Symptom-agnostic endpoints in tuberculosis vaccine efficacy trials

Tuberculosis vaccine prevention-of-disease efficacy trials traditionally rely on symptom-triggered case detection. This approach captures only a subset of bacteriologically confirmed disease and can miss cases that occur between scheduled trial visits or outside trial procedures, slowing endpoint accrual and complicating interpretation of results. At the same time, the diagnostic landscape for tuberculosis is changing rapidly. Advances, including near point-of-care (NPOC) molecular assays using sputum and non-sputum specimens, portable chest radiography with computer-aided detection, and digital tools for decentralised monitoring, now make symptom-agnostic screening strategies increasingly feasible in large clinical trials. A 2026 WHO policy recommending the use of NPOC molecular diagnostics for tuberculosis further highlights the relevance of these approaches. In this Health Policy paper, we outlined a framework for integrating symptom-agnostic screening into tuberculosis vaccine efficacy trials and reviewed emerging diagnostic technologies that could enable this transition. Using parameters informed by the placebo arm of the M72/AS01 E phase 2b trial, we present a worked example illustrating a possible effect on endpoint detection and case-verification burden. In this illustrative scenario, an NPOC-based symptom-agnostic screening strategy was estimated to increase detection of bacteriologically confirmed tuberculosis endpoints by approximately 1·4-fold, as compared with that by symptom-based screening alone, although this finding should not be interpreted as a direct estimate of overall trial efficiency. Realising these benefits will require analytical validation of diagnostic tools, clinical qualification for trial use, and early alignment with regulators and policy bodies. If evaluated through staged evidence generation and implemented with stringent confirmation algorithms, then symptom-agnostic screening could support more interpretable assessments of vaccine impact across the bacteriological spectrum of tuberculosis disease while preserving endpoint specificity.