Safety and immunogenicity of a tetravalent dengue vaccine in children aged 2-17 years: a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: An unmet clinical need remains for an effective tetravalent dengue vaccine suitable for all age groups, regardless of serostatus. We assessed the immunogenicity and safety of three different dose schedules of a tetravalent dengue vaccine (TAK-003) over a 48-month period in children living in dengue-endemic countries. METHODS: We did a large, phase 2, double-blind, placebo-controlled trial at three sites in the Dominican Republic, Panama, and the Philippines. Healthy participants aged 2-17 years were randomly assigned 1:2:5:1 using an interactive web response system with stratification by age to receive either a two-dose primary series (days 1 and 91), one primary dose (day 1), one primary dose plus booster (days 1 and 365), or placebo. Participants and relevant study personnel were masked to the random assignment until completion of the study at month 48. To maintain masking, TAK-003 recipients were administered placebo doses when appropriate. The primary objective was assessment of neutralising geometric mean titres for each serotype to month 48 assessed in the per-protocol immunogenicity subset. Secondary safety endpoints included proportions of participants with serious adverse events and symptomatic virologically confirmed dengue. This study is registered with ClinicalTrials.gov, NCT02302066. FINDINGS: Between Dec 5, 2014, and Feb 13, 2015, 1800 children were randomly assigned to the following groups: two-dose primary series (n=201), one primary dose (n=398), one primary dose plus 1-year booster (n=1002), and placebo (n=199). Of them, 1479 (82%) participants completed the 48-month study. Immunogenicity endpoints were assessed in 562 participants enrolled in the immunogenicity subset, of whom 509 were included in the per-protocol subset. At month 48, antibody titres remained elevated in all TAK-003 groups compared with placebo, irrespective of baseline serostatus. At month 48, geometric mean titres were 378 (95% CI 226-632) in two-dose, 421 (285-622) in one-dose, 719 (538-960) in one-dose plus 1-year booster, and 100 (50-201) in placebo recipients against DENV 1; 1052 (732-1511), 1319 (970-1794), 1200 (927-1553), and 208 (99-437) against DENV 2; 183 (113-298), 201 (135-298), 288 (211-392), and 71 (37-139) against DENV 3; and 152 (97-239), 164 (114-236), 219 (165-290), and 46 (26-82) against DENV 4; and tetravalent seropositivity rate was 89% (79-96), 86% (80-92), 97% (93-99), and 60% (47-72), respectively. Virologically confirmed dengue was recorded in 37 (2%) TAK-003 and 13 (7%) placebo participants, with a relative risk of 0·35 (0·19-0·65). No vaccine-related serious adverse events or severe dengue virus disease were reported. INTERPRETATION: TAK-003 elicited antibody responses against all four serotypes, which persisted to 48 months post-vaccination, regardless of baseline serostatus. No important safety risks were identified. We observed a long-term reduction in risk of symptomatic dengue virus disease in vaccinees. Results from this study provide a long-term safety database and support assessment of the vaccine in the ongoing phase 3 efficacy study. FUNDING: Takeda Vaccines.

Gastroenteritis aguda viral en la era post-introducción de la vacuna contra el rotavirus

Objetivo: Determinar los virus asociados a gastroenteritis aguda en niños de 1 mes a 15 años de edad admitidos al Hospital del Niño de Panamá durante los meses de septiembre 2009 a junio 2010. Material y métodos: Estudio descriptivo. Fueron seleccionados al azar sujetos menores de 15 años admitidos con diagnóstico de gastroenteritis aguada de origen comunitario. Las muestras de heces fueron sometidas a estudios microbiológicos, parapsicológicos y pruebas de ELISA para rotavirus, norovirus, astrovirus y adenovirus. Resultados: Se analizaron 180 muestras de heces. Se identificó uno o más agentes virales en 52.2% de las muestras analizadas, siendo el rotavirus y el norovirus los más frecuentes tanto de forma individual en confecciones. No se demostró diferencias estadísticamente significativas en la duración de los síntomas, frecuencia de las evacuaciones diarreas, días de hospitalización, síntomas , ni distribución por grupo etario. Se indicaron antibióticos en más de la mitad de los casos. Conclusiones: Este es el primer estudio que señala la frecuencia de virus enteritos en población pediátrica panameña y refleja la necesidad de ampliar la vigilancia epidemiológica a otros agentes virales dada la carga de enfermedad, coste de uso inadecuado de antibióticos , y probable modificación de la epidemiología de la enfermedad diarrea en niños.

Objective: to determine the viruses associated to acute gastroenteritis in children from one month to 15 years of age admitted at Hospital del Niño from September 2009 through June 2010. Material and methods: Descriptive study. Subjects younger than 15 years of age with a diagnosis of acute gastroenteritis originated in their community were randomly selected. The stool samples were submitted to microbiological and parasitological studies, and ELISA testing for rotavirus, norovirus, astrovirus and adenovirus. Results: 180 stool samples were analyzed. One or more viral agents were identified in 52% of the analyzed samples, with rotavirus and norovirus resulting in the most frequently identified both individually and in co-infections. No statistically significant differences were found in the duration of the symptoms , frequency of the diarrheic bowel movements, days of hospitalization, symptoms, or age group. Antibiotics were prescribed in more that half of the cases.

[Complications and costs associated with chickenpox in immunocompetent children]. / Complicaciones y costos asociados a la varicela en niños inmunocompetentes.

OBJECTIVES: Chickenpox is a common infection of childhood in countries that have not included the corresponding vaccination in their immunization schedules. Chickenpox is usually benign in immunocompetent children, and treatment is not needed. The objectives of this study were to investigate the frequency and characteristics of chickenpox complications that require hospital treatment in immunocompetent children and the clinical progression in children of mothers with perinatal chickenpox. In addition, the hospital costs associated with chickenpox in the studied children were calculated. METHODS: This was a retrospective study using the clinical records of children with chickenpox hospitalized at the Children's Hospital of Panama, from January 1991 through December 2000. We analyzed the types of complications, the clinical progression, and the hospital costs of the chickenpox patients. RESULTS: Of 5 203 children seen in outpatient consultations, 568 of them (11%) were hospitalized. We included 513 children in our study: 381 (74%) with chickenpox acquired in the community, 92 (18%) the children of mothers with chickenpox, and 40 (8%) with nosocomial chickenpox. The most frequent complications were cutaneous and subcutaneous infections (45%), respiratory infections (25%), and neurological changes (7%). The respiratory and cutaneous complications occurred sooner and among younger patients than did the neurological changes. Overall, 13 of the children (2.5%) died. The case fatality rate was 8% for chickenpox with respiratory and neurological complications and 0% for chickenpox with cutaneous complications. Of the 92 children with a mother with chickenpox, 60 of them (65%) did not develop the disease, and none of the 92 died. In contrast, 2 of the 32 neonates (6%) with perinatal chickenpox died. The mean length of hospitalization was 8.9 days (standard deviation, +/- 17.4 days). Parenteral pharmacotherapy was used with the great majority of the children, particularly antibiotics (54%), acyclovir (17%), and intravenous immunoglobulin (14%). The mean per-patient cost of hospitalization was US$ 1 209. CONCLUSIONS: Our results show that chickenpox is associated with a sizable number of expensive complications and a not-insignificant case fatality rate in immunocompetent children. Routine vaccination against chickenpox could reduce the impact of this disease on the health of children in Panama

Effect of combination antiretroviral therapy on cerebrospinal fluid HIV RNA, HIV resistance, and clinical manifestations of encephalopathy.

OBJECTIVES: This study evaluated the effect of treatment with abacavir/lamivudine/zidovudine versus lamivudine/zidovudine on cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) RNA and clinical manifestations of HIV encephalopathy in children. STUDY DESIGN: HIV-infected children 7 months to 10 years of age (n = 23) were studied. CSF and plasma were obtained at baseline and weeks 8, 16, and 48. Genotype analysis of HIV was attempted at baseline and week 48. Neurologic evaluations were performed at baseline and weeks 16, 32, and 48. RESULTS: At baseline, 83% of children had >2.00 log(10) copies/mL HIV RNA in CSF, but only 10% had HIV RNA measurable at week 48. Among children in whom paired genotyping of HIV was possible, 8 of 11 had identical patterns in both CSF and plasma at baseline, whereas at week 48, only 1 of 9 children had similar patterns. Neurologic abnormalities were observed in 83% of children at baseline but only 35% of children at week 48 (P =.004), suggesting a benefit of treatment. CONCLUSIONS: Antiretroviral therapy was associated with a decline in CSF HIV RNA and an improvement in neurologic status. The development of genotypic mutations was different in CSF and plasma, suggesting discordant viral evolution. These results suggest that antiretroviral treatment in children should include agents with activity in the CNS.