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Clusters of di-, tri-, and tetra-antennary alpha-D-mannopyranosides were synthesized in good yields based on the coupling of amine-bearing mono- or trisaccharide [Man alpha(1 --> 6)[Man alpha(1 --> 3)]Man] haptens to poly-isocyanate or -isothiocyanate tethering cores. The relative binding properties of the resulting multivalent ligands were determined by turbidimetric and solid phase enzyme-linked lectin assays (ELLA) using plant lectins (phytohemagglutinins) Concanavalin A (Con A) and Pisum sativum (pea lectin) having four and two carbohydrate binding sites, respectively. Rapid and efficient cross-linking between tetravalent Con A and mannopyranosylated clusters were measured by a microtiter plate version of turbidimetric analyses. In inhibition of binding of the lectins to yeast mannan, the best tetravalent monosaccharide (30) and trisaccharide (31) inhibitors were shown to be 140 and 1155 times more potent inhibitors than monomeric methyl alpha-D-mannopyranoside against pea lectin and Con A, respectively. Compounds 30 and 31 were thus 35- and 289-fold more potent than the reference monosaccharide based on their hapten contents. As a general observation, the ligands bearing the Man alpha(1 --> 6)[Man alpha(1 --> 3)]Man trimannoside structures were found to be more potent inhibitors for Con A than the ligands having single mannoside residues, whereas pea lectin could not discriminate between the two types of ligands.

BackgroundSOBERANA 02 is a COVID-19 conjugate vaccine candidate based on SARS-CoV-2 recombinant RBD conjugated to tetanus toxoid. SOBERANA Plus antigen is dimeric-RBD. Here we report safety, reactogenicity and immunogenicity from phase I and IIa clinical trials using two-doses SOBERANA 02 (homologous protocol) and three-doses (homologous) or heterologous (with SOBERANA Plus) protocols.MethodWe performed an open-label, monocentric, sequential and adaptive phase I for evaluating safety, reactogenicity and exploring immunogenicity of SOBERANA 02 in two formulations (15 and 25 μg) 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 received a third dose of SOBERANA 02, half received a heterologous dose of SOBERANA Plus-50 μg. Primary outcomes were safety and reactogenicity. The secondary outcome was vaccine immunogenicity evaluated by anti-RBD IgG ELISA, molecular neutralization test of RBD:hACE2 interaction, live-virus neutralization test and specific T-cells response.ResultsThe most frequent AE was local pain, other AEs had frequencies ≤ 5%. No serious related AEs were reported. Phase IIa confirmed the safety results in 60–80 years subjects. In phase-I SOBERANA 02-25µg elicited higher immune response than SOBERANA 02-15 µg; in consequence, the higher dose progressed to phase IIa. Phase IIa results confirmed the immunogenicity of SOBERANA 02-25 μg even in 60–80 age range. Two doses of SOBERANA02-25 μg elicited an immune response similar to that of the Cuban Convalescent Serum Panel; it was higher after both the homologous and heterologous third doses; the heterologous scheme showing a higher immunological response.ConclusionsSOBERANA 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 and https://rpcec.sld.cu/trials/RPCEC00000347

SARS-CoV-2 infection is mediated by the interaction of the spike glycoprotein trimer via its receptor-binding domain (RBD) with the host’s cellular receptor. Vaccines seek to block this interaction by eliciting...

Background: We report results of immunogenicity, safety and reactogenicity of SOBERANA 02 in a two-dose or three-dose heterologous scheme in adults in a phase IIb clinical trial. Method: This phase IIb trial was designed as parallel, multicentre, adaptive, double blind, randomized and placebo-controlled. Subjects (N=810) aged 19-80 years were randomized to receive two doses of the recombinant SARS CoV-2 receptor binding domain (RBD) conjugated to tetanus toxoid (SOBERANA 02) and a third dose of dimeric RBD (SOBERANA Plus) 28 days apart; two production batches of active ingredient of SOBERANA 02 were evaluated. Primary outcome was the percentage of seroconverted subjects with ≥4-fold the anti-RBD IgG concentration. Secondary outcomes were safety, reactogenicity and neutralizing antibodies. Results: Seroconversion rate in vaccinees was respectively 76.3 and 96.8% after two or three doses, compared with 7.3% in placebo group. Anti-RBD IgG increased significantly after first and second dose of SOBERANA 02 respect to placebo group; and the third dose with SOBERANA Plus boosts the response compared to the second dose. Neutralizing IgG antibodies were detected against D614G and VOCs α, β and δ. Specific and functional antibodies were detected until 7-8 months after the third dose. The frequency of serious adverse events (AEs) associated with vaccination was very low (0.1%); with only one serious AE consistent with vaccination. Local pain was the most frequent AE. Conclusions: Two doses of SOBERANA 02 were well tolerated, safe an immunogenic in adults aged 19-80 years old. The heterologous combination with a third dose of SOBERANA Plus increased neutralizing antibodies, detectable 7-8 months after the third dose. Trial registry: https://rpcec.sld.cu/trials/RPCEC00000347