Global diarrhoea-associated mortality estimates and models in children: Recommendations for dataset and study selection.

BACKGROUND: Multiple factors contribute to variation in disease burden, including the type and quality of data, and inherent properties of the models used. Understanding how these factors affect mortality estimates is crucial, especially in the context of public health decision making. We examine how the quality of the studies selected to provide mortality data, influence estimates of burden and provide recommendations about the inclusion of studies and datasets to calculate mortality estimates. METHODS: To determine how mortality estimates are affected by the data used to generate model outputs, we compared the studies used by The Institute of Health Metrics and Evaluation (IHME) and Maternal and Child Epidemiology Estimation (MCEE) modelling groups to generate enterotoxigenic Escherichia coli (ETEC) and Shigella-associated mortality estimates for 2016. Guided by an expert WHO Working Group, we applied a modified Newcastle-Ottawa Scale (NOS) to evaluate the quality of studies used by both modelling groups. RESULTS: IHME and MCEE used different sets of ETEC and Shigella studies in their models and the majority of studies were high quality. The distribution of the NOS scores was similar between the two modelling groups. We observed an overrepresentation of studies from some countries in SEAR, AFR and WPR compared to other WHO regions. CONCLUSION: We identified key differences in study inclusion and exclusion criteria used by IHME and MCEE and discuss their impact on datasets used to generate diarrhoea-associated mortality estimates. Based on these observations, we provide a set of recommendations for future estimates of mortality associated with enteric diseases.

Approaches to use the WHO respiratory syncytial virus surveillance platform to estimate disease burden.

The World Health Organization (WHO) recently completed the first phase of a RSV surveillance pilot study in fourteen countries (two to three in each WHO region) building on the Global Influenza Surveillance and Response System (GISRS). This active surveillance strategy had several objectives including understanding RSV-related health burden in a variety of settings. A range of approaches can be used to estimate disease burden; most approaches could not be applied by participating countries in the WHO surveillance pilot. This article provides the recommendations made by WHO for strengthening and expanding the scope of the RSV surveillance in the next phase to enable burden estimation.

The role of immune correlates of protection on the pathway to licensure, policy decision and use of group B Streptococcus vaccines for maternal immunization: considerations from World Health Organization consultations.

The development of a group B Streptococcus (GBS) vaccine for maternal immunization constitutes a global public health priority, to prevent GBS-associated early life invasive disease, stillbirth, premature birth, maternal sepsis, adverse neurodevelopmental consequences, and to reduce perinatal antibiotic use. Sample size requirements for the conduct of a randomized placebo-controlled trial to assess vaccine efficacy against the most relevant clinical endpoints, under conditions of appropriate ethical standards of care, constitute a significant obstacle on the pathway to vaccine availability. Alternatively, indirect evidence of protection based on immunologic data from vaccine and sero-epidemiological studies, complemented by data from opsonophagocytic in vitro assays and animal models, could be considered as pivotal data for licensure, with subsequent confirmation of effectiveness against disease outcomes in post-licensure evaluations. Based on discussions initiated by the World Health Organization we present key considerations about the potential role of correlates of protection towards an accelerated pathway for GBS vaccine licensure and wide scale use. Priority activities to support progress to regulatory and policy decision are outlined.

Clinical development and regulatory points for consideration for second-generation live attenuated dengue vaccines.

Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines.

The duration of protection of school-aged BCG vaccination in England: a population-based case-control study.

Background: Evidence of protection from childhood Bacillus Calmette-Guerin (BCG) against tuberculosis (TB) in adulthood, when most transmission occurs, is important for TB control and resource allocation. Methods: We conducted a population-based case-control study of protection by BCG given to children aged 12-13 years against tuberculosis occurring 10-29 years later. We recruited UK-born White subjects with tuberculosis and randomly sampled White community controls. Hazard ratios and 95% confidence intervals (CIs) were estimated using case-cohort Cox regression, adjusting for potential confounding factors, including socio-economic status, smoking, drug use, prison and homelessness. Vaccine effectiveness (VE = 1 - hazard ratio) was assessed at successive intervals more than 10 years following vaccination. Results: We obtained 677 cases and 1170 controls after a 65% response rate in both groups. Confounding by deprivation, education and lifestyle factors was slight 10-20 years after vaccination, and more evident after 20 years. VE 10-15 years after vaccination was 51% (95% CI 21, 69%) and 57% (CI 33, 72%) at 15-20 years. Subsequently, BCG protection appeared to wane; 20-25 years VE = 25% (CI -14%, 51%) and 25-29 years VE = 1% (CI -84%, 47%). Based on multiple imputation of missing data (in 17% subjects), VE estimated in the same intervals after vaccination were similar [56% (CI 33, 72%), 57% (CI 36, 71%), 25% (-10, 48%), 21% (-39, 55%)]. Conclusions: School-aged BCG vaccination offered moderate protection against tuberculosis for at least 20 years, which is longer than previously thought. This has implications for assessing the cost-effectiveness of BCG vaccination and when evaluating new TB vaccines.

Observational study to estimate the changes in the effectiveness of bacillus Calmette-Guérin (BCG) vaccination with time since vaccination for preventing tuberculosis in the UK.

BACKGROUND: Until recently, evidence that protection from the bacillus Calmette-Guérin (BCG) vaccination lasted beyond 10 years was limited. In the past few years, studies in Brazil and the USA (in Native Americans) have suggested that protection from BCG vaccination against tuberculosis (TB) in childhood can last for several decades. The UK's universal school-age BCG vaccination programme was stopped in 2005 and the programme of selective vaccination of high-risk (usually ethnic minority) infants was enhanced. OBJECTIVES: To assess the duration of protection of infant and school-age BCG vaccination against TB in the UK. METHODS: Two case-control studies of the duration of protection of BCG vaccination were conducted, the first on minority ethnic groups who were eligible for infant BCG vaccination 0-19 years earlier and the second on white subjects eligible for school-age BCG vaccination 10-29 years earlier. TB cases were selected from notifications to the UK national Enhanced Tuberculosis Surveillance system from 2003 to 2012. Population-based control subjects, frequency matched for age, were recruited. BCG vaccination status was established from BCG records, scar reading and BCG history. Information on potential confounders was collected using computer-assisted interviews. Vaccine effectiveness was estimated as a function of time since vaccination, using a case-cohort analysis based on Cox regression. RESULTS: In the infant BCG study, vaccination status was determined using vaccination records as recall was poor and concordance between records and scar reading was limited. A protective effect was seen up to 10 years following infant vaccination [< 5 years since vaccination: vaccine effectiveness (VE) 66%, 95% confidence interval (CI) 17% to 86%; 5-10 years since vaccination: VE 75%, 95% CI 43% to 89%], but there was weak evidence of an effect 10-15 years after vaccination (VE 36%, 95% CI negative to 77%; p = 0.396). The analyses of the protective effect of infant BCG vaccination were adjusted for confounders, including birth cohort and ethnicity. For school-aged BCG vaccination, VE was 51% (95% CI 21% to 69%) 10-15 years after vaccination and 57% (95% CI 33% to 72%) 15-20 years after vaccination, beyond which time protection appeared to wane. Ascertainment of vaccination status was based on self-reported history and scar reading. LIMITATIONS: The difficulty in examining vaccination sites in older women in the high-risk minority ethnic study population and the sparsity of vaccine record data in the later time periods precluded robust assessment of protection from infant BCG vaccination > 10 years after vaccination. CONCLUSIONS: Infant BCG vaccination in a population at high risk for TB was shown to provide protection for at least 10 years, whereas in the white population school-age vaccination was shown to provide protection for at least 20 years. This evidence may inform TB vaccination programmes (e.g. the timing of administration of improved TB vaccines, if they become available) and cost-effectiveness studies. Methods to deal with missing record data in the infant study could be explored, including the use of scar reading. FUNDING: The National Institute for Health Research Health Technology Assessment programme. During the conduct of the study, Jonathan Sterne, Ibrahim Abubakar and Laura C Rodrigues received other funding from NIHR; Ibrahim Abubakar and Laura C Rodrigues have also received funding from the Medical Research Council. Punam Mangtani received funding from the Biotechnology and Biological Sciences Research Council.

Total synthesis of 6-deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 cancer cell line.

A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.

Long-term safety assessment of live attenuated tetravalent dengue vaccines: deliberations from a WHO technical consultation.

Dengue is a rapidly growing public health threat with approximately 2.5 billion people estimated to be at risk. Several vaccine candidates are at various stages of pre-clinical and clinical development. Thus far, live dengue vaccine candidates have been administered to several thousands of volunteers and were well-tolerated, with minimal short-term safety effects reported in Phase I and Phase II clinical trials. Based on the natural history of dengue, a theoretical possibility of an increased risk of severe dengue as a consequence of vaccination has been hypothesized but not yet observed. In October 2011, the World Health Organization (WHO) convened a consultation of experts in dengue, vaccine regulation and vaccine safety to review the current scientific evidence regarding safety concerns associated with live attenuated dengue vaccines and, in particular, to consider methodological approaches for their long-term evaluation. In this paper we summarize the scientific background and methodological considerations relevant to the safety assessment of these vaccines. Careful planning and a coordinated approach to safety assessment are recommended to ensure adequate long-term evaluation of dengue vaccines that will support their introduction and continued use.

Sustainable development of a GCP-compliant clinical trials platform in Africa: the malaria clinical trials alliance perspective.

BACKGROUND: The Malaria Clinical Trials Alliance (MCTA), a programme of INDEPTH network of demographic surveillance centres, was launched in 2006 with two broad objectives: to facilitate the timely development of a network of centres in Africa with the capacity to conduct clinical trials of malaria vaccines and drugs under conditions of good clinical practice (GCP); and to support, strengthen and mentor the centres in the network to facilitate their progression towards self-sustaining clinical research centres. CASE DESCRIPTION: Sixteen research centres in 10 African malaria-endemic countries were selected that were already working with the Malaria Vaccine Initiative (MVI) or the Medicines for Malaria Venture (MMV). All centres were visited to assess their requirements for research capacity development through infrastructure strengthening and training. Support provided by MCTA included: laboratory and facility refurbishment; workshops on GCP, malaria diagnosis, strategic management and media training; and training to support staff to undertake accreditation examinations of the Association of Clinical Research Professionals (ACRP). Short attachments to other network centres were also supported to facilitate sharing practices within the Alliance. MCTA also played a key role in the creation of the African Media & Malaria Research Network (AMMREN), which aims to promote interaction between researchers and the media for appropriate publicity and media reporting of research and developments on malaria, including drug and vaccine trials. CONCLUSION: In three years, MCTA strengthened 13 centres to perform GCP-compliant drug and vaccine trials, including 11 centres that form the backbone of a large phase III malaria vaccine trial. MCTA activities have demonstrated that centres can be brought up to GCP compliance on this time scale, but the costs are substantial and there is a need for further support of other centres to meet the growing demand for clinical trial capacity. The MCTA experience also indicates that capacity development in clinical trials is best carried out in the context of preparation for specific trials. In this regard MCTA centres involved in the phase III malaria vaccine trial were, on average, more successful at consolidating the training and infrastructure support than those centres focussing only on drug trials.

Comparison of rapid tests for detection of rifampicin-resistant Mycobacterium tuberculosis in Kampala, Uganda.

BACKGROUND: Drug resistant tuberculosis (TB) is a growing concern worldwide. Rapid detection of resistance expedites appropriate intervention to control the disease. Several technologies have recently been reported to detect rifampicin resistant Mycobacterium tuberculosis directly in sputum samples. These include phenotypic culture based methods, tests for gene mutations and tests based on bacteriophage replication. The aim of the present study was to assess the feasibility of implementing technology for rapid detection of rifampicin resistance in a high disease burden setting in Africa. METHODS: Sputum specimens from re-treatment TB patients presenting to the Mulago Hospital National TB Treatment Centre in Kampala, Uganda, were examined by conventional methods and simultaneously used in one of the four direct susceptibility tests, namely direct BACTEC 460, Etest, "in-house" phage test, and INNO- Rif.TB. The reference method was the BACTEC 460 indirect culture drug susceptibility testing. Test performance, cost and turn around times were assessed. RESULTS: In comparison with indirect BACTEC 460, the respective sensitivities and specificities for detecting rifampicin resistance were 100% and 100% for direct BACTEC and the Etest, 94% and 95% for the phage test, and 87% and 87% for the Inno-LiPA assay. Turn around times ranged from an average of 3 days for the INNO-LiPA and phage tests, 8 days for the direct BACTEC 460 and 20 days for the Etest. All methods were faster than the indirect BACTEC 460 which had a mean turn around time of 24 days. The cost per test, including labour ranged from $18.60 to $41.92 (USD). CONCLUSION: All four rapid technologies were shown capable of detecting rifampicin resistance directly from sputum. The LiPA proved rapid, but was the most expensive. It was noted, however, that the LiPA test allows sterilization of samples prior to testing thereby reducing the risk of accidental laboratory transmission. In contrast the Etest was low cost, but slow and would be of limited assistance when treating patients. The phage test was the least reproducible test studied with failure rate of 27%. The test preferred by the laboratory personnel, direct BACTEC 460, requires further study to determine its accuracy in real-time treatment decisions in Uganda.

Low-cost rapid detection of rifampicin resistant tuberculosis using bacteriophage in Kampala, Uganda.

BACKGROUND: Resistance to anti-tuberculosis drugs is a serious public health problem. Multi-drug resistant tuberculosis (MDR-TB), defined as resistance to at least rifampicin and isoniazid, has been reported in all regions of the world. Current phenotypic methods of assessing drug susceptibility of M. tuberculosis are slow. Rapid molecular methods to detect resistance to rifampicin have been developed but they are not affordable in some high prevalence countries such as those in sub Saharan Africa. A simple multi-well plate assay using mycobacteriophage D29 has been developed to test M. tuberculosis isolates for resistance to rifampicin. The purpose of this study was to investigate the performance of this technology in Kampala, Uganda. METHODS: In a blinded study 149 M. tuberculosis isolates were tested for resistance to rifampicin by the phage assay and results compared to those from routine phenotypic testing in BACTEC 460. Three concentrations of drug were used 2, 4 and 10 microg/ml. Isolates found resistant by either assay were subjected to sequence analysis of a 81 bp fragment of the rpoB gene to identify mutations predictive of resistance. Four isolates with discrepant phage and BACTEC results were tested in a second phenotypic assay to determine minimal inhibitory concentrations. RESULTS: Initial analysis suggested a sensitivity and specificity of 100% and 96.5% respectively for the phage assay used at 4 and 10 microg/ml when compared to the BACTEC 460. However, further analysis revealed 4 false negative results from the BACTEC 460 and the phage assay proved the more sensitive and specific of the two tests. Of the 39 isolates found resistant by the phage assay 38 (97.4%) were found to have mutations predictive of resistance in the 81 bp region of the rpoB gene. When used at 2 mug/ml false resistant results were observed from the phage assay. The cost of reagents for testing each isolate was estimated to be 1.3 US dollars when testing a batch of 20 isolates on a single 96 well plate. Results were obtained in 48 hours. CONCLUSION: The phage assay can be used for screening of isolates for resistance to rifampicin, with high sensitivity and specificity in Uganda. The test may be useful in poorly resourced laboratories as a rapid screen to differentiate between rifampicin susceptible and potential MDR-TB cases.

The European and developing countries clinical trails partnership.

The European and Developing Countries Clinical Trials Partnership (EDCTP) is a new venture between 14 states of the European Union (EU) and Norway to support the conduct of clinical trials of drugs and vaccines (and microbicides) against HIV/AIDS, malaria and tuberculosis in Africa, to develop the capacity to conduct such trials in African institutions, and to promote a more integrated approach to health research amongst European countries. It is funded for 5 years with a contribution of euros 200 million from the European Commission, matched by an equivalent sum that is spent directly by national research programmes of EU member states and Norway on activities that fall under the EDCTP remit. EDCTP seeks to be synergistic with other funding bodies supporting research on these diseases and will promote collaborative research, involving support from multiple funding agencies and harnessing and networking expertise across different African and European countries.

Social environment, behavior, and schistosomiasis in an urban population in the northeast of Brazil / Medio social, conducta y esquistosomiasis en una población urbana del nordeste de Brasil

The objective of our study was to gain greater insight into the pattern of water contact in relation to schistosomiasis among residents of São Lourenço da Mata, a town in Pernambuco, a state in the Northeast of Brazil. We had two primary objectives: 1) to identify water contact activities that were more likely to produce infection and 2) to examine the socioeconomic factors behind water contact activities. Using a sample of persons 10­25 years old, we carried out a population-based case-control study to investigate the first objective, and a cross-sectional study for the second objective. We found that leisure water contact with flowing water (stream or river) was significantly associated with schistosomiasis.Variables showing a statistically significant association with leisure water contact were economic sector, income, and level of education of the head of the household; type of housing; possessions inside the house; type of domestic water supply; and method of excreta collection. We introduced these variables into a multivariate model to select the ones that were most closely associated with leisure water contact. We used a stepdown procedure, and two variables were retained in the final model: type of domestic water supply and type of housing. We concluded that a decrease in leisure water contact was associated with better socioeconomic conditions. Our results suggest that with the subjects we studied in São Lourenço da Mata there was a socioeconomic determination for leisure water contact. Our data highlight the importance of a broad and integrated approach in studying water contact activities and in implementing behavioral interventions for schistosomiasis prevention and control

El objetivo de este estudio consistió en contribuir a una mejor comprensión de la relación entre el tipo de contacto con el agua y la esquistosomiasis en los residentes de São Lourenço da Mata, una ciudad del estado de Pernambuco, en el Nordeste de Brasil. Los dos objetivos principales fueron: 1) identificar los tipos de contacto con el agua con mayores probabilidades de producir infección, y 2) investigar los factores socioeconómicos subyacentes a esas actividades. Utilizando una muestra de personas de 10 a 25 años de edad, se realizó un estudio de casos y controles basado en la población para alcanzar el primer objetivo, y un estudio transversal para el segundo objetivo. Se comprobó que las actividades recreativas que implicaban contacto con cursos de agua (arroyos o ríos) estaban significativamente asociadas a la esquistosomiasis; las variables asociadas de forma significativa con dichas actividades fueron el sector económico, los ingresos y el nivel de educación del cabeza de familia; el tipo de domicilio y los enseres que contenía; el tipo de suministro de agua al domicilio, y el sistema de eliminación de los excrementos. Estas variables fueron introducidas de forma escalonada en un modelo multivariado para seleccionar las más estrechamente asociadas al contacto recreativo con el agua. En el modelo final quedaron dos variables: el tipo de suministro de agua al domicilio y el tipo de domicilio. Se concluyó que el menor contacto recreativo con el agua estaba asociado a mejores condiciones socioeconómicas. Los resultados obtenidos indican que, en los sujetos estudiados de São Lourenço da Mata, el contacto recreativo con el agua era determinado por factores socioeconómicos y destacan la importancia de un abordaje amplio e integrado a la hora de estudiar las actividades que implican contacto con el agua y de poner en práctica intervenciones conductuales de prevención y control de la esquistosomiasis