Abstractobjective Dengue fever is globally considered underestimated. This study provides expansion factors (EFs) for dengue endemic selected countries and highlights critical issues in the use of EFs. results Cohort studies differed in case definition, laboratory test used and surveillance methods. The information on SEARO, PAHO and WPRO websites differed in terms of dengue epidemiological variables, population denominators and completeness. The highest incidence was reported by PAHO countries followed by WPRO and SEARO countries. EFs may vary for the different variables and denominators used for calculation. EFs were the highest in SEARO countries and lowest in PAHO countries. A trend for lower local EFs was observed.conclusions The use of EFs for quantifying dengue underreporting may be problematic due to lack of uniformity in reporting dengue both active and passive surveillance data. Quality dengue surveillance data are urgently needed for a better estimate of dengue disease burden and to measure the impact of preventive intervention.

A dynamic school-based cohort of 2-15 year-olds was established in Long Xuyen, Viet Nam to provide epidemiological data for a dengue vaccine efficacy trial. Active surveillance of febrile episodes identified clinically-suspected dengue and acute and convalescent sera were collected. IgG seroconversion between annual seroprevalence surveys identified sub-clinical infections. In 2004, 2190 children were enrolled with 3239, 3146, and 3081 present each year from 2005 to 2007 consecutively. In all, 627 children had a total of 690 clinically-suspected dengue episodes (394 hospitalisations, 296 outpatients) with 284-310 (41.2-45.0%) laboratory-confirmed depending on testing. Dengue serotype 2 was predominant in 2004 and 2005, and serotype 1 in 2006 and 2007. The acute dengue disease incidence rate per 1000 person-years ranged from 16.9 in 2005 to 40.4 in 2007. The average annual incidence of primary dengue infection (IgG seroconversion in previously naïve children) was 11.4% and the symptomatic to asymptomatic primary infection ratio ranged from 1:3-1:6. Study withdrawal rate, a feasibility indicator for conducting efficacy trials, was low: 4.2% per year when excluding children who changed schools. Our 2004-2007 results confirm the high transmission of dengue in children in Long Xuyen and demonstrate the suitability of this study site for a large scale efficacy trial.

Summary Background Few data are available to support the choice between the two currently available pneumococcal conjugate vaccines (PCVs), ten-valent PCV (PCV10) and 13-valent PCV (PCV13). Here we report a head-to-head comparison of the immunogenicity and reactogenicity of PCV10 and PCV13. Methods In this parallel, open-label, randomised controlled trial, healthy infants from two districts in Ho Chi Minh City, Vietnam, were randomly allocated (in a 3:3:5:4:5:4 ratio), with use of a computer-generated list, to one of six infant PCV schedules: PCV10 in a 3 + 1 (group A), 3 + 0 (group B), 2 + 1 (group C), or two-dose schedule (group D); PCV13 in a 2 + 1 schedule (group E); or no infant PCV (control; group F). Blood samples were collected from infants between 2 months and 18 months of age at various timepoints before and after PCV doses and analysed (in a blinded manner) by ELISA and opsonophagocytic assay. The trial had two independent aims: to compare vaccination responses between PCV10 and PCV13, and to evaluate different schedules of PCV10. In this Article, we present results pertaining to the first aim. The primary outcome was the proportion of infants with an IgG concentration of at least 0·35 μg/mL for the ten serotypes common to the two vaccines at age 5 months, 4 weeks after the two-dose primary vaccination series (group C vs group E, per protocol population). An overall difference among the schedules was defined as at least seven of ten serotypes differing in the same direction at the 10% level. We also assessed whether the two-dose primary series of PCV13 (group E) was non-inferior at the 10% level to a three-dose primary series of PCV10 (groups A and B). This trial is registered with ClinicalTrials.gov , number NCT01953510 . Findings Of 1424 infants screened between Sept 30, 2013, and Jan 9, 2015, 1201 were allocated to the six groups: 152 (13%) to group A, 149 (12%) to group B, 250 (21%) to group C, 202 (17%) to group D, 251 (21%) to group E, and 197 (16%) to group F. 237 (95%) participants in group C (PCV10) and 232 (92%) in group E (PCV13) completed the primary vaccination series and had blood draws within the specified window at age 5 months, at which time the proportion of infants with IgG concentrations of at least 0·35 μg/mL did not differ between groups at the 10% level for any serotype (PCV10–PCV13 risk difference −2·1% [95% CI −4·8 to −0·1] for serotype 1; −1·3% [–3·7 to 0·6] for serotype 4; −3·4% [–6·8 to −0·4] for serotype 5; 15·6 [7·2 to 23·7] for serotype 6B; −1·3% [–3·7 to 0·6] for serotype 7F; −1·6% [–5·1 to 1·7] for serotype 9V; 0·0% [–2·7 to 2·9] for serotype 14; −2·1% [–5·3 to 0·9] for serotype 18C; 0·0% [–2·2 to 2·3] for serotype 19F; and −11·6% [–18·2 to −4·9] for serotype 23F). At the same timepoint, two doses of PCV13 were non-inferior to three doses of PCV10 for nine of the ten shared serotypes (excluding 6B). Reac...

IntroductionWHO recommends the use of pneumococcal conjugate vaccine (PCV) as a priority. However, there are many countries yet to introduce PCV, especially in Asia. This trial aims to evaluate different PCV schedules and to provide a head-to-head comparison of PCV10 and PCV13 in order to generate evidence to assist with decisions regarding PCV introduction. Schedules will be compared in relation to their immunogenicity and impact on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae.Methods and analysisThis randomised, single-blind controlled trial involves 1200 infants recruited at 2 months of age to one of six infant PCV schedules: PCV10 in a 3+1, 3+0, 2+1 or two-dose schedule; PCV13 in a 2+1 schedule; and controls that receive two doses of PCV10 and 18 and 24 months. An additional control group of 200 children is recruited at 18 months that receive one dose of PCV10 at 24 months. All participants are followed up until 24 months of age. The primary outcome is the post-primary series immunogenicity, expressed as the proportions of participants with serotype-specific antibody levels ≥0.35 µg/mL for each serotype in PCV10.Ethics and disseminationEthical approval has been obtained from the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (EC00153) and the Vietnam Ministry of Health Ethics Committee. The results, interpretation and conclusions will be presented to parents and guardians, at national and international conferences, and published in peer-reviewed open access journals.Trial registration numberNCT01953510; Pre-results.

BackgroundPreterm infants are highly vulnerable to infectious disease. While many factors are likely to contribute to this enhanced susceptibility, the immature nature of the preterm immune system is postulated as one key factor.MethodsIn our study, we used high-dimensional flow cytometry and cytokine assays to characterise the immune profiles in 25 preterm (range: 30.4-34.1 weeks gestational age) and 25 term infant (range: 37-40 weeks gestational age) cord blood samples.ResultsWe found that preterm infants exhibit reduced frequencies of monocytes, CD56bright NK cells, CD8+ T-cells, γδ T-cells and an increased frequency of intermediate monocytes, CD4+ T-cells, central memory CD4+ and CD8+ T-cells, Tregs and transitional B-cells compared to term infants. Pro-inflammatory cytokines IL-1β, IL-6 and IL-17A were lower in preterm infants in addition to chemokines IL-8, eotaxin, MIP-1α and MIP-1β. However, IL-15 and MCP-1 were higher in preterm infants.ConclusionOverall, we identify key differences in pro-inflammatory immune profiles between preterm and term infants. These findings may help to explain why preterm infants are more susceptible to infectious disease during early life and facilitate the development of targeted interventions to protect this highly vulnerable group.

Highlights 1st study to directly compare effect of 2+1 schedule of PCV10 or PCV13 on carriage. Includes an unvaccinated comparator group. Both PCVs reduce carriage of serotypes in the corresponding vaccine. May be some differences between the vaccines in their impact on carriage. Majority of carriage was vaccine-type, so both vaccines likely to be beneficial.

Background Data are scarce from low-income and middle-income countries (LMICs) to support the choice of vaccination schedule for the introduction of pneumococcal conjugate vaccines (PCV). We aimed to compare the immunogenicity of four different infant PCV10 schedules in infants in Vietnam.Methods In this single-blind, parallel-group, open-label, randomised controlled trial, infants aged 2 months were recruited by community health staff in districts 4 and 7 of Ho Chi Minh City, Vietnam. Eligible infants had no clinically significant maternal or prenatal history and were born at or after 36 weeks' gestation. Participants were randomly assigned (3:3:5:4:5:4) using block randomisation, stratified by district, to one of six PCV10 or PCV13 vaccination schedules. Here we report results for four groups: group A, who were given PCV10 at ages 2, 3, 4, and 9 months (a 3 + 1 schedule); group B, who were vaccinated at ages 2, 3, and 4 months (3 + 0 schedule); group C, who were vaccinated at ages 2, 4, and 9•5 months (2 + 1 schedule); and group D, who were vaccinated at ages 2 and 6 months (two-dose schedule). Laboratory-based assessors were masked to group allocation. Blood samples were collected at different prespecified timepoints between ages 3-18 months depending on group allocation, within 27-43 days after vaccination, and these were analysed for serotype-specific IgG and opsonophagocytic responses. Participants were followed-up until age 24 months. The primary outcome was the proportion of infants with serotype-specific IgG levels of 0•35 µg/mL or higher at age 5 months, analysed as a non-inferiority comparison (10% margin) of the two-dose and three-dose primary series (group C vs groups A and B combined). We also compared responses 4 weeks after two doses administered at either ages 2 and 4 months (group C) or at ages 2 and 6 months (group D). The primary endpoint was analysed in the per-protocol population. Reactogenicity has been reported previously. This study is registered with ClinicalTrials.gov, NCT01953510, and is now closed to accrual.

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