Reactogenicity of Bordetella pertussis vaccines formulations using aluminum adjuvants in Sprague Dawley rats / Reactogenicidad de formulaciones de vacunas de Bordetella pertussis utilizando adyuvantes de aluminio en ratas Sprague Dawley

Combined vaccines for childhood are a strategy in the prevention of several diseases. These can maximize protection and decrease immunization schedules in children. New candidates are getting closer to being able to meet these needs, but they raise numerous strategic questions related to formulation and regulatory aspects. In addition to being immunogenic and protective must have low reactogenicity when combined with other antigens. Adjuvants are important components in achieving these combinations. Therefore, a reactogenicity study was designed for two Bordetella pertussis formulations containing hydroxide or aluminum phosphate in Sprague Dawley rats. Both formulations dose were administered in 0.2 mL intramuscularly. Clinical evaluations, body weight, water consumption, food, temperature, muscle volume, dermal irritability and pathological studies with special interest at the inoculation site were carried out. Only differences in body temperature and muscle volume were found with a slight increase in values with return to normal. The macroscopic study showed lesions at the site of inoculation, consid­ered characteristics of aluminum adjuvants, such as granulomatous abscesses and the increase in regional lymph nodes near the inoculation site. As conclusion, there are no differences between the formulations of B. pertussis with hydroxide or aluminum phosphate resulted in low reactogenicity.

Las vacunas combinadas resultan una estrategia importante en la obtención de vacunas múltiples para la infancia y el uso de adyuvantes es un componente de gran valor en lograr estas combinaciones, además de ser inmunogénicas y protectoras deben tener baja reactogenicidad, cuando se combinan con diferentes antígenos. Por esta razón, se diseñó un estudio de reactogenicidad a dos formulaciones que contenían hidróxido y fosfato de aluminio con antígenos de Bordetella pertussis en ratas Sprague Dawley. Se administró a cada grupo de ensayo una dosis correspondiente de ambas formulaciones en 0,2 mL por vía intramuscular. Se realizaron observaciones clínicas, comportamiento del peso corporal, consumo de agua, alimentos, temperatura corporal, volumen muscular, irritabilidad dérmica y estudios anatomopatológicos macroscópicos, con especial interés en el sitio de inoculación. No se observaron síntomas, ni muertes en los animales durante el estudio. Tampoco se encontraron diferencias entre los grupos experimentales en cuanto al peso corporal, el consumo de agua y de alimentos; los estudios de temperatura corporal y volumetría muscular evidenciaron un ligero incremento en los valores, los cuales involucionaron rápidamente a la normalidad. En el estudio anatomopatológico macroscópico se observaron lesiones a nivel del punto de inoculación, consideradas propias de los adyuvantes que contienen aluminio, tales como formaciones abscedadas de tipo granulomatosas y el aumento de los ganglios linfáticos regionales cercanos al punto de inoculación. Se concluye que las formulaciones en hidróxido y fosfato de aluminio con antígenos de B.pertussis resultaron ser de baja reactogenicidad.

Erradicación de fiebre tifoidea en Holguín. Logro de la Medicina cubana 1972-2016 / Elimination of Typhoid Fever in Holguín. An achievement of cuban Medicine. 1972-2016

Introducción: la fiebre tifoidea es una infección sistémica causada por Salmonella tiphy, a través de la ingesta de alimentos contaminados (fecal-oral). Es un problema de salud pública, especialmente en países en vías de desarrollo. Objetivo: caracterizar la fiebre tifoidea en la provincia de Holguín durante los años 1972-2016. Método: se realizó un estudio descriptivo longitudinal de series de casos reportados de fiebre tifoidea por tarjeta EDO (Enfermedades de Declaración Obligatoria) en la provincia de Holguín desde el año 1972-2016. El universo estuvo constituido por 471 pacientes reportados por fiebre tifoidea, según tarjeta de EDO. Resultados: no se reportaron fallecidos desde el año 1974 y los menores de 15 años fueron los más afectados. El municipio que se mantuvo como de alto riesgo fue Holguín. La aplicación de la vacuna cubana de polisacárido Vi, mucho menos reactogénica y más efectiva que la utilizada anteriormente de calor-fenol, puede ser la causa o parte de la causa para la no ocurrencia de casos en los últimos 10 años en la provincia. Conclusiones: la morbilidad por fiebre tifoidea ha disminuido al igual que el número de brotes y afectados en brotes. Las medidas de control inmediatas y la existencia de un programa de control, además de la nueva vacuna de producción nacional, fabricada por los laboratorios Finlay, han hecho posible tales logros.

Introduction: typhoid fever is a systemic infection caused by Salmonella tiphy through ingestion of contaminated food (fecal-oral). It is a public health problem, especially in developing country. Objective: to characterize typhoid fever in Holguin province during the years 1972-2016. Method: a longitudinal descriptive study of series of reported cases of typhoid by EDO card (Notifiable Diseases) in Holguin province since 1972 to 2016, in order to characterize the typhoid in Holguin province was conducted. The universe consisted of 471 patients reported for typhoid Fever, according to EDO card. Results: no deaths were reported since 1974, children under 15 were the most affected, the Holguin municipality remained as high risk. The application of the Vi much less reactogenic and more effective polysaccharide Cuban vaccine used previously heat-phenol, may be the cause or part of the cause for the non-occurrence of cases in the last 10 years in the province. Conclusions: the morbidity due to typhoid fever has decreased as well as the number of outbreaks and affected in outbreaks. The immediate control measures and the existence of a control program, in addition to the new vaccine of national production, manufactured by the Finlay laboratories, have made such achievements possible.

Safety of the novel influenza viral vector Brucella abortus vaccine in pregnant heifers / Segurança de uma nova vacina vetorial empregando o vírus influenza para Brucella abortus em novilhas prenhes

ABSTRACT: The present study provides the first information about the safety of a new influenza viral vector vaccine expressing the Brucella ribosomal protein L7/L12 or Omp16 containing the adjuvant Montanide Gel01 in pregnant heifers. Immunization of pregnant heifers was conducted via the conjunctival (n=10) or subcutaneous (n=10) route using cross prime and booster vaccination schedules at an interval of 28 days. The vector vaccine was evaluated in comparison with positive control groups vaccinated with B. abortus S19 (n=10) or B. abortus RB51 (n=10) and a negative (PBS+Montanide Gel01; n=10) control group. Clinical studies, thermometry, assessment of local reactogenicity and observation of abortion showed that the vector vaccine via the conjunctival or subcutaneous route was completely safe for pregnant heifers compared to the commercial vaccines B. abortus S19 or B. abortus RB51. The only single adverse event was the formation of infiltration at the site of subcutaneous injection; this reaction was not observed for the conjunctival route.

RESUMO: O presente estudo fornece as primeiras informações sobre a segurança de uma nova vacina usando o vetor viral influenza para expressar as proteínas de Brucella L7/L12 ou Omp16, contendo o adjuvante Montanide Gel01 em novilhas prenhes. A imunização de novilhas prenhes foi realizada através das vias conjuntiva (n=10) ou subcutânea (n=10), empregadas na primovacinação e na dose de reforço. O intervalo foi de 28 dias. A vacina empregando o vetor foi comparada com os grupos de controle positivo, vacinados com B. abortus B19 (n=10) ou B. abortus RB51 (n=10) e um grupo de controle negativo (PBS + Montanide Gel01; n=10). Os estudos clínicos, termometria, reação local e observação do aborto mostraram que a vacina empregando o vetor, aplicada pela via conjuntival ou subcutânea, foi completamente segura para novilhas prenhes, em comparação com as vacinas comerciais B. abortus B19 ou B. abortus RB51. O único efeito adverso foi a formação de infiltrado no local da administração subcutânea; essa reação não foi observada no grupo vacinado pela via conjuntival.

Safety and Reactogenicity of the Inactivated Poliomyelitis Vaccine (Poliorix(TM)) in Korea (2006-2012) / 소아감염

OBJECTIVE: As per the requirement of Korean Food and Drug Administration, this post-marketing surveillance was conducted in Korea to evaluate the safety and reactogenicity of Poliorix(TM) following its introduction in 2006. METHODS: In this open, multicenter study, the vaccine was administered as per the current practice of Korean doctors and in reference to the guidebook by the Korean Pediatric Society and as indicated in the Korean label which was as follows - for primary vaccination three doses were given to infants at ages 2, 4 and 6 months whereas, for the booster dose a single dose was given to children aged 4-6 years. Safety data during this six year surveillance was collected using diary cards which were distributed to the parents to record adverse events. RESULTS: A total of 639 subjects were enrolled into the study. Of these, 617 subjects and 22 subjects received the vaccine as a primary and booster dose, respectively. At least one unsolicited symptom was reported in 11.4% (73/639) of the subjects during the 7-day follow-up period; upper respiratory tract infection (2.5%;16/639) was the most frequently reported unsolicited symptom. One subject reported at least one unsolicited symptom (gastroenteritis) of grade 3 intensity within the 31-day post-vaccination period. Approximately 1.7% (11/639) of subjects reported 13 serious adverse events (SAEs). All SAEs were resolved by the end of the study. CONCLUSION: In Korea, primary and booster vaccination with Poliorix(TM) was well-tolerated in healthy subjects when administered according to the prescribing information as part of routine clinical practice.

Reactogenicidad asociada a la administración intradérmica de la vacuna de polio inactivada con un inyector sin aguja / Reactogenicity associated to the intradermally administered inactivated poliovirus vaccine with a needle-free injector

INTRODUCCIÓN: en la medida en que la meta de la erradicación de la poliomielitis llega a su concreción, la necesidad de contar con una vacuna de polio inactivada asequible y apropiada para el uso en países en vías de desarrollo se ha convertido en una meta para la Organización Mundial de la Salud. OBJETIVO: la evaluación de la reactogenicidad de la vacuna de polio inactivada. MÉTODOS: se realizó un estudio multicéntrico con diseño experimental, correspondiente a Fase I-II de un ensayo clínico controlado, aleatorio y a simple ciegas, en 471 lactantes sanos de ambos sexos nacidos entre los meses de julio y agosto de 2006 en Camagüey, cuyos padres brindaron su consentimiento por escrito y que cumplieron con los criterios de inclusión establecidos. Los niños recibieron a las 6, 10 y 14 semanas del nacimiento, tres dosis de vacuna de polio inactivada del Instituto de Sueros de Dinamarca, autorizada para su uso en esta investigación por las autoridades regulatorias nacionales. Al grupo de estudio A, se le administró por la vía intradérmica la dosis reducida de 0,1 mL de vacuna de polio inactivada en la cara anterolateral del muslo izquierdo utilizando el inyector sin aguja Biojector® 2000. El grupo control B recibió la dosis usual de 0,5 mL por la vía intramuscular profunda, administrada en el mismo sitio descrito antes con una jeringuilla prellenada. Se observaron los eventos adversos durante la primera hora, 24, 48, y 72 h subsiguientes, así como a los 7 y 30 d de administrada la vacuna. La reactogenicidad se evaluó inicialmente por el pediatra del área y luego por el médico de familia mediante la observación de los eventos adversos. RESULTADOS: 79,6 por ciento del total de niños asignados al grupo A y 75 por ciento del grupo B finalizaron el protocolo de investigación. No se detectaron eventos adversos moderados o serios. Predominaron las reacciones adversas locales menores, sobre todo induración, dolor y enrojecimiento en el sitio de la inyección. CONCLUSIÓN: el ensayo demostró la seguridad de la vacuna de polio inactivada para su uso por vía intramuscular y reconoció la seguridad del uso de la vía intradérmica y del inyector sin agujas.

INTRODUCTION: as the goal of poliomyelitis eradication is about to be accomplished, the need for an affordable and appropriate inactivated poliovirus vaccine (IPV) for use in developing countries has become a target for WHO. OBJECTIVE: to evaluate the reactogenicity of the inactivated poliovirus vaccine. METHOD: an experimental-type multicenter study was conducted, as part of a Phase I-II controlled clinical randomized and blinded assay, in 471 healthy infants of both sexes born in July and August 2006 in Camagüey province. The parents of the children who met the inclusion criteria gave their consent in writing. The children received three doses of the inactivated poliovirus vaccine at 6, 10 and 14 weeks after birth. This vaccine came form the Institute of Sera in Denmark and had been approved for use in this assay by the Cuban regularoty authorities, Low 0.1 ml inactivated poliovirus vaccine dose was intradermally administered to the study group A in the anterolateral side of the left thigh using the needle-free injector called Biojector ® 2000. The usual 0.5 mL dose was intramuscularly administered on the same site using a pre-filled syringe. The adverse events were observed during the first hour, 24, 48, and 72 hours after the immunization, as well as 7 and 30 days afterwards. The pediatrician in charge of the health area evaluated the reactogenicity at first and then the family physician was in charge of observing the adverse events in the remaining period. RESULTS: the 79.6 percent of children in group A and 75 percent in group B completed the research protocol. Mild local adverse reactions prevailed, mainly induration, pain and redness at the injection site. CONCLUSION: the clinical trial proved the safety of the inactivated poliovirus vaccine for intramuscular administration, and also showed the safety of the intradermal route of administration and of the needle-free injector.

Post-marketing Surveillance Study of an Inactivated Split-Virion Influenza Vaccine in Korea / 소아감염

PURPOSE: This post-marketing surveillance study (NCT00750360) assessed the safety and reactogenicity of an inactivated, trivalent split-virion influenza vaccine licensed for use in the Korea since 2002. METHODS: Eight hundred and eighty three subjects aged > or =6 months received a single dose of the vaccine; an additional dose was administered to those aged or =6 years: 34.7%), fever ( or =6 years: 13.9%) were the most frequently recorded solicited local and general adverse events. Grade 3 solicited adverse events were reported by < or =4.0% subjects. No vaccine-related SAEs were recorded (KFDA criteria). CONCLUSION: Considering the vaccine's well-established immunogenicity and its favourable safety and reactogenicity profile across all age groups and its high coverage rate in Korea, it may be recommended as a candidate to facilitate annual seasonal influenza vaccination for all ages as part of the Korean National Immunization Program.

Vaccine Related Reactogenicity for Primary Immunization: A Randomized Controlled Trial of 23(Wider) vs. 25 (Narrower) Gauge Needles with Same Lengths.

Objectives To compare vaccine related reactogenicity during primary immunization in healthy infants using 23 vs. 25 gauge needles. Methods This randomized controlled trial was conducted in Vaccination Room of the Advanced Pediatrics Center. 155 participants for primary immunization were assigned to two intervention groups (23 vs. 25 gauge). Parent-reported local and systemic reactions were recorded daily for three days after the immunization. Results Swelling (24%) and tenderness (21%) were the two most common parent-reported local symptoms followed by restriction of movements (18%) and redness (10%) on day 1. Any local reaction on day 1 was statistically similar in 25 gauge vs. 23 gauge group (RR 0.77; 95%CI: 0.32 to 1.82) (P= 0.54), but fever (day 1) showed higher trend in 23 gauge needle group (RR 2.24; 95% CI: 0.92–5.47) (P=0.07). Furthermore, on analysis of serially reported local and systemic reactions for 3 consecutive days by generalized estimating equations, odds of redness, swelling, tenderness, restricted movement and fever were statistically similar between two needle groups. On the other hand, median (±SE) crying time (in seconds) was significantly prolonged in the 25 gauge needle (39±2) as compared to 23 gauge group (30±1.3) (log rank test, P=0.001). Conclusions The use of same length needles with narrower (25) or wider (23) gauge did not show significant differences in local reactogenicity during primary immunization. Fever, however, was reduced marginally in 25 gauge group whereas crying duration was significantly shorter with 23 gauge needle. Finally, larger studies are needed to further evaluate objectively the outcome of reactogenicity.

La reactogenicidad y los aspectos inmune específicos de la vacuna pentavalente combinada: DTPw-HepB-Hib en el lactante menor de un año en el Hospital Distrital de Lambaré, Paraguay en 2007-2008 / The reactogenicity and specific immune aspects of the combined pentavalent vaccine: DTPw-HepB-Hib in breastfed babies under one year of age that attended the District Hospital of Lambaré, Paraguay in 2007 and 2008

La vacunación rutinaria de difteria, pertussis y tétanos a células enteras (DPTw) está presente desde 1940 y con elevadas coberturas en muchos países del mundo. La Organización Mundial de la Salud ha aprobado el uso universal de la vacuna anti-hepatitis B (HB) y combinaciones con DPT, en los últimos años ha sido incorporada la vacuna anti-Haemophilus influenzae tipo b (Hib) en programas de vacunación del niño. Es aplicada en Paraguay desde el 2002 a través del Programa Ampliado de Inmunizaciones del Ministerio de Salud Pública y Bienestar Social. Determinamos la reactoinmunogenicidad secundaria a la vacunación primaria pentavalente combinada en infantes concurrentes al Hospital Distrital de Lambaré­Paraguay en los años 2007-2008. Estudio longitudinal, observacional prospectivo de los efectos secundarios y los aspectos inmune- específicos de la vacuna Berna DTPw-HepB-Hib (QUINVAXEMTM) en lactantes menores de un año, a los 2 meses de edad, datos basales y post vacunales (1 mes luego de 3ª dosis). Efectos locales: 30(75%); rubor 17 (42.5%); tumefacción (menos 20 mm); 13 (32.5%); calor local 11 (27.5%). Efectos generales: fiebre: 37 (92.5%) llanto fuerte y persistente: 32(80%); irritabilidad: 23 (57.5%); hiporreactividad 16 (40%), anorexia 8 (20%); Inmunogenicidad: antes de la 1ª dosis; antitetánica IgG (+) 38/40 (95%), anti-difteria (+) IgG 29/40 (72.5%); anti-HBsAg 0/40 (0%) negativos. Respuesta post-vacuna penta comb. (7m. edad): antitetánica IgG 14/14 (100%) (+); anti-difteria IgG 12/14 (83%) (+); anti-HBsAg 14/14 (100%) positivos. Se evidencia la reactogenicidad de grado variable y decreciente. Niveles de anticuerpos de los componentes DT, satisfactorios y la Hep B excelentes

The combined cellular pentavalent vaccine is one the greatest achievements of human kind in the 20th century and is still successful in the 21st century. It is made up of five components and protects against the following diseases: diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type b. The vaccine provides specific active immunization against infections caused by Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, Haemophilus influenzae type B and the Hepatitis B virus in children from six weeks of age. In Paraguay, it has been used since 2002 through the Widened Program of Immunization (PAI in Spanish) of the Ministry of Public Health. The objective of this work was to determine the secondary reactoinmunogenicity to the primary combined pentavalent vaccination in children attending the District Hospital of Lambaré, Paraguay in 2007 and 2008. This is a longitudinal, prospective observational study to evaluate the secondary effects and immune-specific aspects of the Berna DTPw-HepB-Hib combined pentavalent vaccine (QUINVAXEMTM) applied to breastfed babies under one year old, of both sexes, all races, origins and nutrition statuses in the Hospital of Lambaré. The vaccination was free, according to PAI's guidelines and by consecutive sampling previous written consent of the parents, at 2 months of age. Data were collected at baseline an post-vaccination after one month and a third dose. In a total population of 40 breastfed babies, good nutrition was found in 36 (90%). Local effects were seen in 30 (75%) distributed as follows: blush in 17 (42.5%), tumefaction (less than 20 mm) in 13 (32.5%) and local heat in 11 (27.5%). General effects were distributed as follows: fever in 37 (92.5%), loud and persistent cry in 32 (80%), irritability in 23 (57.5%), hyporeactivity in 16 (40%), anorexia in 8 (20%), hypotonicity and allergy, 2 each (5%), convulsions and paralysis in none. The effects are an average after the three doses with a decreasing trend at the end. The immunogenicity basal data before the 1st dose were as follows: antitetanic IgG (+) 38/40 (95%), antidiphtheria IgG (+) 29/40 (72.5%) and anti HBs Ag (-) 0/40 (0%). Post - vaccination responses (at 7 months old) were as follows: antitetanic IgG (+) 14/14 (100%), antidiphtheria IgG (+) 12/14 (83%) and anti HBs Ag (+) 14/14 (100%). These results show a reactogenicity of variable and decreasing degree. The antibodies levels of the DT components were satisfactory and those of Hep B excellent

La reactogenicidad y los aspectos inmune específicos de la vacuna pentavalente combinada: DTPw-HepB-Hib en el lactante menor de un año en el Hospital Distrital de Lambaré, Paraguay en 2007-2008 / The reactogenicity and specific immune aspects of the combined pentavalent vaccine: DTPw-HepB-Hib in breastfed babies under one year of age that attended the District Hospital of Lambaré, Paraguay in 2007-2008

La vacunación rutinaria de difteria, pertussis y tétanos a células enteras (DPTw) está presente desde 1940 y con elevadas coberturas en muchos países del mundo. La Organización Mundial de la Salud ha aprobado el uso universal de la vacuna anti-hepatitis B (HB) y combinaciones con DPT, en los últimos años ha sido incorporada la vacuna anti-Haemophilus influenzae tipo b (Hib) en programas de vacunación del niño. Es aplicada en Paraguay desde el 2002 a través del Programa Ampliado de Inmunizaciones del Ministeriode Salud Pública y Bienestar Social. Determinamos la reactoinmunogenicidad secundaria a la vacunación primaria pentavalente combinada en infantes concurrentes al Hospital Distrital de Lambaré–Paraguay en los años 2007-2008. Estudio longitudinal,observacional prospectivo de los efectos secundarios y los aspectos inmune- específicos de la vacuna Berna DTPw-HepB-Hib (QUINVAXEMTM) en lactantes menores de un año, a los 2 meses de edad, datos basales y post vacunales (1 mes luego de 3ª dosis). Efectoslocales: 30(75%); rubor 17 (42.5%); tumefacción (menos 20 mm); 13 (32.5%); calor local 11 (27.5%). Efectos generales: fiebre: 37 (92.5%) llanto fuerte y persistente: 32(80%); irritabilidad: 23 (57.5%); hiporreactividad 16 (40%), anorexia 8 (20%); Inmunogenicidad: antes de la 1ª dosis; antitetánica IgG (+) 38/40 (95%), anti-difteria (+) IgG 29/40 (72.5%); anti-HBsAg 0/40 (0%) negativos. Respuesta post-vacuna pentacomb. (7m. edad): antitetánica IgG 14/14 (100%) (+); anti-difteria IgG 12/14 (83%) (+); anti-HBsAg 14/14 (100%) positivos. Se evidencia la reactogenicidad de grado variable y decreciente. Niveles de anticuerpos de los componentes DT, satisfactorios y laHep B excelentes.

The combined cellular pentavalent vaccine is one the greatest achievements of human kind in the 20th century and is still successful in the 21st century. It is made up of fivecomponents and protects against the following diseases: diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type b. The vaccine provides specific active immunization against infections caused by Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, Haemophilus influenzae type B and the Hepatitis B virus in children from six weeks of age. In Paraguay, it has been used since 2002 through the Widened Program of Immunization (PAI in Spanish) of the Ministry of Public Health. Theobjective of this work was to determine the secondary reactoinmunogenicity to the primary combined pentavalent vaccination in children attending the District Hospital of Lambaré, Paraguay in 2007 and 2008. This is a longitudinal, prospective observational study to evaluate the secondary effects and immune-specific aspects of the Berna DTPw- HepB-Hib combined pentavalent vaccine (QUINVAXEMTM) applied to breastfed babies under one year old, of both sexes, all races, origins and nutrition statuses in the Hospitalof Lambaré. The vaccination was free, according to PAI's guidelines and by consecutive sampling previous written consent of the parents, at 2 months of age. Data were collected at baseline an post-vaccination after one month and a third dose. In a total population of 40 breastfed babies, good nutrition was found in 36 (90%). Local effectswere seen in 30 (75%) distributed as follows: blush in 17 (42.5%), tumefaction (less than 20 mm) in 13 (32.5%) and local heat in 11 (27.5%). General effects were distributed as follows: fever in 37 (92.5%), loud and persistent cry in 32 (80%),irritability in 23 (57.5%), hyporeactivity in 16 (40%), anorexia in 8 (20%), hypotonicity and allergy, 2 each (5%), convulsions and paralysis in none. The effects are an average after the three...