Epidemiological benefits of more-effective tuberculosis vaccines, drugs, and diagnostics

Abstract

The Bill and Melinda Gates Foundation supports an ambitious portfolio of novel vaccines, drug regimens, and diagnostic tools for tuberculosis (TB). We elicited the expected efficacies and improvements of the novel interventions in discussions with the foundations managing their development. Using an age-structured mathematical model of TB, we explored the potential benefits of novel interventions under development and those not yet in the portfolio, focusing on the WHO Southeast Asia region. Neonatal vaccination with the portfolio vaccine decreases TB incidence by 39% to 52% by 2050. Drug regimens that shorten treatment duration and are efficacious against drug-resistant strains reduce incidence by 10-27%. New diagnostics reduce incidence by 13-42%. A triple combination of a portfolio vaccine, drug regimen, and diagnostics reduces incidence by 71%. A short mass vaccination catch-up campaign, not yet in the portfolio, to augment the triple combination, accelerates the decrease, preventing >30% more cases by 2050 than just the triple combination. New vaccines and drug regimens targeted at the vast reservoir of latently infected people, not in the portfolio, would reduce incidence by 37% and 82%, respectively. The combination of preventive latent therapy and a 2-month drug treatment regimen reduces incidence by 94%. Novel technologies in the pipeline would achieve substantial reductions in TB incidence, but not the Stop TB Partnership target for elimination. Elimination will require new delivery strategies, such as mass vaccination campaigns, and new products targeted at latently infected people.

Fig. 1.

Streamlined flow chart of the TB natural history model. Novel interventions are indicated in purple text where they intervene in the natural history. None of the novel interventions directly protects against infection. Pre-exposure vaccination decreases the probability of developing disease once infected. After infection, vaccinated individuals have a higher probability of becoming long-term latently infected with a low lifetime risk of developing disease. Latent postexposure vaccination decreases the lifetime probability of developing disease. Latent treatment cures a person, but a person could be reinfected. Once a person develops disease, better diagnostics decreases the time that a person has disease and thus reduces the exposure of others to infection. Once diagnosed, better treatment regimens shorten treatment, achieving a higher success rate, also reducing exposure of others to infection. Adults and children, for whom the natural history of TB is qualitatively similar but quantitatively different, are distinguished in the model but not in this diagram. People are lost by death from all groups, but only TB deaths are shown.

Fig. 2.

Effect by year up to 2050 of interventions and strategies begun in 2015 on TB (all-types) incidence per million (A, C, E, and G) and TB (all types) related mortality per million (B, D, F, and H). (A and B) Vaccination. Shown are neonatal vaccination with basic pre-exposure vaccine, neonatal vaccination with pre-exposure vaccine with additional effects; postexposure vaccination of latently infected people; mass vaccination with basic pre-exposure vaccination; mass vaccination with pre-exposure vaccine with additional effects. (C and D) Novel TB diagnostic tools. (E and F) Five treatment scenarios: active-disease regimens 1, 2 and 3; mass latent therapy, and the active-disease regimen 2 combined with mass latent therapy. (G and H) Combination of active-disease treatment regimen 2, neonatal vaccination with basic pre-exposure vaccine, and NAAT diagnostic tool.

Fig. 3.

The sensitivity of TB incidence and TB-related mortality at 2050 to assumptions about interventions started in 2015. (A) Neonatal vaccination with basic pre-exposure vaccine varying VE_P, the reduction in probability of becoming a fast progressor, from 0 to 100%. (B) Novel NAAT diagnostic, varying the proportion of reduction in average duration of infectiousness from 0 to 1.0 (C) Varying the treatment success proportion, the effect of novel active-disease treatment regimens from the current 0.84 to 1.00.