A blood RNA signature for tuberculosis disease risk: a prospective cohort study.

Background: Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat the tuberculosis epidemic. We aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease.

Methods: In this prospective cohort study, we followed up healthy, South African adolescents aged 12-18 years from the adolescent cohort study (ACS) who were infected with M tuberculosis for 2 years.

Serum indoleamine 2,3-dioxygenase activity is associated with reduced immunogenicity following vaccination with MVA85A.

Background: There is an urgent need for improved vaccines to protect against tuberculosis. The currently available vaccine Bacille Calmette-Guerin (BCG) has varying immunogenicity and efficacy across different populations for reasons not clearly understood. MVA85A is a modified vaccinia virus expressing antigen 85A from Mycobacterium tuberculosis which has been in clinical development since 2002 as a candidate vaccine to boost BCG-induced protection.

TB incidence in an adolescent cohort in South Africa.

Background: Tuberculosis (TB) is a major public health problem globally. Little is known about TB incidence in adolescents who are a proposed target group for new TB vaccines. We conducted a study to determine the TB incidence rates and risk factors for TB disease in a cohort of school-going adolescents in a high TB burden area in South Africa.

Screening for TB in high school adolescents in a high burden setting in South Africa.

Screening for tuberculosis (TB) disease is important for TB control and TB vaccine efficacy trials but this has not been evaluated in adolescents. We conducted a study to determine the prevalence of active TB and performance of specific screening tests for TB in adolescents in a high burden setting. Adolescents aged 12-18 years were recruited from high schools in a rural town in South Africa.

Phenotypic variability in childhood TB: implications for diagnostic endpoints in tuberculosis vaccine trials.

The endpoint definition for infant tuberculosis (TB) vaccine trials should match the TB disease phenotype expected in the control arm of the study population. Our aim was to analyse selected combinations of the clinical, radiological, and microbiological features of pulmonary TB among children investigated under vaccine trial conditions, in order to estimate case frequency for a range of expected TB phenotypes. Two thousand one hundred and eighty five South African children were investigated over a nine-year period (2001-2009).

The tuberculin skin test versus QuantiFERON TB Gold® in predicting tuberculosis disease in an adolescent cohort study in South Africa.

Setting: This study was conducted in a high tuberculosis (TB) burden area in Worcester, South Africa, with a notified all TB incidence rate of 1,400/100,000.

Main Objective: To compare the predictive value of a baseline tuberculin skin test (TST) with that of the QuantiFERON TB Gold (In-tube) assay (QFT) for subsequent microbiologically confirmed TB disease among adolescents.

Methods: Adolescents aged 12-18 years were recruited from high schools in the study area.

HIV-specific gag responses in early infancy correlate with clinical outcome and inversely with viral load.

Many HIV-infected infants progress to AIDS during the first year of life when antiretroviral therapy (ART) is not given. The immune determinants of progression to AIDS are not known. We hypothesized that distinct HIV-specific T cell responses correlate with viral load and survival over the first year of life.

Prospects for a new, safer and more effective TB vaccine.

Tuberculosis in infants and young children remains an all too common cause of morbidity and mortality in high burden countries, despite the fact that the majority of these children receive vaccination with BCG in infancy. BCG confers incomplete and variable protection against pulmonary tuberculosis [PTB] and is unsafe in HIV positive persons. Newer TB vaccines, which, it is hoped, will either replace or complement BCG are being developed and a number of these have reached the stage of clinical trials, with two booster vaccines going into Phase IIB trials in 2009.

Structured approaches for the screening and diagnosis of childhood tuberculosis in a high prevalence region of South Africa.

Objective: To measure agreement between nine structured approaches for diagnosing childhood tuberculosis; to quantify differences in the number of tuberculosis cases diagnosed with the different approaches, and to determine the distribution of cases in different categories of diagnostic certainty.

Methods: We investigated 1445 children aged < 2 years during a vaccine trial (2001-2006) in a rural South African community. Clinical, radiological and microbiological data were collected prospectively.

Comparison of mantoux and tine tuberculin skin tests in BCG-vaccinated children investigated for tuberculosis.

Background: Tuberculin skin tests (TSTs) are long-established screening methods for tuberculosis (TB). We aimed to compare agreement between the intradermal Mantoux and multipuncture percutaneous Tine methods and to quantify risk factors for a positive test result.

Methodology/principal Findings: 1512 South African children younger than 5 years of age who were investigated for tuberculosis (TB) during a Bacille Calmette Guerin (BCG) trial were included in this analysis.

New vaccines against tuberculosis.

The only currently licensed tuberculosis (TB) vaccine, bacille Calmette Guérin, confers incomplete protection against tuberculosis, and is not safe in infants infected with the human immunodeficiency virus. A new, safe vaccine regimen, which better protects against lung disease, is urgently needed to control TB in high-burden countries. Multiple candidate vaccines have shown promise in preclinical studies, and are now entering phase 1 to 2B clinical trials.

A New Vaccine for Tuberculosis: The Challenges of Development and Deployment.

Tuberculosis (TB) is one of the world's leading causes of death due to infection and efforts to control TB would be substantially aided by the availability of an improved TB vaccine. There are currently nine new TB vaccines in clinical development, and the first efficacy trials are due to commence in 2009. There are many complex ethical issues which arise at all stages of TB vaccine development, from the need to conduct trials in developing countries to informed consent and the process of ethical review.

Evaluation of the quality of informed consent in a vaccine field trial in a developing country setting.

Background: Informed consent is an ethical and legal requirement for research involving human participants. However, few studies have evaluated the process, particularly in Africa. Participants in a case control study designed to identify correlates of immune protection against tuberculosis (TB) in South Africa.

Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South Africa.

Background: The efficacy of bacille Calmette-Guérin (BCG) may be enhanced by heterologous vaccination strategies that boost the BCG-primed immune response. One leading booster vaccine, MVA85A (where "MVA" denotes "modified vaccinia virus Ankara"), has shown promising safety and immunogenicity in human trials performed in the United Kingdom. We investigated the safety and immunogenicity of MVA85A in mycobacteria-exposed--but Mycobacterium tuberculosis-uninfected--healthy adults from a region of South Africa where TB is endemic.

Childhood tuberculosis: old and new vaccines.

The world is witnessing an escalation of the tuberculosis (TB) epidemic, particularly in sub-Saharan Africa and South-East Asia. The problem has been compounded by the evolution of the human immunodeficiency virus pandemic, the increase in multidrug-resistant TB and the emergence of extensively drug-resistant TB. This has led to renewed interest in vaccines aimed at preventing tuberculosis.

Determining causes of mortality in children enrolled in a vaccine field trial in a rural area in the Western Cape Province of South Africa.

Aim: A mortality surveillance system was developed to identify and document causes of death among children enrolled in a tuberculosis vaccine field trial in South Africa. The aims of this study were to describe causes of mortality in children enrolled in a phase IV trial comparing intradermal with percutaneous administration of Bacille Calmette Guerin, and to compare causes of mortality recorded on death certificates with those obtained by clinical record review combined with verbal autopsies (CR/VA).

Methods: For children who died, certified causes of death were compared with those determined by CR/VA.

Isolation of non-tuberculous mycobacteria in children investigated for pulmonary tuberculosis.

Objective: To evaluate the frequency and clinical significance of non-tuberculous mycobacteria (NTM) isolates among children investigated for pulmonary tuberculosis in a rural South African community.

Methods: Children were investigated for pulmonary tuberculosis as part of a tuberculosis vaccine surveillance program (2001-2005). The clinical features of children in whom NTM were isolated, from induced sputum or gastric lavage, were compared to those with culture-proven M.

The impact of a change in bacille Calmette-Guérin vaccine policy on tuberculosis incidence in children in Cape Town, South Africa.

Background: A decision by the South African National Department of Health to change the route of administration and strain of bacille Calmette-Guérin (BCG) vaccine was implemented in Cape Town, South Africa, between July and December 2000. This provided an opportunity to compare the incidence of tuberculosis and proportion with disseminated disease in children less than 2 years old before and after the changeover from percutaneous (PC) Tokyo 172 BCG to intradermal (ID) 1331 Danish BCG immunization.

Methods: Clinical records of all tuberculosis patients aged less than 2 years at diagnosis and born between January 1, 1999, and June 30, 2000 (PC cohort) and between January 1, 2001, and June 30, 2002 (ID cohort) were collected.