A randomized, double-blind phase I clinical trial of two recombinant dimeric RBD COVID-19 vaccine candidates: safety, reactogenicity and immunogenicity

Abstract

Background The 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). Methods We 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. Results Most 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. Conclusions Vaccine 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.

A COVID-19 vaccine candidate composed of the SARS-CoV-2 RBD dimer and Neisseria meningitidis outer membrane vesicles

“…In humans, the formulation containing the OMVs elicits a more potent neutralizing effect against RBD mutants present in VOCs, including the triple-mutant RBD of the beta variant. These results, together with those of phase I clinical trial, 40 pave the way for phase II and III clinical trials for the RBD-d/OMV/alum formulation. They also demonstrate the advantages of using N. meningitidis OMVs not only in antibacterial vaccines, but also as adjuvants in antiviral protein subunit vaccines.…”

“…19 Human immunogenicity A phase I clinical trial was conducted to compare these and other vaccine candidates, in groups of 20 subjects following a three-dose schedule at intervals of 28 days. 39 While the safety, reactogenicity and immunogenicity were reported, 40 here we describe additional results which enable to further assess the effect of OMVs on the quality of the antibody response in humans. The analysis was performed with sera from trial participants vaccinated with RBD-d/ OMV/alum (50 mg/20 mg/1250 mg) and RBD-d/alum (50 mg/1250 mg).…”

“…The number of subjects with IgG concentration 470 AU/mL increased after the third dose with respect to the second one: for RBD-d/OMV/alum from 13/20 (65%) to 18/20 (90%) and for RBD-d/alum from 10/20 (50%) to 13/20 (65%). 40 Interestingly, while the IgG response at day 28 after the second (T = 56) and third doses (T = 84) was rather similar, 40 the quality of the IgG response was certainly higher for both formulations on day 28 after the third vaccination (T = 84), as determined by the inhibition of the RBD-ACE2 interaction. In mVNT 50 , the percentage of subjects attaining an ID 50 4 150 comparing the inhibition of the interaction between the phage-displayed RBD mutants and the ACE2 receptor.…”

“…Fig.4Immunogenicity evaluation from a phase I clinical trial 39,40. Subjects immunized with RBD-d/OMV (50 mg/20 mg, blue) vs. RBD-d (50 mg, red) adsorbed in alum.…”