Abstract
<jats:p> Abstract Background Tuberculosis (TB) kills 1.3 million people annually. Global efforts focus on ending pulmonary TB (PTB); however, extrapulmonary TB (EPTB) is rising and poses significant health and economic burden. The PreVenTB Phase III trial evaluated VPM1002 in household contacts aged ≥6 years across India, and did not meet its primary composite endpoint for all TB. Disaggregated prespecified secondary endpoints revealed a substantially stronger EPTB signal (vaccine efficacy 42.3%, 95% CI (−9.1 to 69.4, p=0.09) in the modified intention-to-treat (mITT) population. No existing TB model translates these disaggregated hazard ratios into population-level effectiveness across heterogeneous demographics, or against a dynamic baseline accounting for ongoing National Tuberculosis Elimination Programme (NTEP)-driven incidence decline. Methods We developed a 1,296-compartment deterministic dynamic compartmental model (4 age × 2 HIV × 3 BMI × 3 socioeconomic strata × 18 states). Separate PTB and EPTB vaccine-efficacy posteriors were derived by Bayesian evidence synthesis of the PreVenTB trial's per-protocol and mITT analyses (power-prior-adjusted conjugate normal-normal update; α=0.082) and propagated through Monte Carlo simulation (n=1,000 iterations per scenario). A dynamic no-vaccine baseline was constructed by fitting time-varying case-detection-rate CDR(t) and treatment-success-rate TSR(t) logistic curves to WHO/NTEP data (2015 to 2024; incidence validation R <jats:sup>2</jats:sup> =0.896, RMSE 4.90 per 100,000), projecting PTB and EPTB incidence to 2050. Economic analysis used societal (value-of-statistical-life-inclusive BCR) and health-system (cost-effectiveness acceptability curves) perspectives, discounted at 3% annually. Findings Posterior vaccine effectiveness was substantially higher against EPTB than PTB (EPTB 40.0% [95% CI −5.6 to 69.1%] vs PTB 12.8% [−19.0 to 37.9%]; all-TB 16.2% [−11.7 to 38.6%]). EPTB accounted for 74% of deaths averted (381 of 513) and 73% of DALYs averted (5,347 of 7,308) in the 10-year/dynamic scenario. EPTB cases averted exceeded PTB and concurrent disease combined in every scenario. Mean cases averted ranged from 2,047 (3-year protection, dynamic baseline) to 3,394 (10-year, static) per 1,000,000 vaccinated; mean disability-adjusted life years (DALYs) averted ranged from 4,792 to 8,125. The benefit-cost ratio (BCR; societal perspective) ranged from 3.4 (3-year protection, dynamic baseline) to 8.2 (10-year protection, static baseline), exceeding break-even in every scenario. Median gross incremental cost-effectiveness ratio (ICER) ranged from US$647 (10-year static) to US$1,568 (3-year dynamic) per DALY averted, below India's 3× gross domestic product (GDP)-per-capita threshold (approximately US$8,084) in every scenario. Interpretation This 1,296-compartment model provides the first dynamically-baselined, dual-perspective health-economic evaluation of VPM1002 to separately track pulmonary and extrapulmonary outcomes. EPTB protection is VPM1002's proportionally larger and more statistically reliable efficacy signal and drives a majority of averted cases, mortality, and DALYs. Policy assessments anchored to composite pulmonary endpoints systematically underestimate this vaccine's population value. Funding In part funded by Serum Life Science Europe GmbH. </jats:p>