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ABSTRACT Introduction: SOBERANA® 01 was developed at the Finlay Vaccine Institute to combat the epidemic caused by the SARS-CoV-2 virus. This candidate is based on the Receptor Binding Domain (RBD) in dimeric form combined with purified vesicles from outer membrane of serogroup B meningococcus as immunopotentiator of the immune response adsorbed on aluminum hydroxide. Methods: The antigen was designed with the peculiarity of having a free cysteine at position 538, which allows the formation of RBD dimers. In preclinical studies it was evaluated the immunogenicity of the dimer combined with the outer membrane vesicles and they were performed toxicological studies. In addition, it was designed a Phase I clinical study in subjects from 19 to 59 years old. Results: The antigenic presentation in the form of dimer combined with the vesicles proved to be safe and immunogenic in animal models, observing a significant increase in the immune response when compared to the monomeric form. During the Phase I clinical evaluation, which included apparently healthy subjects between the ages of 19 and 59, it was demonstrated that SOBERANA® 01 lead to a significant increase in the neutralizing antibody response compared to the use of aluminum hydroxide as the sole adjuvant. After the third dose, 100% of the subjects seroconverted to the group immunized with SOBERANA® 01. Conclusions: It was demonstrated the immunogenicity and neutralizing capacity of the antibodies induced by SOBERANA® 01. The analysis of the sera of the vaccinated persons demonstrated that the formulation containing the OMVs causes a more potent neutralizing effect against several RBD mutants present in VOCs, including the RBD triple mutants of the beta variant.

RESUMEN Introducción: SOBERANA® 01 se desarrolló en el Instituto Finlay de Vacunas para el enfrentamiento a la epidemia causada por el virus SARS-CoV-2. Este candidato se basa en el dominio de unión al receptor en forma dimérica, combinado con vesículas purificadas de membrana externa de meningococo del serogrupo B como inmunopotenciador de la respuesta inmune adsorbidos en hidróxido de aluminio. Métodos: Se diseñó el antígeno con la peculiaridad de tener una cisteína libre en la posición 538, que permite la formación de dímeros del dominio de unión al receptor. En estudios preclínicos se evaluó la inmunogenicidad del dímero combinado con las vesículas de membrana externa y se realizaron estudios toxicológicos. Además, se diseñó un estudio clínico fase I en sujetos de 19 años a 59 años. Resultados: La presentación antigénica en forma de dímero combinado con las vesículas demostró ser segura e inmunogénica en modelos animales observando un incremento significativo de la respuesta inmune cuando se compara con la forma monomérica. Durante la evaluación clínica fase I, que incluyeron sujetos aparentemente sanos de entre 19 años y 59 años de edad, se demostró que SOBERANA® 01 conduce a un aumento importante en la respuesta de anticuerpos neutralizantes en comparación con el uso de hidróxido de aluminio como único adyuvante. Después de la tercera dosis, el 100 % de los sujetos seroconvirtieron en el grupo inmunizado con SOBERANA® 01. Conclusiones: Se demostró la inmunogenicidad y la capacidad neutralizante de los anticuerpos inducidos por SOBERANA® 01. El análisis de los sueros de las personas vacunadas demostró que la formulación que contiene las vesículas de membrana externa provoca un efecto neutralizante más potente contra varios mutantes del dominio de unión al receptor presentes en los COV, incluidos los mutantes triples del dominio de unión al receptor de la variante Beta.

Open Letter to President Biden about COVID Vaccines for Cuba
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Crombet, Tania

; García, Dagmar

; Guillén, Gerardo

; Herrera, Luis

; Lage, Agustín

; Mauri, Mayda

; Pérez, Rolando

; Valdés-Sosa, Mitchell

; Valdés-Sosa, Pedro

; Vérez, Vicente

MEDICC Review

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dec 2021, Volume 23 N. 3-4 Pages 74 -

Abstract: En | Text: En | PDF: En

Las vacunas Soberana como continuidad de la obra del Dr. Carlos J. Finlay. Reflexión en homenaje a su nacimiento y al Día de la Medicina Panamericana
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Vérez Bencomo, Vicente

; Valdés Balbín, Yury

; Rivera, Dagmar García

Anales de la Academia de Ciencias de Cuba

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apr 2021, Volume 11 N. 1 elocation e975

Abstract: Es | Text: Es | PDF: Es

Effectiveness of a Serogroup B and C Meningococcal Vaccine Developed in Cuba
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Ochoa-Azze, Rolando

; García-Imía, Luis

; Vérez-Bencomo, Vicente

MEDICC Review

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sep 2018, Volume 20 N. 3 Pages 22 - 29

Abstract: En | Text: En | PDF: En

ABSTRACT INTRODUCTION Serogroup B meningococcal outer membrane vesicle vaccines have been effective against vaccine-type strains, but their effectiveness against heterologous strains has been controversial. The Cuban VA-MENGOC-BCvaccine is of this type, but also includes meningococcus C capsular polysaccharide. OBJECTIVES Assess the effectiveness of VA-MENGOC-BC in reducing meningococcal disease caused by homologous or heterologous serogroup B strains and its serological effectiveness against meningococcus C. METHODS A review of studies of VA-MENGOC-BC’s application in Cuba, Brazil, Uruguay and Colombia was carried out to examine the vaccine’s effectiveness in reducing meningococcal disease during serogroup B outbreaks. Serological effectiveness against serogroup C determined in these studies (indicated by bactericidal antibody titers before and after vaccination) was also analyzed. RESULTS VA-MENGOC-BC’s effectiveness against homologous serogroup B strains has consistently been greater than 80% in all age groups. Effectiveness in heterologous contexts was also above 80% in individuals aged >4 years. Lower effectiveness in heterologous contexts was found in Brazilian children aged <2 years, although still >50%. Effectiveness increased when assessed based on mortality rates, as well as in cases of clinically severe meningococcal disease. The carrier-state pattern was modified after vaccination with reduction of hypervirulent lineages. Some 60% of infants (aged <1 year) attained protective bactericidal antibody titers against serogroup C. Higher protection rates were achieved in older children. CONCLUSIONS In addition to prevention of meningococcal disease caused by homologous serogroup B strains, VA-MENGOC-BC should be considered for heterologous contexts. It is protective against serogroup C in all age groups.

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Activación del polisacárido capsular de Streptococcus pneumoniae serotipo 23F para la obtención de vacunas conjugadas
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Chang-Calderón, Janoi

; Serrano-Rodríguez, Yohanna

; Garrido-Arteaga, Raine

; Pedroso-Fernández, Jessy

; Cardoso-San Jorge, Félix

; Rodríguez-Noda, Laura

; Santana-Mederos, Darielys

; García-Rivero, Dagmar

; Valdés-Balbín, Yury

; Vérez-Bencomo, Vicente

Vaccimonitor

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apr 2017, Volume 26 N. 1 Pages 8 - 16

Abstract: Es | Text: Es | PDF: Es

Safety and Immunogenicity of Cuban Antipneumococcal Conjugate Vaccine PCV7-TT in Healthy Adults
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González, Nadezhda

; Paredes, Beatriz

; Pérez, Sonia

; Mirabal, Mayelín

; Rivero, Ivonne

; González, Carlos A.

; Díaz, Alina

; García, Dagmar

; Rodríguez, Laura

; Pérez, Amarilis

; Soroa, Yamilka

; Santana, Darielis

; Álvarez, Alina

; Valdés, Yury

; Vérez, Vicente

MEDICC Review

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oct 2015, Volume 17 N. 4 Pages 32 - 37

Abstract: En | Text: En | PDF: En

INTRODUCTION Pneumococcal infections are a major cause of morbidity and mortality and are associated with considerable economic burden on health systems. To prevent pneumococcal infections, 7-valent conjugate vaccines have been available for over a decade; more recently, 10- and 13-valent conjugate vaccines have been formulated, which are more immunogenic than vaccines with capsular polysaccharides only. In Cuba, a new vaccine candidate has been developed, PCV7-TT, a conjugate of tetanus toxoid with antigens of seven of the serotypes of Streptococcus pneumoniae with highest circulation in Cuba and in the world: 1, 5, 6B, 14, 18C, 19F and 23F. OBJECTIVE Assess the safety of the vaccine candidate PCV7-TT in healthy adults and conduct a preliminary assessment of its immunogenicity. METHODS A phase I, double-blind clinical trial was performed at the National Toxicology Center in Havana, Cuba. Healthy male volunteers aged 18–35 years were randomly assigned to two groups: 20 received the vaccine candidate PCV7-TT and 20 the polyvalent antipneumococcal vaccine PNEUMO-23 used as control, each in a single intramuscular dose. To assess safety, the occurrence of adverse events was monitored for 30 days following inoculation. To explore immunogenicity, concentrations of serotype-specific antibodies was quantified before and 30 days after inoculation, as well titers of opsonophagocytic antibodies. (National Clinical Trial Registry RPCEC00000133) RESULTS Local adverse events were pain, redness, induration, increased sensitivity to touch, and warmth in the injection area. Pain was registered in 70% of individuals who received PCV7-TT and in 75% of those vaccinated with PNEUMO-23. Reported systemic adverse events were general malaise, headache and drowsiness. All adverse events appeared in the first 72 hours post inoculation and lasted no longer than 3 days. One event was reported that was classified as severe in intensity and serious in consequences, but it was unrelated to vaccination—acute appendicitis in one individual inoculated with the control vaccine. Before vaccination, all participants but one had antibody concentrations ≥0.20 μg/ml against the vaccine strains; after vaccination 100% of individuals were positive and the concentrations of antibodies increased in previously positive volunteers. Some individuals had opsonophagocytic antibodies against serotypes 1, 14, 19F and 23F before vaccination, with highest concentrations against serotypes 14 and 19F. After vaccination, the percent of individuals with opsonophagocytic titers ≥1:8 for all serotypes in the vaccine was >50% in both groups. CONCLUSIONS A single dose of candidate vaccine PCV7-TT was safe when used in healthy adults. Preliminary results showed that it was able to activate an immune response against the serotypes of Streptococcus pneumoniae used.

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Procedure for the conjugation of the Streptococcus pneumoniae serotype 6B capsular polysaccharide to the tetanus toxoid
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Soubal, Jean P

; Peña, Luis

; Santana, Darielys

; Valdés, Yury

; García, Dagmar

; Pedroso, Jessy

; Cardoso, Félix

; González, Humberto

; Fernández, Violeta

; Vérez, Vicente

Biotecnología Aplicada

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sep 2013, Volume 30 N. 3 Pages 208 - 215

Abstract: En Es | Text: En Es | PDF: En | PDF: Es

Streptococcus pneumoniae causes annually 826 000 deaths in children under five years. The serotype 6B, one of higher incidence, is targeted by the Cuban research and development project to develop a conjugate vaccine. There is limited data on how modifications caused by conjugation affect the physicochemical and antigenic characteristics of polysaccharides, particularly for serotype 6B capsular polysaccharide (PS6B), despite being the least immunogenic among S. pneumoniae polysaccharides. In this work, a conjugation procedure was established for PS6B comprising: fragmentation by acid hydrolysis, activation by periodate oxidation, and conjugation to tetanus toxoid (TT) by reductive amination to increase its immunogenicity. Reaction conditions were set to obtain the polysaccharide in three molecular size ranges (1-10, 10-30, 30-100 kDa) and levels of oxidation. PS6B fragmentation below 10 kDa and oxidation above 24 % of the repetitive units implied the loss of antigenicity. Polysaccharide length but not oxidation level had an impact on the physicochemical characteristics of the conjugates in the tested conditions. Unlike the native polysaccharide, conjugated 10-30 kDa and 30-100 kDa PS6B were immunogenic in rabbits, with evidence of thymus-dependent response. The procedure described supports obtaining PS6B-TT conjugates reproducibly in the 30-100 kDa and 10-30 kDa molecular size ranges and with 8-18 % oxidized repeat units, which are immunogenic.

Anualmente Streptococcus pneumoniae provoca 826 mil muertes de niños menores de cinco años. El estudio del serotipo 6B, uno de los de mayor incidencia, es uno de los objetivos del proyecto de investigación-desarrollo para obtener una vacuna conjugada en Cuba. La estrategia de conjugación del polisacárido capsular del serotipo 6B (PS6B) fue fragmentarlo mediante hidrólisis ácida, activarlo mediante oxidación con peryodato y conjugarlo a toxoide tetánico (TT) mediante aminación-reductiva. Existe poca información sobre cómo estas modificaciones afectan las características físico-químicas y antigénicas del polisacárido, en particular para PS6B, a pesar de ser el menos inmunogénico de los polisacáridos de S. pneumoniae. En tal sentido, se estableció un procedimiento para obtener conjugados inmunogénicos de PS6B a TT. Se crearon condiciones de reacción para obtener el polisacárido en tres rangos de tallas y niveles de oxidación. Se determinó que la fragmentación del polisacárido por debajo de 10 kDa y la oxidación de más del 24 % de las unidades repetitivas implican pérdida de antigenicidad. La talla del polisacárido tuvo impacto en las características físico-químicas de los conjugados en las condiciones evaluadas; no así el nivel de oxidación. A diferencia del polisacárido nativo, conjugados de PS6B de 10 a 30 kDa y 30 a 100 kDa fueron inmunogénicos en conejos, con evidencias de respuesta timo-dependiente. Los procedimientos que incluyen la obtención del PS6B de 10 a 30 kDa y 30 a 100 kDa con niveles de oxidación entre 8 y 18 % de las unidades repetitivas oxidadas, permitieron obtener conjugados a TT reproducibles e inmunogénicos.

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Resonancia magnética nuclear: nuevas aplicaciones en la cuantificación y la evaluación de intermediarios de vacunas basadas en polisacáridos
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Garrido, Raine

; Vélez, Herman

; Vérez, Vicente

Vaccimonitor

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apr 2013, Volume 22 N. 1 Pages 35 - 42

Abstract: En Es | Text: En Es | PDF: En | PDF: Es

Nuclear Magnetic Resonance has become the choice for structural studies, identity assays and simultaneous quantification of active pharmaceutical ingredient of different polysaccharide-based vaccine. In the last two decades, the application of quantitative Nuclear Magnetic Resonance had an increasing impact to support several quantification necessities. The technique involves experiments with several modified parameters in order to obtain spectra with quantifiable signals. The present review is supported by some recent relevant reports and it discusses several applications of NMR in carbohydrate-based vaccines. Moreover, it emphasizes and describes several parameters and applications of quantitative Nuclear Magnetic Resonance.

La resonancia magnética nuclear (RMN) constituye una fuerte alternativa para estudios estructurales, evaluación de identidad y cuantificación de ingredientes farmacéuticos activos (IFA). En las dos últimas décadas la aplicación de la resonancia magnética nuclear cuantitativa (RMNc) tuvo un creciente impacto en la cuantificación de compuestos, fundamentalmente orgánicos. Varios resultados obtenidos mediante la RMNc han ido creando un lugar para la técnica en la industria biofarmacéutica. La RMNc incluye experimentos de RMN con algunos parámetros modificados, con el objetivo de obtener señales cuantificables. Basada en algunos de los reportes más relevantes, la presente revisión aborda algunas de las aplicaciones de la RMN para vacunas basadas en polisacáridos o glicoproteínas. El trabajo hace especial énfasis en detallar algunos aspectos que caracterizan la RMNc, así como sus aplicaciones.

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Caracterización de conjugados inmunogénicos de polisacárido capsular Streptococcus pneumoniae serotipo 14
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Chang, Janoi

; Serrano, Yohanna

; Garrido, Raine

; Pedroso, Jessy

; Cardoso, Felix

; García, Dagmar

; González, Domingo

; Herrera, Yanelis

; Santana, Darielys

; Valdés, Yury

; Fernández, Violeta

; Vérez, Vicente

Vaccimonitor

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apr 2013, Volume 22 N. 1 Pages 15 - 21

Abstract: En Es | Text: En Es | PDF: En | PDF: Es

Conjugate vaccines consisting of bacterial polysaccharides linked through a covalent bond to a carrier protein have a major impact on childhood immunization schemes which have dramatically decrease the incidence of bacterial infections. In the case of Streptococcus pneumoniae more than 90 serotypes have been reported, based on the structure of the polysaccharide capsules and at least 23 of them have demonstrated clinical importance. A limited number of 7 or more recently 10 and 13 are included in licensed conjugate vaccines. On the other hand, the increasing need for these vaccines worldwide requires the incorporation of new manufacturers who are facing highly complex technology since the entire conjugation process can not affect the structural features for which the polysaccharide is immunologically recognized. Our paper provides a conjugation procedure for the capsular polysaccharide of Streptococcus pneumoniae serotype 14. The process includes fragmentation, peryodic oxidation and subsequent conjugation to tetanus toxoid or diphtheria toxoid to the polysaccharide, each intermediate was characterized by physico-chemical methods. Yields higher than 50% were obtained in all reactions. The conjugates generated high titers of IgG specific antibodies and immunological memory. In conclusion, the procedure allows immunogenic conjugates of serotype 14.

Las vacunas conjugadas que consisten en polisacáridos bacterianos unidos a través de un enlace covalente a una proteína portadora, han tenido un gran impacto en los esquemas de vacunación infantil, disminuyendo de forma dramática la incidencia de infecciones bacterianas. En el caso de Streptococcus pneumoniae, a pesar de que se han descrito más de 90 serotipos basados en la estructura de las cápsulas polisacarídicas y que al menos 23 tienen una importancia clínica demostrada, solo un número limitado de siete, o más recientemente 10 y 13, están incluidocaracterísticas estructurales por las que el polisacárido es reconocido inmunológicamente. Este trabajo implementó un procedimiento de conjugacs en las vacunas conjugadas licenciadas. Por otra parte, la necesidad creciente de estas vacunas en el mundo requiere la incorporación de nuevos productores que se enfrentan a una elevada complejidad tecnológica, pues en todo el procedimiento de conjugación no se pueden afectar las ión para el polisacárido de la cápsula de Streptococcus pneumoniae serotipo 14. El procedimiento comprendió la fragmentación, oxidación peryódica y posterior conjugación del polisacárido a anatoxina tetánica o diftérica. Cada intermedio fue caracterizado por métodos físico-químicos. En todas las reacciones se obtuvieron rendimientos superiores al 50%. Los conjugados generaron altos títulos de anticuerpos específicos de tipo IgG y memoria inmunológica. Se concluyó que el procedimiento permitió la obtención de conjugados inmunogénicos de serotipo 14.

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