Open label phase I/II clinical trial and predicted efficacy of SARS-CoV-2 RBD protein vaccines SOBERANA 02 and SOBERANA Plus in children (preprint)

ObjectivesTo evaluate heterologous scheme in children 3-18 y/o using two SARS-CoV-2 r-RBD protein vaccines. MethodsA phase I/II open-label, adaptive and multicenter trial evaluated the safety and immunogenicity of two doses of SOBERANA02 and a heterologous third dose of SOBERANA Plus in 350 children 3-18 y/o in Havana Cuba. Primary outcomes were safety (in phase I) and safety/immunogenicity (in phase II) measured by anti-RBD IgG ELISA, molecular and live-virus neutralization tests and specific T-cells response. An immunobridging and prediction of efficacy were additional analysis. ResultsLocal pain was the unique adverse event with >10% frequency, none was serious or severe. Two doses of SOBERANA 02 elicited humoral immune response similar to natural infection; the third dose increased significantly the response in all children, similar to that achieved in vaccinated young adults and higher than in convalescents children. The neutralizing titer was evaluated in a participants subset: all had neutralizing antibodies vs. alpha and delta; 97.9% vs. beta. GMT was 173.8 (CI 95% 131.7; 229.5) vs. alpha, 142 (CI 95% 101.3; 198.9) vs. delta and 24.8 (CI 95% 16.8; 36.6) vs. beta. An efficacy over 90% was estimated. ConclusionHeterologous scheme was safe and immunogenic in children 3-18 y/o. Trial registry: https://rpcec.sld.cu/trials/RPCEC00000374

Safety and immunogenicity of anti-SARS CoV-2 conjugate vaccine SOBERANA 02 in a two-dose or three-dose heterologous scheme in adults: Phase IIb Clinical Trial (preprint)

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 , {beta} and {delta}. 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

Safety, tolerability, and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine: a randomised, double-blind, placebo-controlled, phase 1-2 clinical trial (ABDALA Study). (preprint)

AimTo evaluate the safety and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine (Abdala), administered intramuscularly in different strengths and vaccination schedules. MethodA phase 1-2, randomized, double-blind, placebo-controlled trial was done. Subjects were randomly distributed in 3 groups: placebo, 25 and 50{micro}g RBD. The product was applied intramuscularly, 0.5 mL in the deltoid region. During the first phase, two immunization schedules were studied: short (0-14-28 days) and long (0-28-56 days). In phase 2, only the short scheme was evaluated. The main endpoints were: safety and proportion of subjects with seroconversion of anti-RBD IgG antibodies to SARS-CoV-2. Blood samples were collected in several points according to the corresponding vaccination schedule to determine the level of RBD-specific IgG antibodies (seroconversion rates and geometric mean of the titers), the percentage of inhibition of RBD-ACE-2 binding and levels of neutralizing antibodies. ResultsThe product was well tolerated. Severe adverse events were not reported. Adverse reactions were minimal, mostly mild and local (from the injection site), resolved in the first 24-48 hours without medication. In phase 1, at day 56 (28 days after the third dose of the short vaccination schedule, 0-14-28 days) seroconversion of anti-RBD IgG was seen in 95.2 % of the participants (20/21) for the 50g group and 81 % of the participants (17/21) for the 25g group, and none in the placebo group (0/22); whereas neutralizing antibodies to SARS-CoV-2 were seen in 80 % of the participants (8/10) for the 50g group and 94.7% of the participants (18/19) for the 25g group. For the long schedule, at day 70 (14 days after the third dose) seroconversion of anti-RBD IgG was seen in 100% of the participants (21/21) for the 50g group and 94.7% of the participants (18/19) for the 25g group, and none in the placebo group (0/22); whereas neutralizing antibodies to SARS-CoV-2 were seen in 95 % of the participants (19/20) for the 50g group and 93.8% of the participants (15/16) for the 25g group In phase 2, at day 56 seroconversion of anti-RBD IgG was seen in 89.2% of the participants (214/240) for the 50g group, 77.7% of the participants (185/238) for the 25g group, and 4.6% in the placebo group (11/239); whereas neutralizing antibodies to SARS-CoV-2 were seen in 97.3% of the participants (146/150) for the 50g group and 95.1% of the participants (58/61) for the 25g group. ConclusionAbdala vaccine against SARS-CoV-2 was safe, well tolerated and induced humoral immune responses against SARS-CoV-2 among adults from 19 to 80 years of age. Trial registration / Review protocolRPCEC00000346. Cuban Public Clinical Trial Registry (WHO accepted Primary Registry). Available from: https://rpcec.sld.cu/en/trials/RPCEC00000346-En Information about the ethical aspects and IRB approvalThe protocol was approved by the Ethic Committee of the participating hospital and by the Cuban Regulatory Authority (Center for State Control of Drugs, Medical Devices and Equipment). Summary boxCOVID-19 is a serious global health problem. Vaccines are urgently needed to protect humanity. Multiple vaccine candidates are currently being evaluated. The article shows promising safety and immunogenicity results for a vaccine candidate, based on the recombinant RBD subunit of the spike protein.

Safety and Immunogenicity of anti-SARS CoV-2 vaccine SOBERANA 02 in homologous or heterologous scheme. (preprint)

Background SOBERANA 02 is a COVID19 conjugate vaccine candidate based on SARS CoV2 recombinant RBD conjugated to tetanus toxoid. SOBERANA Plus antigen is dimericRBD. 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. Method We 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 microg) in 40 subjects, 19 to 59 years old. Phase IIa was open label including 100 volunteers 19 to 80 years, receiving two doses of SOBERANA 02 25 microg. In both trials, half of volunteers received a third dose of SOBERANA 02, half received a heterologous dose of SOBERANA Plus 50 microg. 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. Results The most frequent AE was local pain, other AEs had frequencies lower than 5%. No serious related AEs were reported. Phase IIa confirmed the safety results in 60 to 80 years subjects. In phase I SOBERANA 02 25 microg elicited higher immune response than SOBERANA 02 15 microg; in consequence, the higher dose progressed to phase IIa. Phase IIa results confirmed the immunogenicity of SOBERANA 02 25 microg. even in 60 to 80 age range. Two doses of SOBERANA02 25 microg 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. Conclusions SOBERANA 02 was safe and immunogenic in persons aged 19 to 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

Elevated antibody titers in Abdala vaccinees evaluated by Elecsys(R) anti-SARS-CoV-2 S highly correlate with UMELISA SARS-CoV-2 ANTI RBD, ACE-2 binding inhibition and viral neutralization assays. (preprint)

SARS-CoV-2, a recently emerged coronavirus, is causing high morbidity and mortality worldwide since December 2019, posing an enormous health, social and economic problem. Obtaining effective treatments that can diminish deaths and sequelae and vaccines to slow or prevent viral transmission, and reduce disease severity and/or death are of utmost importance. Abdala is a Cuban vaccine based on the recombinant RBD subunit of the spike protein expressed in Pichia pastoris yeast. It demonstrated high efficacy (92.28 %) in phase III clinical trials for reducing transmission, and more than 90% effectiveness in reducing disease severity and mortality. Antibody titers were evaluated in 42 Abdala vaccinees using the Elecsys(R) Anti-SARS-CoV-2 S test. Fifteen days after immunization, sera from vaccinees showed high antibody titers (median of 1595 U/mL). The results obtained in this study also demonstrate correlation between the Cuban test UMELISA SARS-CoV-2 ANTI RBD used during the clinical trials and Elecsys(R) test results.