Background: Circulating antibodies against specific M. tuberculosis (M. tb) antigens offer promising diagnostic biomarkers and an appealing alternative due to their ease of application, cost-effectiveness, and relatively non-invasive nature. This study aimed to quantify and characterize the IgG antibody response against a panel of eight Mycobacterium tuberculosis (M. tb) antigens in TB-exposed and infected patients. The overarching hypothesis was that the IgG profiles and median fluorescence intensity (MFI) against each M. tb antigen could potentially differentiate between pulmonary, extrapulmonary, index contacts and healthy controls in a high TB burden setting. Methods: A multiplex microbead immunoassay (MMIA) was used to measure the serological response in 524 blood samples against eight M. tb antigens namely Rv-3881, Ag85-a, Ag85-b, Ag85-c, P-38, HspX, CFP-10 and MPT-32, with antibody concentrations determined using MFI and antigen’s cut off was established to determine the percentage of patients with positive antibody response for each antigen. Diagnostic accuracy of panel antigens was determined through ROC (Receiver operating characteristic) curve analysis and AUC (area under the curve) with 95% CI by using SPSS version 22. Results: ROC analysis demonstrated that all eight TB antigens in the panel are suitable for diagnosing TB infection in endemic areas, with an AUC ranging from 0.996 to 0.999 (p < 0.001) and a specificity greater than 95%. Among patients with pulmonary TB (P-TB), 61% of smear-positive (SS+ve) individuals exhibited positive IgG antibody response for antigen Ag85-a, 50% for Ag85-b, and 49% for Rv-3881 and P-38 antigens. In smear-negative (SS-ve) patients, 43% showed positive MFI for Rv-3881, 40% for Ag85-a, and 32% for P-38. Groupwise comparisons revealed significantly differential and higher IgG antibody response profiles in P-TB group (both SS+ve and SS-ve) and index TB contacts against all panel antigens with a p < 0.001 except for HspX in SS-ve patients compared to controls with lower median MFIs. The extrapulmonary TB (EP-TB) group exhibited significantly higher IgG response levels against Rv-3881 (Md = 85, p = 0.003), Ag85-a (Md = 6, p = 0.001), Ag85-b (Md = 35, p < 0.001), P-38 (Md = 9, p = 0.002), CFP-10 (Md = 14, p = 0.006), and MPT-32 (Md = 20, p = 0.026) compared to controls, who showed lower MFIs for these antigens. Conclusions: The M. tb antigen-specific IgG antibody profiles, with established cutoffs, could be incorporated
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