Safety and efficacy of the two doses conjugated protein-based SOBERANA-02 COVID-19 vaccine and of a heterologous three-dose combination with SOBERANA-Plus: a double-blind, randomised, placebo-controlled phase 3 clinical trial.

Background: SOBERANA-02 is a COVID-19 conjugate vaccine (recombinant RBD conjugated to tetanus toxoid). Phases 1/2 clinical trials demonstrated high immunogenicity, promoting neutralising IgG and specific T-cell response. A third heterologous dose of SOBERANA-Plus (RBD-dimer) further increased neutralising antibodies. The aim of this study is to evaluate the safety and efficacy of two immunisation regimes: two doses of SOBERANA-02 and a heterologous three-dose combination with SOBERANA-Plus added to it. Methods: From March 8th to June 24th, 2021 we conducted in Havana, Cuba a multicentre randomised, double-blind, placebo-controlled, phase-3 trial evaluating a two doses SOBERANA-02 scheme and a heterologous scheme with one dose SOBERANA-Plus added to it (RPCEC00000354). 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 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. Findings: We included 44,031 participants (52.0% female, 48.0% male; median age 50 years, range 19-80 years; 7.0% black, 24.0% mixed-race, 59.0% white) in a context of initial Beta VOC predominance, with this variant being partially replaced by Delta near the trial's end. Vaccine efficacy in the heterologous combination was 92.0% (95%CI 80.4-96.7) against symptomatic disease. There were no severe COVID-19 cases in the vaccine group against 6 in the placebo group. Two doses of SOBERANA-02 was 69.7% (95%CI 56.5-78.9) and 74.9% (95%CI 33.7-90.5) efficacious against symptomatic and severe COVID-19, respectively. The occurrence of serious and severe adverse events (AE) 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. Interpretation: Our results indicate that the straightforward to manufacture SOBERANA vaccines are efficacious in a context of Beta and Delta VOC circulation, have a favourable safety profile, and may represent an attractive option for use in COVID-19 vaccination programmes. Funding: This study received funds from the National Fund for Science and Technology (FONCI-CITMA-Cuba, contract 2020-20) of the Ministry of Science, Technology and Environment of Cuba.

Safety and immunogenicity of anti-SARS-CoV-2 heterologous scheme with SOBERANA 02 and SOBERANA Plus vaccines: Phase IIb clinical trial in adults.

BACKGROUND: SOBERANA 02 has been evaluated in phase I and IIa studies comparing homologous versus heterologous schedule (this one, including SOBERANA Plus). Here, we report results of immunogenicity, safety, and reactogenicity of SOBERANA 02 in a two- or three-dose heterologous scheme in adults. METHOD: Phase IIb was a parallel, multicenter, adaptive, double-blind, randomized, and placebo-controlled trial. Subjects (n = 810) aged 19-80 years were randomized to receive two doses of SARS-CoV-2 RBD conjugated to tetanus toxoid (SOBERANA 02) and a third dose of dimeric RBD (SOBERANA Plus) 28 days apart; two production batches of active ingredients of SOBERANA 02 were evaluated. Primary outcome was the percentage of seroconverted subjects with ≥4-fold the anti-RBD immunoglobulin G (IgG) concentration. Secondary outcomes were safety, reactogenicity, and neutralizing antibodies. FINDINGS: Seroconversion rate in vaccinees was 76.3% after two doses and 96.8% after the third dose of SOBERANA Plus (7.3% in the placebo group). Neutralizing IgG antibodies were detected against D614G and variants of concern (VOCs) Alpha, Beta, Delta, and Omicron. Specific, functional antibodies were detected 7-8 months after the third dose. The frequency of serious adverse events (AEs) associated with vaccination was very low (0.1%). Local pain was the most frequent AE. CONCLUSIONS: Two doses of SOBERANA 02 were safe and immunogenic in adults. The heterologous combination with SOBERANA Plus increased neutralizing antibodies, detectable 7-8 months after the third dose. TRIAL REGISTRY: https://rpcec.sld.cu/trials/RPCEC00000347 FUNDING: This work was supported by Finlay Vaccine Institute, BioCubaFarma, and the Fondo Nacional de Ciencia y Técnica (FONCI-CITMA-Cuba, contract 2020-20).

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.

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.

Efectividad y seguridad del uso de ior® EPOCIM en pacientes en prediálisis Ensayo clínico / Effectiveness and safety in the use of ior® EPOCIM in predialysis patients. Clinical trial

Introducción: El ior® EPOCIM (eritropoyetina humana recombinante) es un medicamento cubano que se produce en el Centro de Inmunología Molecular, el cual ha resultado ser seguro y no se han reportado eventos adversos graves asociados a su uso en pacientes dialíticos; sin embargo, en pacientes en prediálisis la información divulgada sobre su uso es insuficiente. Objetivo: Evaluar la efectividad y seguridad de ior® EPOCIM en pacientes con Enfermedad Renal Crónica en prediálisis, estadios 3 y 4. Material y Métodos: Se realizó un ensayo clínico multicéntrico, abierto, no aleatorizado, fase IV, que incluyó una muestra de 242 pacientes con y sin anemia. Durante 12 meses se evaluó el tratamiento con iorâ EPOCIM, dosis inicial de 30 U/Kg/dosis e incrementó según respuesta hematológica hasta 150 U/Kg/dosis, para lograr estabilización de la hemoglobina entre 10,5-12,5 g/dl y/o hematocrito entre 33-36 por ciento. Resultados: La hemoglobina inicial promedio fue 10 ± 1,5 g/dl, se incrementó progresivamente hasta el cuarto mes, estabilizando su valor en 11,7 ± 1,2 g/dl, y el hematocrito tuvo similar comportamiento. La función renal se mantuvo estable; la calidad de vida mejoró; hubo mayor beneficio en las escalas de rol físico y salud general. Se reportaron 147 eventos adversos; tuvieron alguna relación causal 13,6 por ciento. El evento más frecuente fue la hipertensión arterial. Ninguna muerte estuvo relacionada con el producto. Conclusiones: El ior® EPOCIM fue seguro y efectivo en los pacientes estudiados con Enfermedad Renal Crónica en prediálisis, estadios 3 y 4(AU)

Introduction: The ior® EPOCIM (human recombinant erythropoietin) is a Cuban medicament produce by the Molecular Immunology Center, which result safety, not being adverse results associated to its use in dialytic patients, but regarding predialysis patients the disclosed information is not enough. Objective: To evaluate effectiveness and safety of ior® EPOCIM in patients with Chronic Kidney Disease (CKD) in pre-dialysis, stages 3 and 4. Material and Methods: Was performed a multicenter, opened, non-randomized phase IV clinical trial, which included 242 patients with and without anemia. During a 12 months period was evaluated the treatment with iorâ EPOCIM, with an initial dose of 30 U/kg/dose; and them increase according to the hematologic response up to a dose of 150 U/Kg/ to achieve the hemoglobins stabilization between 10.5-12.5 g/dL and/or hematocrit between 33-36 percent. Results: The initial mean value for hemoglobin was 10 (SD ± 1.5 g / dl) it gradually increased until the 4th month stabilizing its value in 11.7 (SD ± 1.2 g / dl); hematocrit had similar behavior. Renal function remained stable. The life quality improved, was a greater benefit in the scale of the physical role and general health. 147 adverse events were reported; they had some causal relationship 13.6 percent. The most frequent event was hypertension (44.9 percent). No death was related with the product. Conclusions: ior® EPOCIM was safe and effective in this population(AU)

Eficacia y seguridad de la eritropoyetina en la anemia de la prematuridad / Efficacy and safety of erythropoietin for anemia of prematurity

Introducción: la eritropoyetina alfa recombinante forma parte del tratamiento de la anemia de la prematuridad. En Cuba su uso ha sido limitado y controvertido en cuanto a esquema y dosis empleada. Métodos: ensayo clínico prospectivo, multicéntrico, no aleatorizado, de eficacia y seguridad de eritropoyetina en la disminución de transfusiones en el recién nacido pretérmino de muy bajo peso. Se incluyeron 72 neonatos con edad gestacional menor de 34 semanas posmenstruales, y peso al nacer menor o igual a 1 500 g, con más de 7 días posnatales e ingesta de 50 mL/kg/día. Resultados: todos recibieron eritropoyetina 300 U/kg, subcutánea, 3 veces/semana, hasta las 40 semanas de edad gestacional y suplemento de hierro y vitaminas. La eritropoyetina fue muy segura, solo se notificó con relación posible una retinopatía de la prematuridad, ligera y recuperada. Conclusiones: se transfundieron 7 pacientes (9,7 por ciento) en el curso del estudio. El uso tardío de eritropoyetina en el pretérmino de muy bajo peso confirma su eficacia y seguridad(AU)

Introduction: recombinant alpha erythropoietin is part of the treatment for anemia of prematurity. The use of this one in Cuba has been restricted and controversial as to schedule and dose. Methods: prospective, non-randomized multicenter assay on the safety and efficacy of erythropoietin in the reduction of blood transfusion in very-low-weight preterm newborn. Seventy two neonates with gestational age under 34 post-menstruation weeks, weighing equal or less than 1 500 g, over 7 days of life after birth and fed on 50 mL/kg/day were included in the study. Results: all of them received 300 U/kg erythropoietin by subcutaneous administration three times a week up to reaching 40 weeks of gestational age and an iron and vitamin supplement. Erythropoietin is very safe; it was just possibly related to slight retinopathy of prematurity, but overcome. Conclusions: seven patients were transfused (9.7 percent ) in the course of study. The late use of erythropoietin in very-low-weight preterm child confirms its efficacy and safety(AU)

Eficacia y seguridad de la eritropoyetina en la anemia de la prematuridad / Efficacy and safety of erythropoietin for anemia of prematurity

Introducción: la eritropoyetina alfa recombinante forma parte del tratamiento de la anemia de la prematuridad. En Cuba su uso ha sido limitado y controvertido en cuanto a esquema y dosis empleada.Métodos: ensayo clínico prospectivo, multicéntrico, no aleatorizado, de eficacia y seguridad de eritropoyetina en la disminución de transfusiones en el recién nacido pretérmino de muy bajo peso. Se incluyeron 72 neonatos con edad gestacional menor de 34 semanas posmenstruales, y peso al nacer menor o igual a 1 500 g, con más de 7 días posnatales e ingesta de 50 mL/kg/día.Resultados: todos recibieron eritropoyetina 300 U/kg, subcutánea, 3 veces/semana, hasta las 40 semanas de edad gestacional y suplemento de hierro y vitaminas. La eritropoyetina fue muy segura, solo se notificó con relación posible una retinopatía de la prematuridad, ligera y recuperada.Conclusiones: se transfundieron 7 pacientes (9,7 por ciento) en el curso del estudio. El uso tardío de eritropoyetina en el pretérmino de muy bajo peso confirma su eficacia y seguridad(AU)

Introduction: recombinant alpha erythropoietin is part of the treatment for anemia of prematurity. The use of this one in Cuba has been restricted and controversial as to schedule and dose.Methods: prospective, non-randomized multicenter assay on the safety and efficacy of erythropoietin in the reduction of blood transfusion in very-low-weight preterm newborn. Seventy two neonates with gestational age under 34 post-menstruation weeks, weighing equal or less than 1 500 g, over 7 days of life after birth and fed on 50 mL/kg/day were included in the study.Results: all of them received 300 U/kg erythropoietin by subcutaneous administration three times a week up to reaching 40 weeks of gestational age and an iron and vitamin supplement. Erythropoietin is very safe; it was just possibly related to slight retinopathy of prematurity, but overcome.Conclusions: seven patients were transfused (9.7 percent) in the course of study. The late use of erythropoietin in very-low-weight preterm child confirms its efficacy and safety(AU)

Eficacia y seguridad de la eritropoyetina en la anemia de la prematuridad / Efficacy and safety of erythropoietin for anemia of prematurity

Introducción: la eritropoyetina alfa recombinante forma parte del tratamiento de la anemia de la prematuridad. En Cuba su uso ha sido limitado y controvertido en cuanto a esquema y dosis empleada. Métodos: ensayo clínico prospectivo, multicéntrico, no aleatorizado, de eficacia y seguridad de eritropoyetina en la disminución de transfusiones en el recién nacido pretérmino de muy bajo peso. Se incluyeron 72 neonatos con edad gestacional menor de 34 semanas posmenstruales, y peso al nacer menor o igual a 1 500 g, con más de 7 días posnatales e ingesta de 50 mL/kg/día. Resultados: todos recibieron eritropoyetina 300 U/kg, subcutánea, 3 veces/semana, hasta las 40 semanas de edad gestacional y suplemento de hierro y vitaminas. La eritropoyetina fue muy segura, solo se notificó con relación posible una retinopatía de la prematuridad, ligera y recuperada. Conclusiones: se transfundieron 7 pacientes (9,7 por ciento) en el curso del estudio. El uso tardío de eritropoyetina en el pretérmino de muy bajo peso confirma su eficacia y seguridad

Introduction: recombinant alpha erythropoietin is part of the treatment for anemia of prematurity. The use of this one in Cuba has been restricted and controversial as to schedule and dose. Methods: prospective, non-randomized multicenter assay on the safety and efficacy of erythropoietin in the reduction of blood transfusion in very-low-weight preterm newborn. Seventy two neonates with gestational age under 34 post-menstruation weeks, weighing equal or less than 1 500 g, over 7 days of life after birth and fed on 50 mL/kg/day were included in the study. Results: all of them received 300 U/kg erythropoietin by subcutaneous administration three times a week up to reaching 40 weeks of gestational age and an iron and vitamin supplement. Erythropoietin is very safe; it was just possibly related to slight retinopathy of prematurity, but overcome. Conclusions: seven patients were transfused (9.7 percent ) in the course of study. The late use of erythropoietin in very-low-weight preterm child confirms its efficacy and safety

Efficacy and Safety of ior®EPOCIM forChemotherapy- or Radiotherapy-Induced Anemia in Pediatric Cancer Patients

INTRODUCTION: Recombinant human erythropoietin (RHuEPO) is an erythropoiesis stimulating agent (ESA) used to treat anemia in patients with total or relative erythropoietin deficit. In cancer patients, it is administered to optimize hemoglobin (Hb) levels, correct anemia and reduce the need for transfusions. Cuba produces a RHuEPO, registered in 1998 as ior®EPOCIM, that is widely used in the national public health system, mainly to treat patients with anemia due to chronic kidney disease (CKD).OBJECTIVE: Evaluate the efficacy and safety of ior®EPOCIM in pediatric cancer patients with anemia following chemotherapy or radiotherapy. The working hypothesis posed an Hb increase ≥15 g/l in 70 porcent of patients receiving ior®EPOCIM for 8 weeks(AU)

La eritropoyetina: de la eritropoyesis a la cardioprotección / Erythropoietin: from erythropoiesis to cardioprotection

Muchas de las drogas que han mostrado resultados alentadores en el tratamiento de las enfermedades hematológicas y los tumores sólidos, asocian un elevado potencial cardiotóxico. Dentro de este grupo sobresalen las antraciclinas, identificadas como el tipo de quimioterapia que con mayor probabilidad puede causar daño cardiaco, a corto o largo plazo. Con la mejoría alcanzada en la supervivencia de los pacientes portadores de estas enfermedades, este evento adverso se ha convertido en una de las principales preocupaciones para la comunidad científica. Aun cuando han sido muchos los agentes terapéuticos evaluados como posibles cardioprotectores, los datos clínicos disponibles son limitados y no permiten afirmar que el uso de estos agentes favorezca la supervivencia de los pacientes sometidos a tratamientos cardiotóxicos. La identificación del receptor para la eritropoyetina en tejidos no hematopoyéticos, incluyendo el corazón, así como su marcado efecto cardioprotector durante la isquemia han conducido a la hipótesis de que la eritropoyetina podría ser capaz de prevenir la miocardiopatía inducida por las antraciclinas. Abordar esta hipótesis es el objetivo del presente trabajo(AU)

Many of the drugs that has shown promise in the treatment of hematologic malignancies and solid tumors, associated with a high potential cardiotoxic. Within this group stand anthracyclines, identified as the type of chemotherapy most likely to cause heart damage, short or long term. With the improvement achieved in the survival of patients with these diseases, this adverse event has become a major concern for the scientific community. Although many agents have been evaluated as potential cardioprotective therapeutic, clinical data are limited and does not suggest that the use of these agents promotes the survival of patients undergoing cardiotoxic treatments. The identification of erythropoietin receptor in hematopoietic tissues, including the heart, as well as its marked cardioprotective effect during ischemia have led to the hypothesis that erythropoietin may be able to prevent anthracycline-induced cardiomyopathy. Addressing this hypothesis is the objective of this work(AU)

Actividad antioxidante del clorhidrato de triacetonamina in vitro / Antioxidant activity of triacetoneamine hydrochloride in vitro

Se estudiaron los efectos antioxidantes del clorhidrato de triacetonamina (THC) in vitro a través de una serie de ensayos, en los que se analizó la capacidad secuestrante del OHú y quelante de Fe, con el ensayo de la 2 desoxi-d-ribosa y la capacidad secuestrante del O2ú por la autooxidación del pirogalol (2-12 mM THC). Se estudió además la actividad prooxidante del THC (0,1-0,6 mM), sobre el ADN inducida por Cu-fenantrolina y Fe-bleomicina. También se valoró la actividad prooxidante del TH-NOú (10-12 mM) y del THNOOú (10-12 mM), radicales derivados del THC. Finalmente se determinó el efecto del THC sobre la peroxidación lipídica en homogenato de cerebro de rata. Los resultados demostraron que el THC posee capacidad secuestrante del O2ú, con un comportamiento dependiente de la concentración y CI50 de 10 mM de THC. Se encontró efecto protector sobre la 2 desoxi-d-ribosa, tanto por acción quelante de Fe, como por secuestro directo de OHú con una Ks de 4.6 ´ 108 M-1s-1. El THC mostró efecto dependiente de la concentración para el daño sobre el ADN, mientras que el THNOú no dañó a esta molécula, a diferencia del THNOOú que si produjo daño a las concentraciones ensayadas. La peroxidación lipídica en homogenato de cerebro de rata no fue inhibida

Actividad antioxidante del clorhidrato de triacetonamina in vitro / Antioxidant activity of triacetoneamine hydrochloride in vitro

Se estudiaron los efectos antioxidantes del clorhidrato de triacetonamina (THC) in vitro a través de una serie de ensayos, en los que se analizó la capacidad secuestrante del OH· y quelante de Fe, con el ensayo de la 2 desoxi-d-ribosa y la capacidad secuestrante del O2· por la autooxidación del pirogalol (2-12 mM THC). Se estudió además la actividad prooxidante del THC (0,1-0,6 mM), sobre el ADN inducida por Cu-fenantrolina y Fe-bleomicina. También se valoró la actividad prooxidante del TH-NO· (10-12 mM) y del THNOO· (10-12 mM), radicales derivados del THC. Finalmente se determinó el efecto del THC sobre la peroxidación lipídica en homogenato de cerebro de rata. Los resultados demostraron que el THC posee capacidad secuestrante del O2·, con un comportamiento dependiente de la concentración y CI50 de 10 mM de THC. Se encontró efecto protector sobre la 2 desoxi-d-ribosa, tanto por acción quelante de Fe, como por secuestro directo de OH· con una Ks de 4.6 ´ 108 M-1s-1. El THC mostró efecto dependiente de la concentración para el daño sobre el ADN, mientras que el THNO· no dañó a esta molécula, a diferencia del THNOO· que si produjo daño a las concentraciones ensayadas. La peroxidación lipídica en homogenato de cerebro de rata no fue inhibida(AU)