Live, Attenuated, Tetravalent Butantan-Dengue Vaccine in Children and Adults.

BACKGROUND: Butantan-Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS: In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically confirmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS: Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine efficacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) - 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine efficacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS: A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regardless of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.).

A phase 3, single-arm, open-label study to evaluate the safety, tolerability, and immunogenicity of a 15-valent pneumococcal conjugate vaccine, V114, in a 3+1 regimen in healthy infants in South Korea (PNEU-PED-KOR).

There is an ongoing burden of pneumococcal disease in children despite the use of pneumococcal conjugate vaccines (PCVs). This phase 3, open-label, single-arm, multisite, descriptive study was designed to evaluate the safety and immunogenicity of a 3 + 1 regimen of V114 (VAXNEUVANCE™), a 15-valent PCV, in South Korean infants and toddlers. Adverse events (AEs) were reported for 14 d following any vaccination, and throughout the study period for serious AEs. Serotype-specific immunoglobulin G (IgG) response rates (proportion of participants meeting an IgG threshold value of ≥0.35 µg/mL) and geometric mean concentrations (GMCs) for the 15 serotypes at 30 d postdose 3 (PD3) and at 30 d postdose 4 (PD4) were evaluated as endpoints. Healthy infants enrolled at 42-90 d after birth were vaccinated with V114 (N = 57). The most commonly reported AEs were those solicited in the trial. The majority of reported AEs were transient and of mild or moderate intensity. Few serious AEs were reported; none were vaccine related. No participants died nor discontinued the study vaccine because of an AE. V114 was immunogenic for all 15 serotypes contained in the vaccine, as assessed by IgG response rates at 30 d PD3 and IgG GMCs at 30 d PD3 and at 30 d PD4. V114 was well tolerated and immunogenic when administered as a 3 + 1 regimen in healthy South Korean infants and toddlers.

Despite the use of pneumococcal vaccines, the burden of pneumococcal disease in children persists. V114, a 15-valent pneumococcal conjugate vaccine, was immunogenic and well-tolerated in healthy South Korean infants and toddlers.

Efficacy and safety of Butantan-DV in participants aged 2-59 years through an extended follow-up: results from a double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil.

BACKGROUND: A single-dose dengue vaccine that protects individuals across a wide age range and regardless of dengue serostatus is an unmet need. We assessed the safety and efficacy of the live, attenuated, tetravalent Butantan-dengue vaccine (Butantan-DV) in adults, adolescents, and children. We previously reported the primary and secondary efficacy and safety endpoints in the initial 2 years of follow-up. Here we report the results through an extended follow-up period, with an average of 3·7 years of follow-up. METHODS: In this double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil, healthy participants (aged 2-59 years) who had not previously received a dengue vaccine were enrolled and randomly assigned 2:1 (stratified by age 18-59 years, 7-17 years, and 2-6 years) using a central electronic randomisation system to receive 0·5 mL of Butantan-DV (containing approximately 103 plaque-forming units of each of the four vaccine virus strains) or placebo, administered subcutaneously. Syringes containing vaccine or placebo were prepared by an unmasked trial pharmacist who was not involved in any subsequent participant assessments; other site staff and the participants remained unaware of the group allocations. Vaccine efficacy was calculated with the accrual of virologically confirmed dengue (VCD) cases (by RT-PCR) at least 28 days after vaccination up until the cutoff (at least 2 years of follow-up from the last participant enrolled). The primary endpoint was vaccine efficacy against VCD after day 28 by any dengue virus (DENV) serotype regardless of dengue serostatus at baseline in the per-protocol population. The primary and secondary safety endpoints up until day 21 were previously reported; secondary safety endpoints include the frequency of unsolicited vaccine-related adverse events after day 22. Safety analyses were done on all participants as treated. This trial is registered with ClinicalTrials.gov (NCT02406729) and is ongoing. FINDINGS: Of 16 363 participants assessed for eligibility, 16 235 were randomly assigned between Feb 22, 2016, and July 5, 2019, and received single-dose Butantan-DV (10 259 participants) or placebo (5976 participants). 16 162 participants (Butantan-DV n=10 215; placebo n=5947) were included in the per-protocol population and 16 235 (Butantan-DV n=10 259; placebo n=5976) in the safety population. At the data cutoff (July 13, 2021), participants had 2-5 years of follow-up (mean 3·7 years [SD 1·0], median 4·0 years [IQR 3·2-4·5]). 356 VCD cases were captured through the follow-up (128 in the vaccine group and 228 in the placebo group). Vaccine efficacy against VCD caused by any DENV serotype was 67·3% (95% CI 59·4-73·9); cases caused by DENV-3 or DENV-4 were not observed. The proportions of participants who had serious adverse events were similar between treatment groups (637 [6·2%] in the vaccine group and 395 [6·6%] in the placebo group) up until the cutoff. INTERPRETATION: A single dose of Butantan-DV was generally well tolerated and efficacious against symptomatic VCD (caused by DENV-1 and DENV-2) for a mean of 3·7 years. These findings support the continued development of Butantan-DV to prevent dengue disease in children, adolescents, and adults regardless of dengue serostatus. FUNDING: Instituto Butantan and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Neonatal infections: case definition and guidelines for data collection, analysis, and presentation of immunisation safety data

A vacinação materna é uma importante área de pesquisa e requer definições e padrões de segurança apropriados e internacionalmente comparáveis. O grupo GAIA, parte da Brighton Collaboration, foi criado com o mandato de propor definições padronizadas aplicáveis ​​à pesquisa de vacinas maternas. Este estudo propõe definições internacionais para infecções neonatais. O grupo de trabalho GAIA de infecções neonatais realizou uma revisão de literatura utilizando Medline, EMBASE e a colaboração Cochrane e coletou definições em uso em redes neonatais e de saúde pública. Os critérios comuns derivados da pesquisa extensiva formaram a base para um processo de consenso que resultou em três definições separadas para infecções da corrente sanguínea neonatal (BSI), meningite e infecções do trato respiratório inferior (ITRI). Para cada definição, três níveis de evidência são propostos para assegurar a aplicabilidade das definições a diferentes configurações. Recomendações sobre coleta, análise e apresentação de dados são apresentadas e harmonizadas com o formato Colaboração de Brighton e GAIA e outros padrões internacionais existentes para relatórios de estudo.

Contribution of Mexico's Universal Immunization Program to the Fourth Millennium Development Goal / Contribución del Programa de Vacunación Universal de México al cuarto Objetivo de Desarrollo del Milenio

OBJECTIVE: To identify and describe 1) progress achieved thus far in meeting the commitments of the Fourth Millennium Development Goal (MDG 4) in Mexico, mainly the contribution of the Universal Immunization Program (UIP) over the last 20 years, and 2) new opportunities for further reducing mortality among children under 5 years old. METHODS: An observational, descriptive, retrospective study was carried out to examine registered causes of death in children under 5 between 1990 and 2010. Indicators were built according to the recommendations of the United Nations. RESULTS: In 2010, deaths among children under 5 decreased 64.3% compared to the baseline (1990) figure. Of the total deaths of the children under 5, the neonatal period was the most affected (52.8%), followed by the 1 to 11 months (30.9%), and the 12 to 59 months (16.2%) groups. A 34% overall mortality reduction was observed after the universalization of immunization against influenza, rotavirus, and pneumococcus in children under 5. CONCLUSIONS: Despite a significant reduction in under-5 mortality in Mexico over the last 20 years, largely due to the successes of the UIP, several challenges remain, particularly in improving preventive and curative services during pre- and postnatal care.

OBJETIVO: Determinar y describir 1) el progreso logrado hasta el momento en el cumplimiento de los compromisos del cuarto Objetivo de Desarrollo del Milenio en México, principalmente la contribución del Programa de Vacunación Universal (PVU) durante los 20 últimos años; y 2) las nuevas oportunidades para reducir aún más la mortalidad en niños menores de cinco años. MÉTODOS: Se llevó a cabo un estudio de observación, descriptivo y retrospectivo para analizar las causas registradas de muerte en niños menores de cinco años entre 1990 y el 2010. Se elaboraron indicadores según las recomendaciones de las Naciones Unidas. RESULTADOS: En el 2010, las defunciones en niños menores de cinco años se habían reducido en 64,3% en comparación con las cifras de referencia (1990). La mayor disminución de la mortalidad se observó en recién nacidos (52,8%), seguidos por los lactantes de 1 a 11 meses (30,9%) y los niños de 12 a 59 meses (16,2%). Se observó una reducción total de la mortalidad de 34% tras la universalización de la vacunación contra la gripe, el rotavirus y el neumococo en niños menores de cinco años. CONCLUSIONES: A pesar de una reducción significativa de la mortalidad en menores de cinco años en México durante los 20 últimos años, en gran parte debida a los éxitos del PVU, siguen existiendo diversos retos, en particular en cuanto a la mejora de los servicios preventivos y curativos durante la atención prenatal y posnatal.

Enfermedad diarreica por rotavirus en brotes epidémicos / Diarrheal disease caused by rotavirus in epidemic outbreaks

Objetivo. Determinar el perfil epidemiológico de los brotes de enfermedad diarreica aguda por rotavirus (RV) ocurridos en pacientes pediátricos, mediante una revisión crítica de la literatura publicada entre 2000 y 2010. Métodos. Se realizó una búsqueda de artículos publicados desde enero de 2000 hasta abril de 2010, recogidos por las bases de datos Artemisa, EBSCO, Embase, Imbiomed, Lilacs, Ovid, PubMed y Science Direct. En los estudios que cumplieron con los criterios de inclusión, se identificaron posibles factores de confusión y se atribuyeron riesgos de sesgo con base en el número de ítems considerados inadecuados en cada caso. Se describieron las características epidemiológicas y microbiológicas de los brotes. Resultados. Solo 14 (10,8%) de los 129 títulos identificados formaron parte de la muestra, los cuales sumaron 91 092 casos de diarrea aguda notificados. En 5 250 de estos casos se realizó la búsqueda de RV, la cual arrojó 1 711 (32,5%) aislamientos positivos. Se observó que el RV del grupo A fue el agente causal en 100% de los brotes, mientras que el genotipo G9 fue documentado en 50% de los artículos. Conclusiones. El RV, principalmente el serotipo G9, fue uno de los principales agentes responsables de los brotes de EDA en la última década. Un cuidadoso estudio de brote puede aportar información valiosa para el control y la prevención de la enfermedad por RV.

Objective. Determine the epidemiological profile of outbreaks of acute diarrheal disease caused by rotavirus (RV) occurring in pediatric patients, based on a critical review of the literature published between 2000 and 2010. Methods. A search was carried out for articles published from January 2000 to April 2010, collected by the Artemisa, EBSCO, Embase, Imbiomed, Lilacs, Ovid, PubMed, and Science Direct databases. In the studies that met the inclusion criteria, possible confounding factors were identified and risks of bias were attributed based on the number of items considered inadequate in each case. The epidemiological and microbiological characteristics of the outbreaks were described. Results. The sample was comprised of only 14 (10.8%) of the 129 titles identified, which accounted for 91 092 reported cases of acute diarrhea. In 5 250 of these cases, a search for rotavirus was conducted, yielding 1 711 (32.5%) positive isolations. It was observed that the RV from Group A was the causative agent in 100% of the outbreaks, while genotype G9 was documented in 50% of the articles. Conclusions. Rotavirus, mainly serotype G9, was one of the principal agents responsible for outbreaks of acute diarrheal disease over the past decade. A careful outbreak study can contribute valuable information for RV disease control and prevention.

Enfermedad diarreica por rotavirus en brotes epidémicos / Diarrheal disease caused by rotavirus in epidemic outbreaks

OBJETIVO: Determinar el perfil epidemiológico de los brotes de enfermedad diarreica aguda por rotavirus (RV) ocurridos en pacientes pediátricos, mediante una revisión crítica de la literatura publicada entre 2000 y 2010. MÉTODOS: Se realizó una búsqueda de artículos publicados desde enero de 2000 hasta abril de 2010, recogidos por las bases de datos Artemisa, EBSCO, Embase, Imbiomed, Lilacs, Ovid, PubMed y Science Direct. En los estudios que cumplieron con los criterios de inclusión, se identificaron posibles factores de confusión y se atribuyeron riesgos de sesgo con base en el número de ítems considerados inadecuados en cada caso. Se describieron las características epidemiológicas y microbiológicas de los brotes. RESULTADOS: Solo 14 (10,8 por ciento) de los 129 títulos identificados formaron parte de la muestra, los cuales sumaron 91 092 casos de diarrea aguda notificados. En 5 250 de estos casos se realizó la búsqueda de RV, la cual arrojó 1 711 (32,5 por ciento) aislamientos positivos. Se observó que el RV del grupo A fue el agente causal en 100 por ciento de los brotes, mientras que el genotipo G9 fue documentado en 50 por ciento de los artículos. CONCLUSIONES: El RV, principalmente el serotipo G9, fue uno de los principales agentes responsables de los brotes de EDA en la última década. Un cuidadoso estudio de brote puede aportar información valiosa para el control y la prevención de la enfermedad por RV.

OBJECTIVE: Determine the epidemiological profile of outbreaks of acute diarrheal disease caused by rotavirus (RV) occurring in pediatric patients, based on a critical review of the literature published between 2000 and 2010. METHODS: A search was carried out for articles published from January 2000 to April 2010, collected by the Artemisa, EBSCO, Embase, Imbiomed, Lilacs, Ovid, PubMed, and Science Direct databases. In the studies that met the inclusion criteria, possible confounding factors were identified and risks of bias were attributed based on the number of items considered inadequate in each case. The epidemiological and microbiological characteristics of the outbreaks were described. RESULTS: The sample was comprised of only 14 (10.8 percent) of the 129 titles identified, which accounted for 91 092 reported cases of acute diarrhea. In 5 250 of these cases, a search for rotavirus was conducted, yielding 1 711 (32.5 percent) positive isolations. It was observed that the RV from Group A was the causative agent in 100 percent of the outbreaks, while genotype G9 was documented in 50 percent of the articles. CONCLUSIONS: Rotavirus, mainly serotype G9, was one of the principal agents responsible for outbreaks of acute diarrheal disease over the past decade. A careful outbreak study can contribute valuable information for RV disease control and prevention.