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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)., Competing Interests: Declaration of interests M.E.T.-R., M.G.-C., L.V.-S., S.P.-R., C.V.-S., M.T.P.-G., J.E.-P., E.N.-R., A.P.-D., G.B.-R., I.M.-H., Y.M., Y.G.-M., B.L.S.-V., G.-W.-C., D.D., A.B., and D.G.R. declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. M.R.-G., B.P.-M., B.S.-R., R.G.-M., T.H.-G., I.O.-V., M.D.-H., S.F.-C., Y.C.-R., L.R.-N., D.S.-M., Y.G.-V., T.B.-A., Y.V.-B., D.G.-R., and V.V.-B. work at Finlay Vaccine Institute or the Center of Molecular Immunology, institutions that develop and manufacture the vaccine candidates, but they have not received an honorarium for this paper. B.S.-R., S.F.-C., Y.C.-R., L.R.-N., D.S.-M., Y.V.-B., D.G.R., D.G.-R., and V.V.-B. have filed patent applications related to the vaccine SOBERANA 02., (Copyright © 2022 Elsevier Inc. All rights reserved.)