Abstract / Summary
Abstract Introduction Extrapulmonary tuberculosis (EPTB) is rising in India and carries higher case fatality than pulmonary tuberculosis (PTB). A Phase III trial of VPM1002 missed its primary composite endpoint, but secondary endpoints showed a stronger EPTB signal (vaccine efficacy 42.3%, 95% CI -9.1 to 69.4). We identified no published model resolving tuberculosis by disease type, nutritional and socioeconomic status, and dose event against a dynamic baseline. Methods We built a deterministic model with 1,152 population compartments (72 strata by age, HIV status, body-mass index and socioeconomic status), calibrated to WHO India incidence and mortality for 2015 - 2024. Separate PTB and EPTB effectiveness posteriors, derived by Bayesian evidence synthesis of the trial's per-protocol and modified intention-to-treat estimates, were propagated through 1,000 Monte Carlo iterations. Three doses were modeled at 10-year intervals assuming 3 or 10 years of protection. Economic analysis used societal and health-system perspectives with 3% discounting. Results Posterior median effectiveness was higher against EPTB (42.9%, 95% credible interval [CrI] -5.6 to 69.1) than PTB (14.0%, -19.0 to 37.9). Per 1,000,000 targeted under 10-year protection, three doses averted 5,218 cases (95% uncertainty interval 153 - 10,157), 682 deaths (24 - 1,255) and 9,463 disability-adjusted life-years (DALYs; 328 - 17,404); under 3-year protection, 1,961 cases and 3,708 DALYs. EPTB accounted for about two-thirds of averted deaths and DALYs but about half of averted cases. Under 10-year protection, the first booster added 46% more cases and 34% more DALYs at an incremental benefit-cost ratio of 19.1 (initial dose 20.7); the second booster added 8% more cases and 4.5% more DALYs at 6.8. Median gross incremental cost-effectiveness ratios were US$329 (10-year) and US$832 (3-year) per DALY averted. Conclusion Composite-endpoint models cannot show this dissociation. A booster a decade later was nearly as economically efficient but averted less disease. This is an adolescent and adult booster program, not a replacement for infant BCG.