Evaluating the influence of vaccine archetypes and epidemiological conditions on clinical trial metrics for tuberculosis vaccine candidates
Year: 2026
Type: article
Abstract: BACKGROUND: Conducting tuberculosis vaccine trials in high-transmission settings offers potential gains in efficiency, yet the impact of repeated exposure in the presence of incomplete protection on measured vaccine efficacy is uncertain. We evaluated the effect of vaccine characteristics and epidemiological context on estimates of vaccine efficacy and requisite sample size for tuberculosis vaccine trials. METHODS: We simulated clinical trials of hypothetical tuberculosis vaccines using a stochastic compartmental model of tuberculosis natural history. We considered vaccines that confer "leaky" (50% per-exposure reduction) versus "all-or-none" protection against infection and/or disease that were evaluated in QuantiFERON Gold Plus (QFT) positive, negative or mixed populations with 2% (medium burden; incidence 400 per 100,000), 5% (high burden; 800 per 100,000) or 50% (very high burden; 4500 per 100,000) annual risk of infection (ARI), including protection against infection alone. We compared estimates of vaccine efficacy and statistical power to detect differences according to sample size for each vaccine archetype and epidemiologic setting. FINDINGS: Simulated trials of vaccines protecting against disease, alone or with protection against infection, gave comparable estimates of efficacy across epidemiological settings, whether all-or-none or leaky. The largest reduction was for a leaky vaccine protecting against both infection and disease in QFT negative participants, whose efficacy fell from 75% at medium ARI to 67% at very high ARI (relative reduction 11%). A vaccine acting only by preventing infection fell further, from 50% to 36% (28%). Trials at very high ARI could nonetheless achieve 90% power with 80-96% fewer participants than at medium ARI. INTERPRETATION: While vaccines conferring leaky protection against infection and disease tested in settings with very high ARI could modestly underestimate efficacy, trials could be adequately powered with a fraction of the sample size in such settings. Further, trials could enroll a mixture of QFT negative and positive individuals, increasing generalizability.
Source: Vaccine
Institutions: Amsterdam UMC Location University of Amsterdam, Amsterdam Institute for Global Health and Development, Stanford Medicine, Stanford University, London School of Hygiene & Tropical Medicine, Centro de Investigación Biomédica en Red, Hospital Clínic de Barcelona, Manhiça Health Research Centre, Barcelona Institute for Global Health, Centro de Investigación Biomédica en Red Enfermedades Infecciosas, Universitat de Barcelona, Universidade Federal de Mato Grosso do Sul, Yale University, Fundação Oswaldo Cruz
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,620
Funders: BioNTech, Bill and Melinda Gates Foundation, King Baudouin Foundation United States, World Health Organization, Fundació la Marató de TV3, Wellcome Trust, Open Philanthropy Project, Good Ventures Foundation, Koning Boudewijnstichting, National Institutes of Health, Economic and Social Research Council, European Research Council, National Institute of Allergy and Infectious Diseases, European and Developing Countries Clinical Trials Partnership
Awards: G1303243219, G1311021887, G1365327442, G1510993032, G1678426632, G2003503971, G2041373822, Improving scientific and public health decision making by developing technologies to increase use of robust methods to calibrate and analyse complex mathematical models, G2223609549, Infection prevention and control for drug-resistant tuberculosis in South Africa in the era of decentralised care: a whole systems approach, G2660122252, Evaluating a new stool based qPCR for diagnosis of tuberculosis in children and people living with HIV, G3470180491, G3514876419, G3567583227, Stichting Amsterdam Institute for Global Health and Development - to evaluate the extent to which Prevention of Mtb Infection is a surrogate for Prevention of TB Disease, Defining drivers of TB transmission in the era of universal ART, and implications for finding the walking well, G388548809, G4050995190, G4060541036, G4141407896, G4303542363, G4367187193, G4454553618, G4672374498, G4789575852, G49588791, G510537663, G5322665643, G5697490169, Improving scientific and public health decision making by developing technologies to increase use of robust methods to calibrate and analyse complex mathematical models, Predicting the Future: Incipient Tuberculosis, G6137153663, Automated smartphone-based cough audio classification for rapid tuberculosis triage testing (Cough Audio triaGE for TB), G7063735130, G7071437352, G7485403872, London School of Hygiene and Tropical Medicine - to support optimal funding and implementation of tuberculosis interventions coordinated through the tuberculosis modelling consortium (TB-MAC), G7610024329, Creating evidence to support tuberculosis (TB) national and global decision- makers in reducing the global burden of TB, Investigation of CXCR3 Chemokine System Gene Expression in Irritable Bowel Syndrome (IBS) and Coeliac Disease (CD), Mentoring patient-oriented translational research in tuberculosis, G7972582696, G8057699476, G8278091538, G8432911371, G8482337451, Creating evidence to support tuberculosis (TB) national and global decision- makers in reducing the global burden of TB, G9000290115, G927319347, G996267264
OpenAlex ID: W7204757249