# Estimating the population impact of new tuberculosis vaccines depending on efficacy against infectious asymptomatic tuberculosis: A modelling study

## TL;DR

New TB vaccines could significantly reduce disease spread if they target both symptomatic and asymptomatic infections, according to a modeling study in India.

## Contribution

The study introduces a dynamic TB model to assess vaccine impact based on efficacy against different disease stages, emphasizing asymptomatic TB.

## Key findings

- Over 3 years, all vaccine scenarios averted similar proportions of symptomatic TB episodes (1.6-2.3%).
- Over 20 years, vaccines targeting infectious asymptomatic disease averted 19.4-23.3% more symptomatic episodes.
- Modeling highlights the importance of vaccine efficacy against asymptomatic TB for long-term impact.

## Abstract

Tuberculosis (TB) remains a leading cause of infectious disease death. New TB vaccines are currently in late-stage trials and may be available before the end of the decade. Modelling predicts new TB vaccines may reduce global burden but rely on assumptions about vaccine efficacy by TB disease stage and TB natural history, which may be incorrect. We explored the sensitivity of estimates of the impact of new TB vaccines to uncertainties in efficacy by disease stage and natural history.

We developed a dynamic compartmental TB model for India, including early TB disease stages (non-infectious disease, infectious asymptomatic disease, and infectious symptomatic disease). Scenarios assumed 50% vaccine efficacy for 10 years and prevented progression to (a) only infectious symptomatic disease, or (b) any infectious disease (infectious asymptomatic disease and infectious symptomatic disease), or (c) any disease (non-infectious disease, infectious asymptomatic disease, and infectious symptomatic disease). We estimated impact on averting disease episodes over 2030–2050, compared to no-new-vaccine introduction. Results suggest, over 3 years, there was little difference in the proportion of cumulative symptomatic disease episodes averted by vaccines preventing only infectious symptomatic disease, any infectious disease, or any disease (1.6%, 2.3%, and 2.3%, respectively). However, over 20 years, compared to vaccines preventing only infectious symptomatic disease, vaccines preventing any infectious disease, or any disease, averted a markedly higher proportion of symptomatic disease episodes (7.3%, 19.4%, and 23.3%, respectively), due to preventing continued transmission from infectious asymptomatic disease. A key limitation with any mathematical modelling study is the uncertainty associated with the inputs, and further data collection is required to better understand the transmissibility, morbidity, and dynamics of asymptomatic disease, to improve modelling estimates and inform wider policy.

Our modelling estimates that the population impact of new TB vaccines may depend on efficacy against infectious asymptomatic disease. TB vaccine trials should include analyses of participant sputum samples (collected during or at the end of trials and analysed at the end of trials) to enable better estimates of the potential value of new TB vaccines against infectious asymptomatic disease.

New tuberculosis (TB) vaccines may be available soon, with a recently completed phase 2b trial of the vaccine candidate M72/AS01E demonstrating encouraging results of around 50% (95% confidence interval = 2.1%, 74.2%) impact on the incidence of symptomatic TB.

Recent modelling studies suggest that introducing a new vaccine that prevents TB could yield substantial global health and economic benefits.

With recognition of infectious asymptomatic TB, we aimed to explore the sensitivity of estimates of the impact of new TB vaccines to uncertainties in vaccine efficacy by TB disease stage.

We used a mathematical model to explore three scenarios varying how the vaccine could prevent progression to disease: preventing progression to infectious symptomatic disease only, preventing progression to any infectious disease, or preventing progression to any disease.

Results suggested that over the short term, all scenarios averted a similar proportion of cumulative symptomatic TB episodes.

However, over the longer term, the differences became more pronounced, and vaccines preventing any infectious disease or any disease averted a higher proportion of symptomatic TB episodes compared to a vaccine that only prevented infectious symptomatic TB.

This study suggests that the population-level impact of new TB vaccines may depend on the efficacy of the vaccine against asymptomatic TB.

TB vaccine trials should measure impact against asymptomatic TB to enable better estimates of the potential full value of new TB vaccines.

Study limitations include limited data availability to parameterise the natural history and infectivity of asymptomatic TB, which could be improved with further data collection.

Hira Tanvir and colleagues estimate the potential impact of new tuberculosis vaccines under three scenarios of efficacy and conclude that to achieve the greatest impact, vaccines must prevent asymptomatic and symptomatic disease.