A Blueprint to Address Research Gaps in the Development of Biomarkers for Pediatric Tuberculosis.

Childhood tuberculosis contributes significantly to the global tuberculosis disease burden but remains challenging to diagnose due to inadequate methods of pathogen detection in paucibacillary pediatric samples and lack of a child-specific host biomarker to identify disease. Accurately diagnosing tuberculosis in children is required to improve case detection, surveillance, healthcare delivery, and effective advocacy. In May 2014, the National Institutes of Health convened a workshop including researchers in the field to delineate priorities to address this research gap. This blueprint describes the consensus from the workshop, identifies critical research steps to advance this field, and aims to catalyze efforts toward harmonization and collaboration in this area.

The nasopharyngeal microbiome in South African children with lower respiratory tract infection: a nested case-control study of the Drakenstein Child Health Study.

Background: Lower respiratory tract infection (LRTI) is a leading cause of infant morbidity and mortality globally. LRTI may be caused by viral or bacterial infections, individually or in combination. We investigated associations between LRTI and infant nasopharyngeal (NP) viruses and bacteria in a South African birth cohort. Methods: In a case-control study of infants enrolled in the Drakenstein Child Health Study (DCHS), LRTI cases were identified prospectively and age-matched with controls from the cohort. NP swabs were tested using quantitative real-time polymerase chain reaction (qPCR) and 16S rRNA gene amplicon sequencing. We calculated adjusted Conditional Odds Ratios (aORs) for qPCR targets and used mixed effects models to identify differentially abundant taxa between LRTI cases and controls and explore viral-bacterial interactions. Results: Respiratory Syncytial Virus (RSV) [aOR: 5.69, 95% CI: 3.03-10.69], human rhinovirus (HRV) [1.47, 1.03-2.09], parainfluenza virus [3.46, 1.64-7.26], adenovirus [1.99, 1.08-3.68], enterovirus [2.32, 1.20-4.46], Haemophilus influenzae [1.72, 1.25-2.37], Klebsiella pneumoniae [2.66, 1.59-4.46], or high-density (> 6.9 log10 copies/mL) Streptococcus pneumoniae [1.53, 1.01-2.32] were associated with LRTI. Using 16S sequencing, LRTI was associated with increased relative abundance of Haemophilus (q = 0.0003) and decreased relative abundance of Dolosigranulum (q = 0.001), Corynebacterium (q = 0.091) and Neisseria (q = 0.004). In samples positive for RSV, Staphylococcus and Alloprevotella were present at lower relative abundance in cases than controls. In samples positive for parainfluenza virus or HRV, Haemophilus was present at higher relative abundance in cases. Conclusions: The associations between bacterial taxa and LRTI are strikingly similar to those identified in high-income countries, suggesting a conserved phenotype. RSV was the major virus associated with LRTI. H. influenzae appears to be the major bacterial driver of LRTI, acting synergistically with viruses. The Gram-positive bacteria Dolosigranulum and Corynebacteria may protect against LRTI, while Staphylococcus was associated with reduced risk of RSV-related LRTI. Funding: National Institutes of Health of the USA, Bill and Melinda Gates Foundation, National Research Foundation South Africa, South African Medical Research Council, L'Oréal-UNESCO For Women in Science South Africa, Australian National Health and Medical Research Council.

Type 1 helper T cells and FoxP3-positive T cells in HIV-tuberculosis-associated immune reconstitution inflammatory syndrome.

RATIONALE: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) induced by combination antiretroviral therapy (cART) has been attributed to dysregulated expansion of tuberculin PPD-specific IFN-gamma-secreting CD4(+) T cells. OBJECTIVES: To investigate the role of type 1 helper T cell expansions and regulatory T cells in HIV-TB IRIS. METHODS: Longitudinal and cross-sectional studies of Mycobacterium tuberculosis-specific IFN-gamma enzyme-linked immunospot responses and flow cytometric analysis of blood cells from a total of 129 adults with HIV-1-associated tuberculosis, 98 of whom were prescribed cART. MEASUREMENTS AND MAIN RESULTS: In cross-sectional analysis the frequency of IFN-gamma-secreting T cells recognizing early secretory antigenic target (ESAT)-6, alpha-crystallins 1 and 2, and PPD of M. tuberculosis was higher in patients with TB-IRIS than in similar patients treated for both HIV-1 and tuberculosis who did not develop IRIS (non-IRIS; P

MVA-85A, a novel candidate booster vaccine for the prevention of tuberculosis in children and adults.

MVA-85A, in development by Oxford-Emergent Tuberculosis Consortium Ltd and the EU-funded research program TB-VAC, is a live attenuated viral vaccine expressing the immunodominant tuberculosis (TB) antigen 85A, and is intended for use in a heterologous prime-boost strategy to prevent TB. MVA-85A is highly immunogenic in both animals and humans, eliciting strong polyfunctional CD4+ T-cell responses when administered as a boost following BCG vaccination or when administered to individuals previously exposed to TB. Animal studies have demonstrated trends toward reduced pathology and bacillary burden for animals vaccinated with BCG prime followed by MVA-85A boost compared with BCG alone; however, these positive effects appear to be modest, and interpretation is limited by the small number of animals tested. The vaccine has an excellent safety profile in BCG-naïve, previously BCG-vaccinated and TB-exposed adults, as well as in BCG-vaccinated adolescents and children. At the time of publication, MVA-85A was in a more advanced stage of clinical development than other novel TB vaccine candidates, with a large-scale, proof-of-concept phase IIb clinical trial underway for the determination of safety, immunogenicity and prevention of TB in infants.