Heterogeneity in Mycobacterium tuberculosis immunoreactivity in urban Malawi: revisiting surveillance needs for tuberculosis elimination

Tuberculosis (TB) remains the leading infectious cause of mortality globally. However, significant reductions have been achieved, particularly in high-burden urban settings in southern Africa, and transmission is concentrating in vulnerable populations and neighbourhoods. This heterogeneity urgently demands effective, efficient surveillance strategies to inform targeted interventions and monitor progress toward TB elimination. Existing passive surveillance metrics such as case notifications are often unreliable due to healthcare access disparities, while cross-sectional disease prevalence surveys are prohibitively expensive and inefficient. This thesis applies modern advances to revisit the role of Mycobacterium tuberculosis (Mtb) immunoreactivity surveillance, an approach widely used in the mid-20th century by countries with declining TB epidemics. Firstly, a systematic review of population-based Mtb immunoreactivity surveys since 1993 consolidates results from 81 surveys and almost 500,000 participants, in 33 high TB incidence settings. This provides empirical evidence that Mtb infection rates vary markedly by age (peaking around age 30) and sex (higher in men), with important implications for survey design and interpretation. There is no standardized protocol for modern Mtb immunoreactivity surveillance, and critical choices around recruitment strategies, target age groups and diagnostic approaches remain unresolved. A published protocol for an interferon-gamma release assay (IGRA) survey in Blantyre, Malawi, therefore acts as a framework for design and implementation, exploring convenience sampling in healthcare centres and random household sampling based on artificial-intelligence-informed satellite imagery. A nested diagnostic evaluation of a novel IGRA, QIAreach QFT, investigates its potential to improve feasibility and accessibility of immunoreactivity testing. IGRA results are then presented from 1,545 children aged 1-4 in Blantyre, Malawi. Estimated annual risk of Mtb infection was 2.7%, and was higher in poorer households. Mtb risk varies considerably between neighbourhoods and correlates poorly with neighbourhood-level case notification rates, supporting the hypothesis that case notifications do not accurately reflect underlying undiagnosed infectious disease prevalence. Taken together, the findings from this thesis demonstrate the value of immunoreactivity surveillance for understanding TB transmission dynamics, and provide a methodological blueprint for its use to target public health interventions in pursuit of TB elimination.