A CD8+ T cell diagnostic to identify children with pulmonary tuberculosis

DESCRIPTION provided by applicant Tuberculosis TB disease which results from infection with Mycobacterium tuberculosis Mtb is a leading cause of infectious morbidity and mortality in children andlt years old worldwide In TB endemic regions in which the vast majority of the worldandapos s annual million adult cases of TB disease reside children andlt years old account for of the total patients and those children who are infected tend to have more severe often fatal forms of TB A significant contributor to the deadliness of TB in children andlt years ol is the poor performance of standard TB diagnostics in this age group especially as compared to adults Poor diagnostics result in delayed and missed diagnoses which in turn lead to increased morbidity and mortality in children Currently what is needed is a simple robust immunodiagnostic blood test that will differentiate childhood TB pneumonia from pneumonia not due to TB We hypothesize that the detection of CD T cells directed toward Mtb peptides can be utilized to distinguish young children with TB pneumonia from those with pneumonia not due to TB In this regard CD T cells preferentially recognize heavily Mtb infected cells and as OHSU investigators we have observed in Ugandan children andlt years old that Mtb reactive CD T cells are detected in children with TB and not detected in asymptomatic children with Mtb infection exposure Taken together these data suggest that CD T cells correlate with bacterial burden In parallel we have defined immunodominant clinically validated CD TB antigens through our large scale antigen discovery program that are exclusively licensed to ViTi Inc from OHSU To develop an improved diagnostic for children in our Phase I study we used a bioinformatic approach to define regions enriched for high affinity binding to HLA within these immunodominant CD antigens We selected peptides representing these regions likely to contain clusters of immunogenic epitopes and using IFN ELISPOT assay tested the recognition of these peptides by CD T cells isolated from individuals with and without latent TB infection LTBI From these data we selected sets of peptides comprising two peptide pools one optimized for sensitivity and one for specificity for Mtb infection to be used in prototype immunodiagnostic blood tests which we will subsequently refer to as ViTi ONESENS and ViTi ONESPEC respectively In this Phase II proposal of diagnostic accuracy we will first determine the sensitivity and specificity of these prototype immunodiagnostic blood tests in cohorts of Ugandan children andlt years old hospitalized with pneumonia Then to further improve upon on these prototype tests we will apply the same strategy we used in the Phase study to additional novel immunodominant CD antigens licensed by OHSU to ViTi Inc to create improved peptide pools to be used in ViTi TWOSENS and ViTi TWOSPEC Finally we will determine the sensitivity and specificity of ViTi TWOSENS and ViTi TWOSPEC in the same cohorts of Ugandan children andlt years old hospitalized with pneumonia PUBLIC HEALTH RELEVANCE Tuberculosis TB is one of the most important causes of infectious morbidity and mortality in children worldwide Young children are more likely to develop severe disease from the causative agent Mycobacterium tuberculosis Mtb Moreover childhood TB pneumonia is difficult to diagnose resulting in delayed and missed diagnoses further contributing to morbidity and mortality The purpose of these studies is to develop a simple robust immunodiagnostic blood test that distinguishes TB pneumonia from pneumonia not due to TB in young children