Symptom-agnostic endpoints in tuberculosis vaccine efficacy trials
Year: 2026
Type: review
Abstract: 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.
Source: The Lancet Global Health
Authors: Morten Ruhwald, Alemnew F Dagnew, Gavin Churchyard, Adam Penn-Nicholson, Puneet Dewan, Alberto L Garcia-Basteiro, Emily B Wong, Willem A Hanekom, Mark Hatherill, Reinout van Crevel, Saskia den Boon, Patricia Hall-Eidson, Rein M G J Houben, Ann M Ginsberg, Frank Cobelens, Katherine C Horton, Richard G White
Institutions: Novo Nordisk Foundation, University of the Witwatersrand, Aurum Institute, Vanderbilt University Medical Center, FIND, Gates Foundation, Manhiça Health Research Centre, Barcelona Institute for Global Health, Universitat de Barcelona, University of Alabama, University of Alabama at Birmingham, Africa Health Research Institute, UAB Medicine, University of Cape Town, South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Queen Mary University of London, Radboud University Medical Center, Blizard Institute, World Health Organization, London School of Hygiene & Tropical Medicine, Amsterdam Institute for Global Health and Development, Amsterdam University Medical Centers, University of Amsterdam
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,680
OpenAlex ID: W7215072196