Dosis única de la vacuna oral de la cepa viva atenuada 638 de Vibrio cholerae essegura e inmunogénica en voluntarios adultos en Mozambique / A single dose of live-attenuated 638 Vibrio cholerae oral vaccine is safe and immunogenic in adult volunteers in Mozambique

Se realizó un ensayo clínico controlado con placebo, aleatorizado y a doble ciego, para evaluar la seguridad, reactogenicidad e inmunogenicidad del candidato vacunal liofilizado contra el cólera de la cepa viva atenuada 638 de V. cholerae O1 El Tor Ogawa. Se incluyeron 120 voluntarios de ambos sexos, aparentemente sanos, entre 18 y 50 años de edad, en Maputo, Mozambique, un área endémica de cólera, donde la seroprevalencia del virus de inmunodeficiencia humana (VIH) es de 20 por ciento a 30 por ciento. Ochenta sujetos recibieron como tratamiento una dosis oral de 2 x 10 9 UFC del candidato vacunal 638 y otros 40 una dosis del placebo que contenía solo los lioprotectores. Se realizó seguimiento ambulatorio de los eventos adversos durante 30 días. La respuesta inmune se evaluó por medio de la estimación de la tasa de seroconversión y la media geométrica del título (MGT) de anticuerpos vibriocidas en los sueros de los voluntaries, antes y a los 14 y 21 días posteriores a la inmunización. No se reportaron eventos adversos graves. La incidencia de eventos adversos reportados en el grupo que recibió la vacuna fue similar al del grupo placebo. Los eventos adversos encontrados fueron independientes de la detección de anticuerpos contra el VIH-1, VIH-2, hepatitis (H) A, HC y el antígeno de superficie del virus de la hepatitis B. La presencia de helmintos no modificó la incidencia de eventos adversos. La cepa vacunal fue aislada en 37 (46,25 por ciento) voluntarios que recibieron la vacuna. A los 14 días el pico de la MGT de anticuerpos vibriocidas en el grupo de la vacuna fue de 9056 frente a 39 en el grupo placebo, con una seroconversión total de 97,4 por ciento a los 21 días. Se concluye que el candidato vacunal 638 es seguro e inmunogénico en una región endémica de cólera(AU)

A placebo-controlled randomized, double-blind, clinical trial was carried out to assess the safety, reactogenicity,and immunogenicity of the lyophilized vaccine candidate against cholera derived from the live attenuated 638Vibrio cholerae O1 El Tor Ogawa strain. One hundred and twenty presumably healthy female and male adultvolunteers aged between 18 and 50 years were included. They were from Maputo, Mozambique a cholera endemicarea, where, in addition, human immunodeficiency virus (HIV) seroprevalence is from 20 to 30 percent A dose of 2 x 109 colony forming units (CFU) was given to 80 subjects and other 40 received only vaccine lyoprotectors as a placebocontrol. Out-patient follow-up of adverse events was carried out during the following 30 days after vaccination.The immune response was evaluated by the estimation of seroconversion rate and the geometric mean titer(GMT) of vibriocidal antibodies in the sera from volunteers that was collected previously, and at days 14 and 21after immunization. No serious adverse events were reported. The adverse events found in the vaccine groupwere similar to those of the placebo groups. They were independent from the detection of antibodies againstHIV-1, HIV-2, hepatitis (H) A; HC and hepatitis B surface antigen. The presence of helminthes did not modify the incidence of adverse events. The 638 vaccine strain was isolated in 37 (46,25 percent) vaccinated volunteers feces. The peak of the GMT of vibriocidal antibodies in the vaccine group was 9056 versus 39 in the placebo group at 14 dayswith a total seroconversion of 97,4 percent at 21 days. The 638 vaccine candidate is safe and immunogenic in a cholera endemic region(AU)

Nuevos enfoques sobre la aplicación de vacunas orales contra el cólera / New approaches to the implementation of oral cholera vaccines

El cólera constituye un problema de salud para muchos países en el mundo: las elevadas tasas de morbilidad y mortalidad registradas en los últimos años inquietan a la comunidad científica, pues el aumento de su incidencia podría generar una crisis global en su control. Existen factores claves en su reemergencia, entre ellos están el debilitamiento general de las actividades de salud pública, sobre todo las involucradas en la vigilancia y el deterioro de los laboratorios encargados de identificar cuanto antes a los microorganismos emergentes, así como la circulación en África y Asia de nuevas cepas de Vibrio cholerae O1 El Tor, las que producen la toxina del cólera clásico y reemplazan a la original del biotipo El Tor, ocasionando manifestaciones clínicas más graves, situación que representa un obstáculo importante para el control de esta enfermedad. En la lucha contra ésta en casos de desastre, la Organización Mundial de la Salud no recomienda el uso de las vacunas actuales, porque ocurre una rápida disminución en la protección, lo que da un sentido falso de la seguridad, debiéndose dirigir los recursos a los métodos de control más útiles. Dada la repercusión global que implica la reemergencia del cólera, en este trabajo se exponen algunos aspectos epidemiológicos, así como consideraciones en torno a las medidas de prevención y el control de esta entidad clínica, a partir de la revisión de diferentes fuentes de información actualizadas y la exposición de nuevos conceptos sobre su control, observaciones que serán de utilidad e interés para profesionales de todos los niveles de la atención sanitaria(AU)

Cholera is a health problem for many countries in the world. The high morbidity and mortality rates observed recently have concerned the scientific community, since the increase of the incidence of this disease could generate a global crisis in its control. Key factors in the reemergence of Cholera are: the general weakening of public health activities, especially those involved in the monitoring and deterioration of the laboratories responsible for early identification of emerging microorganisms as well as the circulation of new strains of Vibrio cholerae O1 El Tor in Africa and Asia, which produces the classical cholera toxin and replaces the original one of El Tor biotype, causing more severe clinical manifestations, which represents a major obstacle to control this disease. In the fight against this disease during the occurrence of disasters, the World Health Organization (WHO) does not recommend the use of existing vaccines against cholera because a rapid decline of protection occurs; giving a false sense of safety so resources must be directed to the most useful control methods. Due to the global impact the re-emergence of cholera involves, some epidemiological aspects and considerations on prevention and control of this clinical entity are presented in this article, starting by the review of different updated information sources and the presentation of new concepts on its control, which will be useful and interesting for health care professionals(AU)

Randomized, double-blind, placebo-controlled trial to evaluate the safety and immunogenicity of live oral cholera vaccine 638 in Cuban adults.

A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety, reactogenicity and the immunogenicity of a 2 x 10(9)CFU dose of the 638 lyophilized live attenuated cholera vaccine for oral administration, formulated and produced at Finlay Institute, City of Havana, Cuba. Thirty-six healthy female and male adult volunteers from 18 to 40 years old were involved, clinically examined and laboratory tested after the informed consent signature. Adverse events were monitored and seroconversion rates and geometrical mean titer (GMT) of vibriocidal antibodies were tested in volunteer's sera samples. Neither serious adverse events nor other damages to the volunteers due to vaccine or placebo feeding were reported during the clinical follow-up period of this study; none of the adverse events registered within the first 72 h after inoculation were life-threatening for volunteers. Neither severe nor moderate adverse events were reported. Sixty-one percent of subjects showed mild expected adverse events in an interval lower than 24h up to the first 72 h, 75% of these in the vaccinated group and 18% in the placebo group. Fourteen days after inoculation the GMT of vibriocidal antibodies in the vaccine group significantly increased in comparison to the placebo group. All subjects in the vaccine group (24) seroconverted (100%). Results show that this vaccine is safe, well tolerated and immunogenic in healthy female and male volunteers.

Propuesta de un algoritmo para evaluar la causalidad de eventos adversosen los Ensayos Clínicos de Vacunas / Proposal of an algorithm to assess causality of adverse events in vaccine clinical trials

En el transcurso de los ensayos clínicos usualmente se designa a una comisión, la cual se encarga de evaluar la causalidad de los eventos adversos que se reportan y transcriben en los cuadernos de recogida de datos. Para llegar a contestar la pregunta de: ¿si una vacuna que se está estudiando ha causado un evento adverso?, los decisores pueden tomar diferentes caminos, por lo que obviamente la conclusión final podría variar mucho y la evaluación deficiente puede generar conclusiones erróneas, lo que confirma la necesidad de disponer de un procedimiento para definir lascategorías que se utilizarán para analizar y clasificar la relación de causalidad. Una forma de contestar a la pregunta es mediante la construcción de un algoritmo. En relación con los ensayos clínicos no encontramos en la literatura un algoritmo que sea el patrón clave para establecer o descartar la causalidad, sin embargo es factible diseñarlo partiendo de la metodología internacional utilizada poscomercialización, lo cual fue el propósito de este trabajo. Se diseñó una primera propuesta que fue analizada individual y colectivamente por el grupo multidisciplinario de la Gerencia Médica del Instituto Finlay. Finalmente se aprobó por consenso el algoritmo que puede ser útil para aplicar en los ensayos clínicos dentro y fuera de la institución(AU)

During clinical trials it is common to appoint a commission which is in charged of assessing the causality of adverse events which are reported and transcribed to the collection data logbooks. To be able to answer the question: Does the vaccine understudy cause an adverse event.? different pathways could be taken by decision makers, so it is obvious that the final conclusion could vary too much and a poorly assessment can generate mistaken conclusions. That confirms the need of having a procedure to define which categories must be used to analyze and to classify the relation of causality. To create an algorithm isone answer to the question. We reviewed the literature and did not find any algorithm which could be considered a master key to set or to reject causality, so this paper aims at designing an algorithm beginning with the international methodology used in post commercialization. A first proposal was designed which was individually and collectively analyzed by the multidisciplinary group of the Medical Management from Finlay Institute. Finally, the proposed algorithm was approved by consensus, which could be useful to apply in clinical trials inside and outside of the institution(AU)

The vaccine candidate Vibrio cholerae 638 is protective against cholera in healthy volunteers.

Vibrio cholerae 638 is a living candidate cholera vaccine strain attenuated by deletion of the CTXPhi prophage from C7258 (O1, El Tor Ogawa) and by insertion of the Clostridium thermocellum endoglucanase A gene into the hemagglutinin/protease coding sequence. This vaccine candidate was previously found to be well tolerated and immunogenic in volunteers. This article reports a randomized, double-blind, placebo-controlled trial conducted to test short-term protection conferred by 638 against subsequent V. cholerae infection and disease in volunteers in Cuba. A total of 45 subjects were enrolled and assigned to receive vaccine or placebo. The vaccine contained 10(9) CFU of freshly harvested 638 buffered with 1.3% NaHCO(3), while the placebo was buffer alone. After vaccine but not after placebo intake, 96% of volunteers had at least a fourfold increase in vibriocidal antibody titers, and 50% showed a doubling of at least the lipopolysaccharide-specific immunoglobulin A titers in serum. At 1 month after vaccination, five volunteers from the vaccine group and five from the placebo group underwent an exploratory challenge study with 10(9) CFU of DeltaCTXPhi attenuated mutant strain V. cholerae 81. Only two volunteers from the vaccine group shed strain 81 in their feces, but none of them experienced diarrhea; in the placebo group, all volunteers excreted the challenge strain, and three had reactogenic diarrhea. An additional 12 vaccinees and 9 placebo recipients underwent challenge with 7 x 10(5) CFU of virulent strain V. cholerae 3008 freshly harvested from a brain heart infusion agar plate and buffered with 1.3% NaHCO(3). Three volunteers (25%) from the vaccine group and all from the placebo group shed the challenge agent in their feces. None of the 12 vaccinees but 7 volunteers from the placebo group had diarrhea, and 2 of the latter exhibited severe cholera (>5,000 g of diarrheal stool). These results indicate that at 1 month after ingestion of a single oral dose (10(9) CFU) of strain 638, volunteers remained protected against cholera infection and disease provoked by the wild-type challenge agent V. cholerae 3008. We recommend that additional vaccine lots of 638 be prepared under good manufacturing practices for further evaluation.