Safety and immunogenicity of anti-SARS CoV-2 vaccine SOBERANA 02 in homologous or heterologous scheme: Open label phase I and phase IIa clinical trials

Abstract

Background: SOBERANA 02 is a COVID-19 vaccine based on SARS-CoV-2 recombinant RBD conjugated to tetanus toxoid (TT). SOBERANA Plus antigen is dimeric-RBD. Here we report safety and immunogenicity from phase I and IIa clinical trials using two-doses of SOBERANA 02 and three-doses (homologous) or heterologous (with SOBERANA Plus) protocols.

Method: We performed an open-label, sequential and adaptive phase I to evaluate safety and explore the immunogenicity of SOBERANA 02 in two formulations (15 or 25 μg RBD-conjugated to 20 μg of TT) 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 were selected to receive a third dose of the corresponding SOBERANA 02 and half received a heterologous dose of SOBERANA Plus. Primary outcome was safety. The secondary outcome was immunogenicity evaluated by anti-RBD IgG ELISA, molecular neutralization of RBD:hACE2 interaction, live-virus-neutralization and specific T-cells response.

Results: The most frequent adverse event (AE) was local pain, other AEs had frequencies ≤ 5%. No serious related-AEs were reported. Phase IIa confirmed the safety in 60 to 80-years-old subjects. In phase-I SOBERANA 02-25 µg elicited higher immune response than SOBERANA 02-15 µg and progressed to phase IIa. Phase IIa results confirmed the immunogenicity of SOBERANA 02-25 µg even in 60-80-years. Two doses of SOBERANA02-25 µg elicited an immune response similar to that of the Cuban Convalescent Serum Panel and it was higher after the homologous and heterologous third doses. The heterologous scheme showed a higher immunological response. Anti-RBD IgG neutralized the delta variant in molecular assay, with a 2.5-fold reduction compared to D614G neutralization.

Conclusions: SOBERANA 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, https://rpcec.sld.cu/trials/RPCEC00000347.

Keywords: COVID-19; Conjugate vaccine; Heterologous immunization scheme; SARS-CoV-2; Subunit vaccine.

Fig. 1

Phase I Flow Chart. Footnote: Immunogenicity after 1st, 2nd or 3rd dose refers to 28 days after each dose.

Fig. 2

Phase IIa Flow Chart. Footnote: Immunogenicity after 1st, 2nd or 3rd dose refers to 28 days after each dose.

Fig. 3

Solicited local and systemic adverse event after each dose by age subgroups (Phase IIa).

Fig. 4

Kinetics of anti-RBD IgG production after two doses of SOBERANA 02-25 µg and a third homologous or heterologous dose (pooled analysis from phase I and phase IIa). FOOTNOTE: Subjects 19–80 years-old received two doses (T0, T28) of SOBERANA 02-25 µg and a third dose (T56) homologous (Hom: blue points) or heterologous with SOBERANA Plus (Het: green points). Anti-RBD IgG concentration is expressed in arbitrary units/mL (median, 25th-75th percentile). CCSP: Cuban Convalescent Serum Panel (red triangles). p values represent the statistic differences with T0 or T56 as indicated, using Wilcoxon signed rank test. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Anti-RBD IgG antibodies inhibit the interaction between RBD and human ACE2 receptor after two doses of SOBERANA 02-25 µg and a third homologous or heterologous dose (pooled analysis from phase I and phase IIa). FOOTNOTE: Subjects 19–80 years old received two doses (T0, T28) of SOBERANA 02-25 µg and a third dose (T56) homologous, (Hom: blue points) or heterologous with SOBERANA Plus (Het: green points). A: % inhibition of RBD:hACE2 interaction at 1/100 serum dilution (median, 25th-75th percentile). B: Molecular virus neutralization titre mVNT50: highest serum dilution inhibiting 50% of RBD:hACE2 interaction; (GMT, IC 95%). CCSP: Cuban Convalescent Serum Panel (red triangles). p values represent statistic differences with T0 or T56, as indicated. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Neutralizing titre of SARS-CoV-2 (D614G) live-virus after two doses of SOBERANA 02-25 µg and a third homologous or heterologous dose (pooled analysis from phase I and phase IIa). FOOTNOTE: Subjects 19–80 years old received two doses (T0, T28) of SOBERANA 02-25 µg and a third dose (T56) homologous, (Hom: blue points) or heterologous (SOBERANA Plus, Het: green points). cVNT50: Conventional live-virus neutralization titre (GMT, IC 95%). CCSP: Cuban Convalescent Serum Panel (red triangles). p values represent the statistic differences with T0 or T56, as indicated, using paired Student t test with log-transformed variables. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

Anti-RBD IgG antibodies inhibit the interaction between the human ACE2 receptor and phages displaying D614G -RBD or δ-RBD variant. FOONOTE: Sera from 16 individuals vaccinated with heterologous schedule were tested (GMT, IC 95%). During the trial clinical trials, the predominant circulating strain was D614G. p value represents the statistic differences as indicated, using paired Student t test with log-transformed variables.

Fig. 8

IFN-γ- and IL-4-secreting cells in peripheral blood mononuclear cells stimulated with RBD. FOONOTE: Subjects 19–80 years old received two doses (on days 0, 28; N = 24) of SOBERANA 02-25 µg and a third dose (on day 56) homologous (SOBERANA 02, Hom: blue points, N = 13) or heterologous (SOBERANA Plus, Het: green points; N = 11). p value represents the statistic differences as indicated. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)