CIGB-247 is a cancer vaccine that is a formulation of a recombinant protein antigen representative of the human vascular endothelial growth factor (VEGF) with a bacterially-derived adjuvant (VSSP). The vaccine has shown an excellent safety profile in mice, rats, rabbits, not-human primates and in recent clinical trials in cancer patients. Response to the vaccine is characterized by specific antibody titers that neutralize VEGF/VEGFR2 binding and a cytotoxic tumor-specific response. To expand our present anti-VEGF active immunotherapy strategies, we have now studied in mice and non-human primates the effects of vaccination with a formulation of our recombinant VEGF antigen and aluminum phosphate adjuvant (hereafter denominated CIGB-247-A). Administered bi-weekly, CIGB-247-A produces high titers of anti-VEGF IgG blocking antibodies in 2 mice strains. Particularly in BALB/c, the treatment impaired subcutaneous F3II mammary tumor growth and reduced the number of spontaneous lung macro metastases, increasing animals' survival. Spleen cells from specifically immunized mice directly killed F3II tumor cells in vitro. CIGB-247-A also showed to be immunogenic in non-human primates, which developed anti-VEGF blocking antibodies and the ability for specific direct cell cytotoxic responses, all without impairing the healing of deep skin wounds or other side effect. Our results support consideration of aluminum phosphate as a suitable adjuvant for the development of new vaccine formulations using VEGF as antigen.
Developing affordable and easily manufactured SARS-CoV-2 vaccines will be essential to achieve worldwide vaccine coverage and long-term control of the COVID-19 pandemic. Here the development is reported of a vaccine based on the SARS-CoV-2 receptor-binding domain (RBD), produced in the yeast Pichia pastoris. The RBD was modified by adding flexible N- and C-terminal amino acid extensions that modulate protein/protein interactions and facilitate protein purification. A fed-batch methanol fermentation with a yeast extract-based culture medium in a 50 L fermenter and an immobilized metal ion affinity chromatography-based downstream purification process yielded 30-40 mg/L of RBD. Correct folding of the purified protein was demonstrated by mass spectrometry, circular dichroism, and determinations of binding affinity to the angiotensin-converting enzyme 2 (ACE2) receptor. The RBD antigen also exhibited high reactivity with sera from convalescent individuals and Pfizer-BioNTech or Sputnik V vaccinees. Immunization of mice and non-human primates with 50 µg of the recombinant RBD adjuvanted with alum induced high levels of binding antibodies as assessed by ELISA with RBD produced in HEK293T cells, and which inhibited RBD binding to ACE2 and neutralized infection of VeroE6 cells by SARS-CoV-2. Additionally, the RBD protein stimulated IFNγ, IL-2, IL-6, IL-4 and TNFα secretion in splenocytes and lung CD3+-enriched cells of immunized mice. The data suggest that the RBD recombinant protein produced in yeast P. pastoris is suitable as a vaccine candidate against COVID-19.
Background: COVID-19 in paediatric ages could result in hospitalizations and death. In addition, excluding children from vaccination could turn them into reservoirs of the SARS-COV-2. Safe and effective COVID-19 vaccines are urgently needed for large-scale paediatric vaccination. ISMAELILLO study aimed to evaluate safety and immunogenicity of two strengths of a new recombinant receptor-binding domain (RBD) protein vaccine (Abdala) in paediatric population.Methods: A double-blinded, multicentre, randomised, phase 1/2 clinical trial was conducted in nine polyclinics in the province of Camagüey, Cuba. Healthy children and adolescents were stratified according to age (3–11 years, or 12–18 years old) and they were assigned by randomization (1:1; block size four) in two dosage levels groups of vaccine to receive three intramuscular doses of 25 µg or 50 µg of RBD, 14 days apart. Main safety endpoint was analyzed in who had received at least one dose vaccination, as the percentage of serious adverse reactions during vaccination, up to 28 days after the third dose (Day 56). The primary immunogenicity endpoint assessed was seroconversion rate of anti-RBD IgG antibody at day 56. The immunogenicity outcomes were assessed in the per-protocol population. This trial is registered with Cuban Public Registry of Clinical Trials, RPCEC00000381.Findings: Between July 15, 2021, and August 16, 2021, 644 paediatric subjects were screened, of whom 592 were enrolled, after verifying that they met the selection criteria: firstly 88 were included in Phase 1 of the study and 504 who completed Phase 2. The vaccine was well tolerated. Injection site pain was the most frequently reported local event (143 [8·4%] of 1707 total doses applied), taking place in 66/851 (7·8%) in the 25 μg group and in 77/856 (9·0%) in the 50 μg. The most common systemic adverse event (AE) was cephalea: 23/851 (2·7%) in the 25 μg group and 19/856 (2·2%) in the 50 μg. Reactogenicity was mild or moderate in severity, represented in 75% of cases by local symptoms, completely resolved in the first 24-48 hours. Twenty-eight days after the third dose, seroconversion anti-RBD IgG were observed in 98·2% of the children and adolescents (231/234) for the 50 μg group and 98·7% (224/228) for the 25 μg group without differences between both strength. The specific IgG antibody geometric mean titres (GMT) showed higher titres between participants who received Abdala 50 µg (231·3; 95% CI 222·6-240·4) compared to those who received 25 µg (126·7; 95% CI 121·9-131·7). The mean ACE2 inhibition %, were 59·4% for 25 µg, and for 50 µg, 72·9%, (p <0·01). Both strength elicited neutralising activity against the SARS-CoV-2, specifically, (18·3; 95% CI 14·7-22·78) for Abdala 25 µg and (36·4; 95% CI 30·26-43·8) for 50 µg to the selected sample analyzed.Interpretation: Abdala vaccine was safe and well tolerated at both antigenic strength levels tested in participants aged between 3 and 18 years of age. Regarding immunogenicity, Abdala Vaccine stimulated the production of specific IgG antibodies against the RBD of SARS-CoV-2, as well as ACE2 inhibition titres and neutralising antibodies (Nab) in the children and adolescents.Trial Registration: This trial is registered with Cuban Public Registry of Clinical Trials, RPCEC00000381.Funding: Centre for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.Declaration of Interest: ZCE, NLFB, ROM, ICL, MAV, FHB, GLP, GFC, JLRR, GMS, MLF, MAA, and VLMG, are employees of the Center for Genetic Engineering and Biotechnology, Havana, Cuba (CIGB), sponsor of the trial as manufacture centre of Abdala vaccine. ACE, is employee of the Camaguey-based CIGB unit. All the other authors declare no competing interests.Ethical Approval Statement: The study was designed and conducted under the observance of Good Clinical Practice guidelines, as well as national regulatory requirements 16-19 The protocol was approved, after its evaluation, by twoResearch Ethics Committees: Pedro Kourí Institute of Tropical Medicine (IPK) Research Ethics Committee and the one corresponding to the Provincial Centre of Hygiene and Epidemiology of Camagüey. The clinical trial was also authorized by the Cuban national authority, (CECMED).
A phase 1–2, prospective, multicenter, randomized, open-label clinical trial (Code RPCEC00000382), with parallel groups, involving 1161 participants, was designed to assess the safety and immunogenicity of two Cuban COVID-19 vaccines (Mambisa and Abdala) in boosting COVID-19 immunity of convalescent adults after receiving one dose of either vaccine. The main safety outcome was severe vaccination adverse events occurring in <5% of vaccinees. Main immunogenicity success endpoints were a ≥4-fold anti-RBD IgG seroconversion or a ≥20% increase in ACE2-RBD inhibitory antibodies in >55% of vaccinees in Phase 1 and >70% in Phase 2. Neutralizing antibody titers against SARS-CoV-2 variants were evaluated. Both vaccines were safe—no deaths or severe adverse events occurred. Mild intensity adverse events were the most frequent (>73%); headaches predominated for both vaccines. Phase 1 responders were 83.3% (p = 0.0018) for Abdala. Mambisa showed similar results. Phase 2 responders were 88.6% for Abdala (p < 0.0001) and 74.2% for Mambisa (p = 0.0412). In both phases, anti-RBD IgG titers, inhibition percentages and neutralizing antibody titers increased significantly after the booster dose. Both vaccines were safe and their immunogenicity surpassed the study endpoints.
Background: The COVID-19 pandemic demanded the urgent development of vaccines against SARS-CoV-2 for both adults and paediatric population. We evaluated the safety, immunogenicity and efficacy of Abdala, a protein subunit COVID-19 vaccine, in children and adolescents aged 3-18 years.Methods: A phase 2, open-label, uncontrolled, single-arm clinical trial was carried out in Centre of Medical and Surgical Research, Havana, Cuba. Subjects aged from 3 to 18 years (healthy or with controlled comorbidities), whose parents gave their written informed consent were eligible. The Abdala vaccine was administered intramuscularly to all participants, 0·5 mL in the deltoid region, in a three-dose immunization schedule at 0-14-28 days. The main endpoints were safety and the extrapolation of the efficacy of Abdala in paediatric population from an immunobridging analysis with a non-inferiority design, based on the comparison of the geometric mean and seroresponse of neutralizing antibodies to SARS-CoV-2 ,with adults (19-21 years) from Phase 3 trial, where clinical efficacy of the vaccine was previously demonstrated. The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000390.Findings: From 13 to 17 September, 2021, 703 children and adolescents were included in the context of predominantly SARS-CoV-2's Delta variant circulation. The incidence of adverse reactions were 264/703 (37·6%) individuals. Adverse reactions were mostly mild, and from the injection site, which resolved in the first 24-48 hours. No severe adverse events with demonstrated cause-effect relationship attributable to the vaccine were reported. For the non-inferiority comparison of 297 children, aged 3-11 years, with 297 adults aged 19-21 years, the GMT ratio of SARS-CoV-2 neutralising antibodies (NAb) was 0·87 (95% CI 0·69 - 1·08) and 1.07 (95% CI 0·82 - 1·39) in the same comparison for 203 adolescents, aged 12-18 years and 203 adults . For both age groups the lower limit of GMT was higher than 0·67. The differences in seroresponse rates of Nab for children was 1 % (95% CI -2 %, 4 %) and -3% (95% CI -7 %, 1 %) for adolescents. For both paediatric groups the differences were higher than -10%. Pearson's linear between the logarithm of the NAb titters against SARS-CoV-D614 G and Omicron BA1 showed strong and significant correlations after the completion of the immunization schedule: 0·86 (0·76-0·92) in children, 0·90 (95% CI 0·83-0·94) for adolescents, and 0·90 (0·83-0·94) in adults.Interpretation: The Abdala vaccine was safe, well tolerated and immunogenic in paediatric population (aged 3-18 years), with demonstrated efficacy based of non-inferior analysis with adults. In addition, the vaccine is very suitable to fit into massive vaccination strategies, considering the advantages to use the same vaccine strength for both adults and children (RBD 50 µg), the same schedule of administration, as well as the easy storage and handling conditions at 2-8˚C.Trial Registration: The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000390.Funding: Centre for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.Declaration of Interest: Authors FHB, JQG, YMB, KaUP, KlUP, JLRR, MAV, ZCE, MLF, MAA and VLMG, are employees of the Centre for Genetic Engineering and Biotechnology, Havana Network, where Abdala vaccine active ingredient is produced and the formulation was developed. The remaining authors have no conflict of interests. No honoraria, consulting fees or payments for seminar presentations, speeches or appearances have been received by any of the authors.Ethical Approval: The protocol followed the Declaration of Helsinki guidelines and was evaluated by the Ethics and Review Committee of the Centre of Medical and Surgical Research in Havana (clinical site), who granted ethical approval of the study.
Abstract Background The pandemic of COVID-19 raised the urgent need of safe and efficacious vaccines against SARS-CoV-2. We evaluated the efficacy and safety of a new SARS-CoV-2 virus receptor-binding domain (RBD) vaccine. Methods A phase 3, multicentre, randomised, double-blind, placebo-controlled trial was carried out at 18 clinical sites in three provinces of the south-eastern region of Cuba. Subjects (healthy or those with controlled chronic diseases) aged between 19 and 80 years, who gave written informed consent were eligible. Subjects were randomly assigned (1:1, in blocks) to two groups: placebo, and 50 µg RBD vaccine (Abdala). The product was administered intramuscularly, 0.5 mL in the deltoid region, in a three dose immunization schedule at 0-14-28 days. The organoleptic characteristics and presentations of vaccine and placebo were identical. All participants (subjects, clinical researchers, statisticians, laboratory technicians, and monitors) remained blinded during the study period. The main endpoint was to evaluate the efficacy of the Abdala vaccine in the prevention of symptomatic COVID-19. The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000359. Findings Between March 22 to April 03, 2021, 48290 subjects were included (24144 and 21146 in the placebo and Abdala groups, respectively). The product was well tolerated. No severe adverse events with demonstrated cause-effect relationship attributable to vaccine were reported. The incidence of adverse reactions in the placebo and Abdala vaccine arms were 446/24144 (1.9%) and 615/24146 (2.5%), respectively. Adverse reactions were mostly mild, and from the injection site, which resolved in the first 24-48 hours. The Abdala vaccine efficacy against symptomatic COVID-19 was 92.28% (95% CI 85.74-95.82). In the case of mild/moderate disease the vaccine efficacy was 91.96% (84.69-95.78) and 94.46% (58.52-99.28) for the severe forms (serious/critical disease). There were five critical patients (of which four died), all in the placebo group, indicating that Abdala vaccine efficacy for both conditions was of 100%. Interpretation The Abdala vaccine was safe, well tolerated, and highly effective, fulfilling the WHO target product profile for COVID-19 vaccines. Funding Centre for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.
Este trabajo surge del proyecto “Los procesos de innovacion en las practicas educativas basados en la incorporacion de las TIC”. Tiene como objetivos: 1) Analizar informacion dada por estudiantes y docentes sobre el desempeno estudiantil e 2) Inferir, para el contexto, las implicancias en los procesos de ensenanza y aprendizaje. Se consideran las fases metodologicas de la investigacion de diseno correspondientes al analisis de informacion obtenida de la aplicacion de instrumentos como el Cuestionario y la Hoja de Control. La triangulacion se realizo para constatar la credibilidad de los resultados que emergen de diferentes fuentes al adoptar un enfoque mixto (cuali-cuantitativo). Integraron la muestra 12 estudiantes que cursaron durante el ano 2014 la asignatura Fisica I en la Facultad de Ciencias Exactas y Naturales de la Universidad Nacional de Catamarca. La metodologia de ensenanza incorporo el uso de simulaciones en la estrategia de resolucion de problemas sobre el tema Cinematica y Dinamica traslacional. La creacion de un ambiente de aprendizaje constructivista no cumplio con las expectativas sobre todo en relacion a la comprension conceptual de los estudiantes.
Objectives We evaluated the safety, immunogenicity and efficacy of Abdala, a protein subunit vaccine for 2019 coronavirus disease (COVID-19), in children and adolescents. Methods A phase 2, open-label, single-arm clinical trial was carried out. Subjects aged 3 to 18 years were eligible. Abdala vaccine was administered intramuscularly at 0-14-28 days. The main endpoints were safety and the immunobridging analysis with a non-inferiority design, to infer the efficacy of the vaccine in paediatric population based on the comparison of neutralizing antibodies (NAb) to SARS-CoV-2, with adults (19-21 years). The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000390. Results From September 13th to September 17th, 2021, 703 participants were included in the context of a predominantly SARS-CoV-2 Delta variant circulation. The number of individuals who experienced adverse reactions was 264/703 (37·6%). Adverse reactions were mostly mild and occurred at the injection site, which resolved within the first 24-48 h. There were no reports of severe adverse events. For the non-inferiority comparison of 297 children (3-11 years) with 297 adults, the geometric mean (GMT) ratio of SARS-CoV-2 NAb was 0·87 (95% CI 0·69-1·08) and 1·07 (0·82-1·39) in the same comparison for 203 adolescents (12-18 years) and 203 adults. For both age groups, the lower limit of GMT was higher than 0·67. The differences in seroresponse rates of Nab for children were 1% (-2%, 4%) and -3% (-7%, 1%) for adolescents, higher than -10% in both age groups. Conclusions The Abdala vaccine was safe and immunogenic in a paediatric population aged 3-18 years, with inferred efficacy based on non-inferior analysis. The vaccine is very suitable to fit into massive vaccination strategies, considering the advantages of using the same vaccine strength (RBD 50 μg) and schedule of administration for both adults and children, as well as the easy storage and handling conditions at 2-8 °C.
BackgroundCOVID-19 in paediatric ages could result in hospitalizations and death. In addition, excluding children from vaccination could turn them into reservoirs of the SARS-COV-2. Safe and effective COVID-19 vaccines are urgently needed for large-scale paediatric vaccination. ISMAELILLO study aimed to evaluate safety and immunogenicity of two strengths of a new recombinant receptor-binding domain (RBD) protein vaccine (Abdala) in paediatric population.MethodsA double-blinded, multicentre, randomised, phase 1/2 clinical trial was conducted in nine polyclinics in the province of Camagüey, Cuba. Healthy children and adolescents were stratified according to age (3–11 years old, or 12–18 years old) and they were randomly assigned (1:1; block size four) in two dosage level groups of vaccine to receive three intramuscular doses of 25 μg or 50 μg of RBD, 14 days apart. Main safety endpoint was analyzed as the percentage of serious adverse reactions during vaccination up to 28 days after the third dose (Day 56) in participants who received at least one dose vaccination. The primary immunogenicity endpoint assessed was seroconversion rate of anti-RBD IgG antibody at day 56. The immunogenicity outcomes were assessed in the per-protocol population. This trial is registered with Cuban Public Registry of Clinical Trials, RPCEC00000381.FindingsBetween July 15, 2021, and August 16, 2021, 644 paediatric subjects were screened, of whom 592 were enrolled after verifying that they met the selection criteria: firstly 88 were included in Phase 1 of the study and 504 who completed Phase 2. The vaccine was well tolerated. Injection site pain was the most frequently reported local event (143 [8·4%] of 1707 total doses applied), taking place in 66/851 (7·8%) in the 25 μg group and in 77/856 (9·0%) in the 50 μg. The most common systemic adverse event (AE) was headache: 23/851 (2·7%) in the 25 μg group and 19/856 (2·2%) in the 50 μg. Reactogenicity was mild or moderate in severity, represented in 75% of cases by local symptoms, completely resolved in the first 24–48 h. Twenty-eight days after the third dose, seroconversion anti-RBD IgG were observed in 98·2% of the children and adolescents (231/234) for the 50 μg group and 98·7% (224/228) for the 25 μg group without differences between both strength. The specific IgG antibody geometric mean titres (GMT) showed higher titres between participants who received Abdala 50 μg (231·3; 95% CI 222·6–240·4) compared to those who received 25 μg (126·7; 95% CI 121·9–131·7). The mean ACE2 inhibition %, were 59·4% for 25 μg, and for 50 μg, 72·9% (p < 0·01). Both strength elicited neutralising activity against the SARS-CoV-2, specifically (18·3; 95% CI 14·7–22·78) for Abdala 25 μg and (36·4; 95% CI 30·26–43·8) for 50 μg to the selected sample analyzed.InterpretationAbdala vaccine was safe and well tolerated at both antigenic strength levels tested in participants aged between 3 and 18 years. Regarding immunogenicity, Abdala Vaccine stimulated the production of specific IgG antibodies against the RBD of SARS-CoV-2 as well as the production of ACE2 inhibition titres and neutralising antibodies (Nab) in children and adolescents.FundingCentre for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba.
