GLOBHELS-Global helse

Tuberculosis (TB) is a major public health problem. The collaborative network (TB Trials) between scientists in Denmark, India, Norway, South Africa and the U. S. has conducted 3 large prospective cohort studies (adolescent, neonatal and a household cohort study) of TB in Palamaner, South India, using state of the art immunology to identify correlates of protective immunity and disease. Synergistic research collaboration in pediatric TB has also been extended to a network of scientists in North India (All India Institute of Medical Sciences, New Delhi). We have recently shown, in clinical samples from Indian children with confirmed TB disease and from their asymptomatic siblings, that 12 host immune biomarkers are consistently associated with clinical groups towards culture-positive TB on the TB disease spectrum or towards a decreased likelihood of TB disease, suggesting a correlation with TB-related pathology and high relevance to a future Point Of Care (POC) test for pediatric TB (Jenum et al, Sci Rep. 2016 Jan 4;6:18520). We also show that in a novel test for latent TB infection (interferon-gamma release assay (IGRA); Quantiferon-GIT), that the sensitivities of the QFT and the traditional tuberculin skin test (TST) for clinical TB in children <3 years of age are equally poor in the South Indian population in Palamaner, India (31%, 23%, respectively). Stunted children are more susceptible to Mycobacterium tuberculosis (MTB) infection and more prone to indeterminate QFT results. Moreover, we find that the TST is less reliable in children with wasting (Jenum et al, Pediatr Infect Dis J. 2014;33(10):e260-9). We further show that TB exposure is more frequent in concordant positive children (TST and QFT; both positive) and results are consistent with elevated expression of genes associated with inflammatory responses. TST and/or Quantiferon-GIT test positivity appears to reflect distinct but overlapping aspects of host immunity (Dhanasakeran et al, Genes Immun. 2014;15(5):265-74). Further, in this project, we have also explored host immune biomarkers which are potentially relevant to TB management, in children with confirmed exposure with Non-Tubercular Mycobacteria (NTM). The findings from our present study suggest that NTM exposure modulates TB-relevant immune biomarkers in the host by eliciting some of the same immune responses as MTB infection. This may be of importance when evaluating immune correlates of protection in the setting of TB vaccine trials and potential TB diagnostic biomarkers (Dhanasakeran et al. PLoS Negl Trop Dis. 2014 Oct 16;8(10):e3243). Identifying the rate of TB infection (not just disease), is a crucial step before proceeding to large-scale vaccine trials. The relative incidence of TB disease in the South Indian neonatal and adolescent cohorts appears to be low, but the incidence of latent MTB infection appears to be high (Uppada et al, BMC Public Health. 2016 Jul 26; 16:641). We also provide reliable estimates of TB incidence in Indian neonates (159.2/100,000 person-years). We further show that active surveillance identified more probable TB cases in the Indian setting and reduced all-cause mortality. Finally, sequential blood samples collected in the house hold study cohort are being currently analysed in transcriptomic studies, with an extended panel of gene markers to compare the immune responses in those who develop disease and those who do not despite having been infected. We hope, to be able to, soon report on prognostic biomarkers useful for TB vaccine studies as well as for the appropriate treatment of individual patients.

Tuberculosis (TB) is a major public health problem. Despite strides in case detection and treatment, the prevalence of TB continues to rise at an alarming rate. The collaborative network (TBTrials) between scientists in Denmark, India, Norway, South Afric a and the U. S. have conducted 2 large prospective cohort studies (adolescent and neonatal) and will soon complete a household cohort study of tuberculosis (TB) in Palamaner, South India, using state of the art immunology to identify correlates of protect ive immunity and incipient disease. Identifying the true rate of infection (including sub-clinical infection, not just disease), and measuring immune responses in these groups is a crucial step before proceeding to large-scale vaccine trials. New data ind icating that a subpopulation containing those most at risk of progressing to active disease can be identified, and that the magnitude of the immune response may be a useable proxy marker for progressive infection, suggests that targeted vaccine trials may be possible. The relative incidence of TB disease in the South Indian adolescent cohort appears to be low compared but the incidence of latent M. tuberculosis (MTB) infection appears to be high. This cohort is thus, ideal for the analysis of the negative predictive value (NPV) of an in vitro antigen stimulation test that measures responses to MTB virulence factors ESAT-6 and CFP10. Sequential blood samples collected in these cohorts will be used to perform retrospective case-control analyses to compare t he immune responses in those who develop disease and those who do not despite having been infected. By tying immunology, field studies and TB vaccine research into a cohesive plan, we will develop a research program that is not dependant on long-term stud ies to start paying dividends, and that can attract funding to be self-sustaining beyond the proposed research project.