Modelo bayesiano de series temporales estructurales. Aproximación a la evaluación de impacto de VA-MENGOC-BC®

Introducción: Una nueva intervención de salud pública, como la introducción de una vacuna, implica el monitoreo de indicadores que aseguren una intervención efectiva, y que exista la posibilidad de cuantificar sus beneficios. Obtener estimaciones precisas del impacto de una intervención de salud se considera un desafío importante. Objetivos: Estimar el impacto causal de uno de los productos líderes del Instituto Finlay de La Habana: la vacuna cubana registrada y comercializada VA-MENGOC-BC®. Métodos: Se seleccionaron datos en los anuarios estadísticos de salud desde 2009 hasta 2017. Se usaron como variable de interés, la tasa de incidencia de la enfermedad meningocócica en Cuba ( 100 000 habitantes y un conjunto de covariables que no se afectaron por la intervención: tasas de incidencia de fiebre tifoidea, de incidencia de tuberculosis, de mortalidad por enfermedades infecciosas (parasitarias e intestinales) todas ( 100 000 habitantes. Se consideró 1989 como año de la intervención. Se aplicó el método bayesiano de series temporales estructurales, que evaluó el impacto causal de la vacunación sostenida con VA-MENGOC-BC® desde 1989 hasta el presente. Resultados: Se estimó un impacto causal acumulativo significativo en la reducción de la incidencia de la enfermedad meningocócica. Se verificó que se produjo una disminución de la enfermedad en 97,2 %. Conclusiones: La aplicación del método de series de tiempo estructural bayesina para estimar el impacto de la vacuna VA-MENGOC-BC®, constituyó una herramienta novedosa para evaluar el contrafactual. Se proporcionó una apreciación del impacto de la vacunación con VA-MENGOC-BC®, una vacuna implementada y reconocida a nivel mundial.

Introduction: A new public health intervention, such as the introduction of a vaccine, implies monitoring the indicators that guarantee its effectiveness, and the possibility of quantifying its benefits. Obtaining accurate estimates of the impact of a health intervention is considered a major challenge. Objective: To estimate the causal impact of one of the leading products of the Finlay Institute in Havana: the registered and marketed Cuban vaccine VA-MENGOC-BC®. Methods: Data from the health statistics yearbooks from 2009 to 2017 were selected. The incidence rate of the meningococcal disease in Cuba per 100 000 population and a set of co-variables that were not affected by the intervention, such as incidence rate of typhoid fever, tuberculosis, and fatality cases due to infectious diseases (parasitic or intestinal) per 100 000 population were used as variables of interest. The intervention year was 1989. The Bayesian structural time series model was applied to evaluate the causal impact of the continued vaccination with VA-MENGOC-BC® from 1989 to date. Results: A significant cumulative causal impact in reducing the incidence of meningococcal disease was estimated. A decrease of 97.2% in the disease was verified. Conclusions: The application of the Bayesian structural time series model to estimate the impact of the vaccine VA-MENGOC-BC® was a novel tool to estimate the counterfactual. It was provided an estimate of the impact of the vaccination with VA-MENGOC-BC®, an implemented and globally well-known vaccine.

Insight into Prevention of Neisseria Gonorrhoeae: A Short Review.

Neisseria gonorrhoeae (gonococcus) and Neisseria meningitidis (meningococcus) are important global pathogens which cause the sexually transmitted diseases gonorrhea and meningitis, respectively, as well as sepsis. We prepared a review according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA), with the aims of (a) evaluating the data on the MenB vaccination as protection against sexually transmitted infections by N. gonorrhoeae and (b) to briefly comment on the data of ongoing studies of new vaccines. We evaluated existing evidence on the effect of 4CMenB, a multi-component vaccine, on invasive diseases caused by different meningococcal serogroups and on gonorrhea. Non-B meningococcal serogroups showed that the 4CMenB vaccine could potentially offer some level of protection against non-B meningococcal serogroups and N. gonorrhoeae. The assessment of the potential protection conferred by 4CMenB is further challenged by the fact that further studies are still needed to fully understand natural immune responses against gonococcal infections. A further limitation could be the potential differences between the protection mechanisms against N. gonorrhoeae, which causes local infections, and the protection mechanisms against N. meningitidis, which causes systemic infections.

Effect of Biomodulina-T® and VA-MENGOC-BC® on lymphocyte subpopulations in older adults.

INTRODUCTION: The elderly population suffers from the natural process called immunosenescence, which may be related to the high mortality rates it has against the SARS-CoV2 virus, which is why therapies that improve the immune status are required. The combined treatment of the VA-MENGOC-BC® (V-BC) vaccine and the Biomodulina T® (BT) drug could achieve this purpose. This treatment could immunomodulate both the innate and adaptive branches of the immune system simultaneously. OBJECTIVE: To determine the effect of BT and V-BC on the immunomodulation of lymphocyte subpopulations in older adults. METHODS: Our study was carried out in 30 apparently healthy Cuban adults over 65 years of age. The study included three groups of 10 subjects per treatment: a combination of both and the monotherapies. Before and 7 days after treatment, 2 mL of peripheral blood was drawn from each subject. Multiparametric flow cytometry was used to identify lymphocyte subpopulations. For the comparison between the groups, point estimates and the confidence intervals of the Odds Ratio were made. RESULTS: We found that subpopulations of B lymphocytes and natural cytotoxic T (NKT) cells increased only with the administration of BT. Additionally, combination treatments and V-BC did not generate statistically significant immunomodulatory changes in any of the studied lymphocyte subpopulations. CONCLUSIONS: BT presented an immunoenhancing effect on the B and NKT lymphocyte subpopulations of older adults. The three-dose treatment scheme a novel and specific treatment strategy for this formulation. We also were verified that the combined application of V-BC and BT did not have the expected benefits. All these findings suggest that BT administration is a promising approach for immune restoration and to offering protection in elderly patients against COVID-19.

Estudio de tolerancia local de la vacuna antimeningocóccica VA-MENGOC-BC® en ratas Sprague Dawley. Evaluación a los 24 y 36 meses en estante / Local tolerance study of the VA-MENGOC-BC® antimeningococcal vaccine in Sprague Dawley rats. Evaluation at 24 and 36 months of shelf

La meningitis meningocóccica continua siendo un problema de salud en diferentes países y para la prevención de esta enfermedad se han obtenido diferentes vacunas. La vacuna VA-MENGOC-BC® ha constituido ser eficaz y segura en la prevención de la meningitis meningocóccica contra los serogrupos B y C. Esta ha demostrado buena estabilidad en el tiempo sin cambiar su calidad como producto; fue conservada a estante durante 24 y 36 meses a temperaturas de 4 a 8 °C. Se evaluó su posible potencial toxicológico a través de un estudio de tolerancia local en ratas Sprague Dawley para extender su vida útil. Los animales inmunizados se observaron diariamente para evaluar síntomas locales y sistémicos de toxicidad. Se realizaron evaluaciones del peso corporal, consumo de agua y alimento, termometría, musculometría e irritabilidad dérmica por el método de Draize. Se realizaron estudios anatomopatológicos periódicos para observar posibles efectos adversos. No se observaron síntomas de toxicidad ni muertes. No se encontraron diferencias entre los grupos experimentales en cuanto al peso corporal, el consumo de agua y de alimentos, no se evidenció fiebre, ni irritabilidad local. Anatomopatológicamente a nivel del punto de inoculación se observaron procesos granulomatosos de tipo macrofágicos característicos en las vacunas que contienen hidróxido de aluminio. Estos resultados permitieron concluir que la vacuna VA-MENGOC-BC® que permaneció en estante durante 24 y 36 meses no evidenció efectos adversos locales, ni sistémicos en las ratas(AU)

Meningococcal meningitis continues to be a health problem in different countries and different vaccines have been obtained for the prevention of this disease. VA-MENGOC-BC® vaccine has been effective and safe in the prevention of meningococcal meningitis against serogroups B and C. This has shown good stability over time without changing its quality as a product; it was stored on a shelf for 24 and 36 months at temperatures of 4 to 8 °C. Their possible toxicological potential was evaluated through a local tolerance study in Sprague Dawley rats. Immunized animals were observed daily to evaluate local and systemic toxicity symptoms. Body weight, water and feed intake, thermometry, musculometry were performed and dermal irritability by the Draize method. Anatomopathological studies to observe possible adverse effects were made. No symptoms of toxicity or deaths were observed. No differences were found between the experimental groups in terms of body weight, water and food consumption, no fever or local irritability was evident. Anatomopathologically no lesions of diagnostic value were observed, at the site of inoculation, granulomatous processes of macrophagic type characteristic in vaccines containing aluminum hydroxide were observed. These results allowed us to conclude that the VA-MENGOC-BC® vaccine that remained on the shelf for 24 and 36 months did not show any local or systemic effects in rats(AU)

Efectividad de la vacuna antimeningocócica VA-MENGOC-BC® en el primer año de vida, Cuba, 1997-2008 / Effectiveness of the anti-meningococcal vaccine VA-MENGO-BC® in the first year of life of Cuban children, 1997-2008

Introducción: la enfermedad meningocócica constituye un importante problema de salud mundial. Desde 1991 la vacuna VA-MENGOC-BC® se aplica en Cuba a los niños menores de 1 año. Objetivo: evaluar la efectividad de la vacuna VA-MENGOC-BC®. Métodos: para la evaluación poslicenciamiento de VA-MENGOC-BC® se estudiaron los lactantes con enfermedad meningocócica notificados entre 1997 y 2008. Resultados: ocurrieron 114 casos para una incidencia media anual de 7,1/100 000 lactantes. La estimación de la efectividad vacunal media resultó de 84,0 por ciento, oscilando entre 68 y 104 por ciento. La ocurrencia de enfermedad meningocócica en los no vacunados fue de 20,2 por ciento (23/114); 79,8 por ciento (91/114) en lactantes con edad de vacunación y en 75,8 por ciento (69/91) se precisó la fecha de inmunización. Tenían una sola dosis de vacuna aplicada 26,4 por ciento (24/91) y 73,6 por ciento (67/91) recibió el esquema completo (2 dosis). La enfermedad meningocócica predominó en los primeros 6 meses de edad, declinó a partir de este momento y comenzó de nuevo su ascenso a los 10 y 11 meses. Predominó la forma meníngea (89,5 por ciento); la letalidad general fue de 7 por ciento (8/114), con 4,4 por ciento para la meningococemia y 2,6 por ciento para la meningitis. Conclusiones: la efectividad de VA-MENGOC-BC® fue satisfactoria. Se sugiere realizar un análisis por un grupo de expertos sobre la necesidad de aplicar una tercera dosis.

Introduction: meningococcal disease is an important health problem worldwide. Since 1991 the vaccine VA-MENGOC-BC has been used in Cuban under one-year old infants. Objective: to evaluate the effectiveness of the vaccine VA-MENGO-BC®. Methods: for the evaluation after licensing this vaccine, all the infants affected by meningococcal disease between 1997 and 2008 were studied. Results: a total number of 114 cases were recorded. The annual average incidence was 7.1 per 100 000 infants. The mean vaccinal effectiveness for the period was 84.0 percent, ranging from 68 percent to 104 percent. The frequency of disease in unvaccinated children was 20.2 percent (23/114); 79.8 percent (91/114) within the vaccination age, but only 75.8 percent (69/91) of them had confirmed the immunization date. Only 26.4 percent (24/91) had one single dose applied whereas 73.6 percent (67/91) had completed their vaccination schedule (2 doses). The meningococcal disease prevailed in the first six months of life, declined afterwards and then started to rise again at 10 and 11 months of age. The meningeal form of clinical presentation predominated (89.5 percent); case-fatality rate was 7.0 percent (8/114), being 4,4 percent for meningococcemia and 2,6 percent for meningitis. Conclusions: the vaccine VA-MENGOC-BC® effectiveness in infants was satisfactory. It is suggested that further analysis be made by a group of experts on the use of a booster dose.

Efectividad de la vacuna antimeningocócica VA-MENGOC-BC® en el primer año de vida, Cuba, 1997-2008 / Effectiveness of the anti-meningococcal vaccine VA-MENGO-BC® in the first year of life of Cuban children, 1997-2008

Introducción: la enfermedad meningocócica constituye un importante problema de salud mundial. Desde 1991 la vacuna VA-MENGOC-BC® se aplica en Cuba a los niños menores de 1 año. Objetivo: evaluar la efectividad de la vacuna VA-MENGOC-BC®. Métodos: para la evaluación poslicenciamiento de VA-MENGOC-BC® se estudiaron los lactantes con enfermedad meningocócica notificados entre 1997 y 2008. Resultados: ocurrieron 114 casos para una incidencia media anual de 7,1/100 000 lactantes. La estimación de la efectividad vacunal media resultó de 84,0 por ciento, oscilando entre 68 y 104 por ciento. La ocurrencia de enfermedad meningocócica en los no vacunados fue de 20,2 por ciento (23/114); 79,8 por ciento (91/114) en lactantes con edad de vacunación y en 75,8 por ciento (69/91) se precisó la fecha de inmunización. Tenían una sola dosis de vacuna aplicada 26,4 por ciento (24/91) y 73,6 por ciento (67/91) recibió el esquema completo (2 dosis). La enfermedad meningocócica predominó en los primeros 6 meses de edad, declinó a partir de este momento y comenzó de nuevo su ascenso a los 10 y 11 meses. Predominó la forma meníngea (89,5 por ciento); la letalidad general fue de 7 por ciento (8/114), con 4,4 por ciento para la meningococemia y 2,6 por ciento para la meningitis. Conclusiones: la efectividad de VA-MENGOC-BC® fue satisfactoria. Se sugiere realizar un análisis por un grupo de expertos sobre la necesidad de aplicar una tercera dosis(AU)

Introduction: meningococcal disease is an important health problem worldwide. Since 1991 the vaccine VA-MENGOC-BC has been used in Cuban under one-year old infants. Objective: to evaluate the effectiveness of the vaccine VA-MENGO-BC®. Methods: for the evaluation after licensing this vaccine, all the infants affected by meningococcal disease between 1997 and 2008 were studied. Results: a total number of 114 cases were recorded. The annual average incidence was 7.1 per 100 000 infants. The mean vaccinal effectiveness for the period was 84.0 percent, ranging from 68 percent to 104 percent. The frequency of disease in unvaccinated children was 20.2 percent (23/114); 79.8 percent (91/114) within the vaccination age, but only 75.8 percent (69/91) of them had confirmed the immunization date. Only 26.4 percent (24/91) had one single dose applied whereas 73.6 percent (67/91) had completed their vaccination schedule (2 doses). The meningococcal disease prevailed in the first six months of life, declined afterwards and then started to rise again at 10 and 11 months of age. The meningeal form of clinical presentation predominated (89.5 percent); case-fatality rate was 7.0 percent (8/114), being 4,4 percent for meningococcemia and 2,6 percent for meningitis. Conclusions: the vaccine VA-MENGOC-BC® effectiveness in infants was satisfactory. It is suggested that further analysis be made by a group of experts on the use of a booster dose.(AU)

Enfermedad meningocócica: un estudio de caso control en Ciudad Habana, noviembre 2003-julio 2005 / Meningococcal Disease: a case control study in the City of Havana, November 2003- July 2005

Cuba ejecuta un programa de inmunización antimeningocócica desde 1991. El propósito de este estudio fue identificar posibles factores asociados a la ocurrencia de casos en grupos de vacunados. Un total de nueve casos con enfermedad meningocócica (EM) en Ciudad Habana se registraron en el período noviembre de 2003- julio 2005 en menores de 20 años, pero se estudiaron solo 7, por encontrarse uno fuera del país y otro fallecido. Se seleccionaron aleatoriamente 34 controles comunitarios para comparar con los casos e identificar algunos factores de riesgo asociados y evaluar los anticuerpos bactericidas y ELISA existentes contra la proteína de membrana externa del serogrupo B. El 100% de los casos estudiados presentó la forma meníngea, con una estadía hospitalaria promedio de 9,8 días y una letalidad de 14,3 por ciento (1/7). En el análisis bivariado se encontró la no lactancia materna asociada (OR 3,17 IC95 por ciento = 0,44-27,85) a la ocurrencia de la enfermedad, sin significación estadística (p>0,05) por el pequeño universo de estudio. Finalmente, la regresión logística multivariada indicó asociación con la no lactancia materna (OR 3,22 IC95 por ciento = 0,52-19,52) con la ocurrencia de la enfermedad, pero igualmente esta no fue significativa. La prueba de Mann Whitney para la comparación de los títulos de anticuerpos para el antígeno B en casos y controles mostró una diferencia muy significativa (p< 0,01) a favor de los enfermos, por la respuesta de la memoria inmune a la infección natural. La vacuna cubana es protectora para la enfermedad meningocócica serogrupo BC. En el 57 por ciento de los casos de EM los síntomas comenzaron como promedio cuatro años después de la aplicación de la segunda dosis de la vacuna(AU)

Cuba has carried out a meningococcal immunization program since 1991. Current article aims at knowing the factors associated to meningococcal disease (MD) in vaccinated persons. The universe were the nine cases under 20 years old registered as MD from November 2003 to July 2005 in the City of Havana and 34 community controls to compare to the cases and to identify associated risk factors and to evaluate existing bactericide and ELISA antibodies against the outer membrane protein from serogroup B. Only seven cases were studied because one was out of the country and the other was a dead case. The 100% of studied cases showed the meningitis form, with an average hospital stay of 9.8 days and a lethality of 14,3 percent (1/7). Bivariate analysis showed no maternal nursing (OR 3.17 IC 95 percent = 0,44-27.85) associated to the occurrence of the disease. But it was not significant (p>0.05) due to the study universe. Multivariate analysis found out association with no maternal nursing (OR 3.22 IC95 percent = 0.52-19.52) but it also was not significant. Mann Whitney test to compare antibody titers against B antigen in both groups, showed a very significant difference (p<0.01) for the immune memory response to natural infection. The Cuban vaccine protects from MD caused by serogroup BC. The onset symptoms of the illness occurred with an average of four years after the second dose of the vaccine in 57 percent of the cases(AU)

La técnica de Western Blot aplicada a la vacuna antimeningocócica VA MENGOC BC® / Western Blot technique applied to VA MENCOG BC® antimeningococcal vaccine

Se desarrolló y validó la técnica de Western Blot aplicada a la vacuna antimeningocócica VA MENGOC BC® producida en el Instituto Finlay con el objetivo de demostrar criterio de identidad. Con el empleo de esta técnica se identificaron las proteínas antigénicas del tipo P1, P3, P5, 70 y 80 K presentes en la vesícula de membrana externa y vacuna final, por lo cual se utilizó como antisuero la gamma antimeningocócica. Los parßmetros desarrollados en la validación de la técnica fueron: especificidad, límite de detección, repetibilidad, precisión intermedia, reproducibilidad y robustez. La técnica de identidad cumplió con los parámetros se±alados anteriormente, por lo que se considera validada.

ABSTRACT Western Blot technique applied to VA MENGOC BC® antimeningococcal vaccine was developed and validated and produced in "Carlos J. Finlay" Institute to demonstrate the identity criterion. Using this technique it was possible to identify antigenic proteins type P1, P3, P5 70 and 80 K present in the vesicle of external membrane and final vaccine, thus, we used the antimeningococcal gamma. Parameters developed in validation of this technique included: specificity, detection limit, repetition, average accuracy, reproduction, and strength, identity technique fulfilled with abovementioned parameters, considering like validated.

La técnica de Western Blot aplicada a la vacuna antimeningocócica VA MENGOC BC® / Western Blot technique applied to VA MENCOG BC® antimeningococcal vaccine

Se desarrolló y validó la técnica de Western Blot aplicada a la vacuna antimeningocócica VA MENGOC BC® producida en el Instituto Finlay con el objetivo de demostrar criterio de identidad. Con el empleo de esta técnica se identificaron las proteínas antigénicas del tipo P1, P3, P5, 70 y 80 K presentes en la vesícula de membrana externa y vacuna final, por lo cual se utilizó como antisuero la gamma antimeningocócica. Los parßmetros desarrollados en la validación de la técnica fueron: especificidad, límite de detección, repetibilidad, precisión intermedia, reproducibilidad y robustez. La técnica de identidad cumplió con los parámetros se±alados anteriormente, por lo que se considera validada(AU)

ABSTRACT Western Blot technique applied to VA MENGOC BC® antimeningococcal vaccine was developed and validated and produced in "Carlos J. Finlay" Institute to demonstrate the identity criterion. Using this technique it was possible to identify antigenic proteins type P1, P3, P5 70 and 80 K present in the vesicle of external membrane and final vaccine, thus, we used the antimeningococcal gamma. Parameters developed in validation of this technique included: specificity, detection limit, repetition, average accuracy, reproduction, and strength, identity technique fulfilled with abovementioned parameters, considering like validated(AU)