ABSTRACT
BackgroundSOBERANA-02 is a COVID-19 conjugate vaccine (recombinant RBD conjugated to tetanus toxoid). Phases 1/2 clinical trials demonstrated high immunogenicity, promoting neutralizing IgG and specific T-cell response. A third heterologous dose of SOBERANA-Plus (RBD-dimer) further increased neutralizing antibodies. MethodsFrom March 8th to September 30th, 2021 we conducted in Havana, Cuba a multicentre randomized, double-blind, placebo-controlled, phase-3 trial evaluating two doses of SOBERANA-02 and a heterologous scheme with one dose SOBERANA-Plus added to it. 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 occurring 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. FindingWe included 44{middle dot}031 participants in a context of Beta VOC predominance, with this variant being gradually replaced by Delta near the trial end. Vaccine efficacy in the heterologous combination was 92{middle dot}0% (95%CI 80{middle dot}4-96{middle dot}7) against symptomatic and 100% against severe COVID-19. Two doses of SOBERANA-02 was 69{middle dot}7% (95%CI 56{middle dot}5-78{middle dot}9) and 74{middle dot}9% (95%CI 33{middle dot}7-90{middle dot}5) efficacious to protect against symptomatic and severe COVID-19, respectively. The occurrence of serious and severe AEs 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. InterpretationOur results indicate that the straightforward to manufacture SOBERANA vaccines are efficacious in a context of Beta and Delta VOC dominance and that they constitute an attractive, feasible option for low- and middle-income countries, where besides financial constraints ease of vaccine storage and distribution is of concern. FundingThis study received funds from Finlay Vaccine Institute and National Fund for Science and Technology (FONCI-CITMA-Cuba, contract 2020-20). of Ministry of Science, Technology and the Environment (Contract Project-2020-20) in Cuba.
ABSTRACT
BackgroundThe Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is the target for many COVID-19 vaccines. Here we report results for phase 1 clinical trial of two COVID-19 vaccine candidates based on recombinant dimeric RBD (d-RBD). MethodsWe performed a randomized, double-blind, phase I clinical trial in the National Centre of Toxicology in Havana. Sixty Cuban volunteers aged 19-59 years were randomized into three groups (20 subjects each): 1) FINLAY-FR-1 (50 mcg d-RBD plus outer membrane vesicles from N. meningitidis); 2) FINLAY-FR-1A-50 mcg d-RBD (three doses); 3) FINLAY-FR-1A-25 mcg d-RDB (three doses). The FINLAY-FR-1 group was randomly divided to receive a third dose of the same vaccine candidate (homologous schedule) or of FINLAY-FR-1A-50 (heterologous schedule). The primary outcomes were safety and reactogenicity. The secondary outcome was vaccine immunogenicity. Humoral response at baseline and following each vaccination was evaluated using live-virus neutralization test, anti-RBD IgG ELISA and in-vitro neutralization test of RBD:hACE2 interaction. ResultsMost adverse events were of mild intensity (63.5%), solicited (58.8%), and local (61.8%); 69.4% with causal association with vaccination. Serious adverse events were not found. The FINLAY-FR-1 group reported more adverse events than the other two groups. After the third dose, anti-RBD seroconversion was 100%, 94.4% and 90% for the FINLAY-FR-1, FINLAY-FR-1A-50 and FINLAY-FR-1A-25 respectively. The in-vitro inhibition of RBD:hACE2 interaction increased after the second dose in all formulations. The geometric mean neutralizing titres after the third dose rose significantly in the group vaccinated with FINLAY-FR-1 with respect to the other formulations and the COVID-19 Convalescent Serum Panel. No differences were found between FINLAY-FR-1 homologous or heterologous schedules. ConclusionsVaccine candidates were safe and immunogenic, and induced live-virus neutralizing antibodies against SARS-CoV-2. The highest values were obtained when outer membrane vesicles were used as adjuvant. Trial registryhttps://rpcec.sld.cu/en/trials/RPCEC00000338-En
