOBERANA Plus) protocols. METHOD: We performed an open-label, sequential and adaptive phase I to evaluate safety and explore the immunogenicity of SOBERANA 02 in two formulations (15 or 25 µg RBD-conjugated to 20 µg of TT) in 40 subjects, 19-59-years-old. Phase IIa was open-label including 100 volunteers 19-80-years, receiving two doses of SOBERANA 02-25 µg. In both trials, half of volunteers were selected to receive a third dose of the corresponding SOBERANA 02 and half received a heterologous dose of SOBERANA Plus. Primary outcome was safety. The secondary outcome was immunogenicity evaluated by anti-RBD IgG ELISA, molecular neutralization of RBD:hACE2 interaction, live-virus-neutralization and specific T-cells response. RESULTS: The most frequent adverse event (AE) was local pain, other AEs had frequencies ≤ 5%. No serious related-AEs were reported. Phase IIa confirmed the safety in 60 to 80-years-old subjects. In phase-I SOBERANA 02-25 µg elicited higher immune response than SOBERANA 02-15 µg and progressed to phase IIa. Phase IIa results confirmed the immunogenicity of SOBERANA 02-25 µg even in 60-80-years. Two doses of SOBERANA02-25 µg elicited an immune response similar to that of the Cuban Convalescent Serum Panel and it was higher after the homologous and heterologous third doses. The heterologous scheme showed a higher immunological response. Anti-RBD IgG neutralized the delta variant in molecular assay, with a 2.5-fold reduction compared to D614G neutralization. CONCLUSIONS: SOBERANA 02 was safe and immunogenic in persons aged 19-80 years, eliciting neutralizing antibodies and specific T-cell response. Highest immune responses were obtained in the heterologous three doses protocol. TRIAL REGISTRY: https://rpcec.sld.cu/trials/RPCEC00000340, https://rpcec.sld.cu/trials/RPCEC00000347.