Informing development strategies for new tuberculosis vaccines: mathematical modelling and novel epidemiological tools

Abstract

Background: With an estimated 10.4 million incident tuberculosis (TB) cases in 2015, and the current trajectory of 1.5%/year incidence rate decline, new TB vaccines are urgently needed to help meet the WHO goal of tuberculosis elimination by 2050. However, insufficient epidemiological evidence exists to inform TB vaccine development strategies and to assist clinical trial site selection and design. Research to meet these data needs is critical to accelerate TB vaccine development. To maximise the future impact of new TB vaccines, estimates of the population-level impact of vaccine characteristics and implementation strategies are needed to inform design of TB vaccine target product profiles. To accelerate and de-risk clinical trials, appropriate epidemiological data are required to inform trial site selection, sample size calculations and recruitment strategy. However, data availability at trial sites is limited, and prospective studies are resource-intensive, so new methods are needed to collect appropriate data to inform TB vaccine trial design. To inform data-driven development strategies for new TB vaccines, the aims of this thesis were to 1) estimate the epidemiological impact of new TB vaccine characteristics and implementation in China to inform design of target product profiles; and 2) to develop a novel epidemiological spatial mapping tool capable of informing clinical trial design for new TB vaccines in low-income, high-burden settings. Methods: A deterministic, age-structured, Mycobacterium tuberculosis transmission model was developed and calibrated to age-stratified epidemiological and demographic data from China. This was employed to estimate the population-level epidemiological impact of new TB vaccines over the 2025-2050 time horizon, through an exploration of potential vaccine characteristics and implementation strategies. A new methodology for empirical data collection to determine spatial distribution of TB notifications was developed. The electronic PArticipant Locator application (ePAL app) combined 3,243 community-identified points of interest with high resolution satellite maps, within an electronic tablet-based case report form. The app was integrated in to the National Tuberculosis Programme in Blantyre, Malawi, for collection of demographics, health status and coordinates of place of residence for patients ≥18 years initiating TB treatment. Accuracy of ePAL-recorded co-ordinates was evaluated against GPS coordinates obtained at the participant’s place of residence. Results: Mathematical modelling predicted a shift towards a reactivation-driven, ageing TB epidemic in China by 2050. Vaccines protective against disease, effective post-infection and providing at least 5 years protection were essential for achieving higher levels of impact. Vaccination of older adults provided greater population-level impact than vaccinating adolescents for all equivalent vaccines explored, even if much lower coverage were achieved in older adult vaccination. Recommendations for post-infection vaccines were robust to substantial reductions in efficacy and duration of protection in older adults, whereas for pre-infection vaccines in some of these scenarios adolescent vaccination may be equivalent or preferred. Vaccinating older adults with post-infection vaccines provided substantially higher impact than pre-infection vaccines. 1,899 TB patients were registered using ePAL in the 12-month study period, with high patient acceptance (98.7%, 1,899/1,924). ePAL achieved clinic-based collection of patient location of residence accurate to a median of 84 metres (IQR: 35-317 metres) in a high population density urban setting without a municipal address system. Advantages of the ePAL system included real-time availability of high-resolution spatial data, low set up costs, and ease of use by health staff as part of routine TB registration. Data were used to identify areas with high TB burden, potentially suitable for TB vaccine trials. Conclusions: The research presented in this thesis informs the development of appropriate TB vaccines and target populations to maximise future population-level impact. A prevention of disease vaccine efficacious post-infection and delivered to older adults would contribute towards maximising population-level impact in China. Adolescent-targeted tuberculosis vaccines are likely to have low impact in ageing, reactivation-driven epidemics like China, which suggests a modification of the current strategic focus on adolescents among certain funders. Clinical trials should assess disease endpoints, include M.tb-infected and older adult populations, and extend beyond the usual 2-3 years follow up. To support design of disease endpoint trials, ePAL may provide an accurate, easily implementable, low-cost tool for identification of areas of high TB burden in settings without addresses.