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Randomized Controlled Trial
. 2022 Nov 11;3(11):760-773.e5.
doi: 10.1016/j.medj.2022.08.001. Epub 2022 Aug 8.

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

María Eugenia Toledo-Romani  1 , Mayra García-Carmenate  2 , Leslyhana Verdecia-Sánchez  3 , Suzel Pérez-Rodríguez  2 , Meybis Rodriguez-González  4 , Carmen Valenzuela-Silva  5 , Beatriz Paredes-Moreno  4 , Belinda Sanchez-Ramirez  6 , Raúl González-Mugica  4 , Tays Hernández-Garcia  6 , Ivette Orosa-Vázquez  6 , Marianniz Díaz-Hernández  6 , María Teresa Pérez-Guevara  7 , Juliet Enriquez-Puertas  7 , Enrique Noa-Romero  7 , Ariel Palenzuela-Diaz  8 , Gerardo Baro-Roman  8 , Ivis Mendoza-Hernández  9 , Yaima Muñoz  9 , Yanet Gómez-Maceo  3 , Bertha Leysi Santos-Vega  2 , Sonsire Fernandez-Castillo  10 , Yanet Climent-Ruiz  4 , Laura Rodríguez-Noda  4 , Darielys Santana-Mederos  4 , Yanelda García-Vega  6 , Guang-Wu Chen  11 , Delaram Doroud  12 , Alireza Biglari  12 , Tammy Boggiano-Ayo  6 , Yury Valdés-Balbín  4 , Daniel G Rivera  13 , Dagmar García-Rivera  4 , Vicente Vérez-Bencomo  14 ; SOBERANA Research Group
Collaborators, Affiliations
Randomized Controlled Trial

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

María Eugenia Toledo-Romani et al. Med. .

Abstract

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).

Keywords: COVID-19; Translation to patients; conjugate vaccine; heterologous schedule; phase IIb clinical trial; recombinant RBD.

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Conflict of interest statement

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.

Figures

None
Graphical abstract
Figure 1
Figure 1
Flow chart of clinical trial phase IIb EC, exclusion criteria (1, history of unresolved neoplasm; 2, blood transfusion for megaloblastic anemia); MD, medical decision; VA, voluntary; SAE (multiform erythema).
Figure 2
Figure 2
Immunogenicity after vaccination in subjects aged 19–80 years (A) Kinetics of anti-RBD IgG concentration expressed in arbitrary units/mL (median, 25th–75th percentile). (B) Percentage of inhibition of RBD:hACE2 interaction at 1/100 serum dilution (median, 25th–75th percentile). (C) Molecular virus neutralization titer mVNT50, highest serum dilution inhibiting 50% of RBD:hACE2 interaction (GMT, 95% CI). (D) Conventional live-virus neutralization titer cVNT50 (GMT, CI 95%) against SARS-CoV-2 D614G variant. Blue dots: response after two doses (on T0, T28) of SOBERANA 02. Green dots: response at T70 or T84 after receiving the third dose on T56, this one of SOBERANA Plus. Brown dots: subjects receiving placebo. CCSP (purple), Cuban convalescent serum panel. p value: statistic differences (on T70 or T84) compared with T56 or T0.
Figure 3
Figure 3
Live-virus neutralization titer against SARS-CoV-2 variants Sera from 18 subjects vaccinated with complete schedule (two doses SOBERANA 02 + one dose SOBERANA Plus, 28 days apart) were evaluated (cVNT50: GMT, 95% CI) against variants B.1.1.7 Alpha, B.1.617.2 Delta, BA1.21K Omicron, and B.1.351 Beta and compared with D614G variant. p values represent the statistic differences as indicated, using paired Student t test with log-transformed variables.
Figure 4
Figure 4
Immunogenicity in vaccinated subjects 7–8 months after completing the immunization schedule (two doses SOBERANA 02 + one dose SOBERANA Plus, 28 days apart) (A) Anti-RBD IgG concentration expressed in arbitrary units/mL (median, 25th–75th percentile). (B) Molecular virus neutralization titer mVNT50, highest serum dilution inhibiting 50% of RBD:hACE2 interaction (GMT, 95% CI). (C) Conventional live-virus neutralization titer cVNT50 (GMT, CI 95%) against SARS-CoV-2 D614G variant. Blue dots: response at T56, after two doses of SOBERANA 02 of SOBERANA 02 on T0, T28. Green dots: response at T70 or T84 after receiving on T56 the third dose, this one SOBERANA Plus. Brown dots: response after 7–8 months. CCSP (purple), Cuban convalescent serum panel. p value: statistic differences.
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