Diagnosis of active tuberculosis (TB) in high-prevalence settings remains a major problem, because gamma interferon release assays (IGRAs) do not discriminate between active TB and the high proportion of the population exposed or latently infected with MTb, and sputum-based methods are either insensitive (microscopy) or poorly accessible (Gene Xpert). Using well-characterised serum panels provided by the Foundation for Innovative New Diagnostics (FIND) and the China CDC, we have re-examined the potential utility of MTb-specific antibody responses as a tool for diagnosis of TB that would be readily amenable to development of simple, point-of-care tests for the areas where TB is most prevalent. Among a wide range of recombinant proteins, native protein and glycan antigens, and synthetic glycan antigens we have selected the most promising antigens for more detailed analysis of antibody subtype-specific responses. In addition, non-specific markers of infection and inflammation have been examined for utility in combined algorithms for detection or exclusion of active TB.
Consistent with the failure of MTb antibody tests over many years, no single MTb antigen or antibody class was found to give satisfactory discrimination between patients with confirmed active TB, suspected infection but proven non-TB, and healthy controls. However we observed that IgG, IgA and dimeric IgA responses to individual antigens were only poorly correlated, with the result that antibody reactivity for each class is an independent biomarker with partly additive sensitivity while maintaining assay specificity. In addition, C-reactive protein (CRP) as a marker of inflammation was useful in ruling out TB in many subjects (very low CRP), while very high CRP can also be used in the algorithm along with antibody responses. Best performance of this current diagnostic algorithm exceeds 90% sensitivity and specificity and is close to addressing the target product profile for this unmet medical need. Further improvement is expected with the inclusion of synthetic glycan antigens being examined in ongoing studies, ahead of blinded testing of panels in 1/2014.