Mathematical modelling to accelerate development of critical new Tuberculosis vaccines

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Epidemiology and Population Health

Abstract

Tuberculosis is the leading cause of death from a single infectious disease worldwide. 2015 saw 10.4 million cases-the majority in India, Indonesia, China, Nigeria, Pakistan and South Africa-leading to 1.4 million deaths. HIV/AIDS was associated with a further 0.4 million TB deaths. The emergent TB drug resistance epidemic compounds this picture, with approximately 480,000 new cases of multi-drug resistant TB (MDR-TB) in 2015. The WHO End TB strategy delineates a roadmap from 2015-2035 which aims to eliminate TB as a public health problem by 2050. A new post-infection vaccine targeted at adults and adolescents is likely to be critical to achieve these targets, a view supported by modelling studies and recognised by WHO. Modelling also predicts cost-effectiveness of vaccines in low and middle-income countries. In addition to vaccines, existing interventions are being scaled up and new TB diagnostics and drug treatments have advanced to the later stages of the development pipeline. Four new diagnostic assays will be evaluated in 2017. Nine new drugs are also in advanced clinical trial phases. By reducing the global burden of TB, these new interventions may, paradoxically, reduce
the anticipated cost-effectiveness of new vaccines. Additionally, both drug resistant TB (DR-TB) cases and associated costs are projected to rise, creating a need to estimate the impact and costefficiency of novel vaccines on DR-TB.
These developments have converged to create a critical knowledge gap: what are the preferred characteristics of novel TB vaccines, and their likely impacts on drug sensitive and drug resistant tuberculosis, in the context of the expected roll out of novel drugs and diagnostics?
2 Updated country-level epidemiologic and health economic models estimating these effects are required urgently. This project aims to address these questions, thereby supporting global TB vaccine development strategy and decision making.
This PhD studentship aims to generate a body of epidemiologic and health economic knowledge to support tuberculosis candidate vaccine selection. It will quantitatively model the impact of vaccination on drug sensitive (DS-) and drug resistant (DR-) TB, in the context of the expected rollout of new diagnostic and drug interventions, and the WHO 2035 and 2050 TB targets.
We will extend existing age-structured dynamic mathematical models of Mycobacterium tuberculosis transmission, calibrated to the current and historic epidemiologic characteristics of three divergent contexts (China, India and South Africa), to include DR strata and a health economic evaluation. Initially, we will model select, probable, baseline scenarios, without novel vaccines, but including probable new drugs and diagnostics. Within these, we will simulate the impact of potential TB vaccine candidates with varying characteristics. This will provide estimates of the direct and indirect impact and cost-effectiveness of new potential TB vaccines candidates on DS- and DR-TB.
The outlined project addresses an unmet need among vaccine stakeholders. It aims to inform Target Product Profile development, vaccine candidate selection and deployment beside other TB control measures. It is relevant to the MRC LID programme's "Global Infectious Diseases" theme, and its strategic priorities in vaccine research, mathematical modelling and health policy impact analysis. It applies to all the priority areas of the wider MRC 2014-2019 refreshed strategic plan ("Research Changes Lives"), including aim 1 ("Picking research that delivers") and aim 3 ("Going global"). Further, it strongly aligns with the MRC Skills Priorities of advanced quantitative skills and interdisciplinary working as it entails training in advanced quantitative methods and interdisciplinary approaches, including vaccinology, mathematical modelling, and health economics.

Publications

10 25 50
 
Description Our group provide evidence to WHO to develop consensus document on clinical development pathways for M72, including fast tracking a narrow indication for young adults in high endemicity areas (June)
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
URL http://www9.who.int/entity/tb/areas-of-work/research/m72as01_clinical_development_who_meeting_report...
 
Description Our group submitted evidence used to create the WHO Preferred Product Characteristics for therapeutic vaccines to improve tuberculosis treatment outcomes
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
 
Description Full public health value of TB vaccines
Amount £350,000 (GBP)
Funding ID 2020/985800-0 
Organisation World Health Organization (WHO) 
Sector Public
Country Global
Start 01/2020 
End 01/2020
 
Description Mathematical modelling to estimate the health impact, cost-effectiveness and budget impact of novel TB vaccines on MDR-TB
Amount $189,794 (USD)
Organisation Aeras 
Sector Charity/Non Profit
Country Global
Start 08/2017 
End 12/2019
 
Description Modeling of TB vaccine investments and impact
Amount $1,000,000 (USD)
Funding ID INV-001754 
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 09/2019 
End 09/2022
 
Title MDRVX 
Description Age-, treatment history and drug-resistance stratified deterministic dynamic transmission model of tuberculosis with vaccine stratum. 
Type Of Material Computer model/algorithm 
Year Produced 2018 
Provided To Others? No  
Impact Ongoing work to model the impact of novel TB vaccines on MDR-TB epidemics in China, India and Russia. We expect the final output of the project to be circulated to country level stakeholders, where it is expected to contribute to policy decisions. 
 
Description MDRVX - Countries and Funders 
Organisation Aeras
Department Aeras Global TB Vaccine Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution We are conducting mathematical modelling to assess the potential impact of novel TB vaccine profiles on the MDR-TB epidemic in the Chinese, Indian and Russian settings. This modelling is intended to inform decision making regarding target product profiles, clinical trials, market assessments and target vaccination strategies by our collaborators (Aeras, TBVI, Gates Foundation and WHO).
Collaborator Contribution Aeras, TBVI, BMGF and the WHO provide expertise in vaccine pipeline profiles and potential vaccination strategies to inform the parameterisation of the models under development. Country-level collaborators, such as the China CDC and India RNTCP, help inform country-specific tailoring of the model and calibration targets. All collaborators also provide feedback on the work and link the project with relevant experts.
Impact Interim results have been presented at: - The Union Conference on Lung Health (Hague, October 2018; oral presentation) - To the WHO Global TB programme senior executive - To the China Center for Disease Control TB unit
Start Year 2018
 
Description MDRVX - Countries and Funders 
Organisation Bill and Melinda Gates Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution We are conducting mathematical modelling to assess the potential impact of novel TB vaccine profiles on the MDR-TB epidemic in the Chinese, Indian and Russian settings. This modelling is intended to inform decision making regarding target product profiles, clinical trials, market assessments and target vaccination strategies by our collaborators (Aeras, TBVI, Gates Foundation and WHO).
Collaborator Contribution Aeras, TBVI, BMGF and the WHO provide expertise in vaccine pipeline profiles and potential vaccination strategies to inform the parameterisation of the models under development. Country-level collaborators, such as the China CDC and India RNTCP, help inform country-specific tailoring of the model and calibration targets. All collaborators also provide feedback on the work and link the project with relevant experts.
Impact Interim results have been presented at: - The Union Conference on Lung Health (Hague, October 2018; oral presentation) - To the WHO Global TB programme senior executive - To the China Center for Disease Control TB unit
Start Year 2018
 
Description MDRVX - Countries and Funders 
Organisation Chinese Center for Disease Control and Prevention (China CDC)
Department National Center for Chronic and Noncommunicable Disease Control and Prevention
Country China 
Sector Public 
PI Contribution We are conducting mathematical modelling to assess the potential impact of novel TB vaccine profiles on the MDR-TB epidemic in the Chinese, Indian and Russian settings. This modelling is intended to inform decision making regarding target product profiles, clinical trials, market assessments and target vaccination strategies by our collaborators (Aeras, TBVI, Gates Foundation and WHO).
Collaborator Contribution Aeras, TBVI, BMGF and the WHO provide expertise in vaccine pipeline profiles and potential vaccination strategies to inform the parameterisation of the models under development. Country-level collaborators, such as the China CDC and India RNTCP, help inform country-specific tailoring of the model and calibration targets. All collaborators also provide feedback on the work and link the project with relevant experts.
Impact Interim results have been presented at: - The Union Conference on Lung Health (Hague, October 2018; oral presentation) - To the WHO Global TB programme senior executive - To the China Center for Disease Control TB unit
Start Year 2018
 
Description MDRVX - Countries and Funders 
Organisation Tuberculosis Vaccine Initiative (TBVI)
Country Netherlands 
Sector Charity/Non Profit 
PI Contribution We are conducting mathematical modelling to assess the potential impact of novel TB vaccine profiles on the MDR-TB epidemic in the Chinese, Indian and Russian settings. This modelling is intended to inform decision making regarding target product profiles, clinical trials, market assessments and target vaccination strategies by our collaborators (Aeras, TBVI, Gates Foundation and WHO).
Collaborator Contribution Aeras, TBVI, BMGF and the WHO provide expertise in vaccine pipeline profiles and potential vaccination strategies to inform the parameterisation of the models under development. Country-level collaborators, such as the China CDC and India RNTCP, help inform country-specific tailoring of the model and calibration targets. All collaborators also provide feedback on the work and link the project with relevant experts.
Impact Interim results have been presented at: - The Union Conference on Lung Health (Hague, October 2018; oral presentation) - To the WHO Global TB programme senior executive - To the China Center for Disease Control TB unit
Start Year 2018
 
Description MDRVX - Countries and Funders 
Organisation World Health Organization (WHO)
Department Initiative for Vaccine Research
Country Switzerland 
Sector Public 
PI Contribution We are conducting mathematical modelling to assess the potential impact of novel TB vaccine profiles on the MDR-TB epidemic in the Chinese, Indian and Russian settings. This modelling is intended to inform decision making regarding target product profiles, clinical trials, market assessments and target vaccination strategies by our collaborators (Aeras, TBVI, Gates Foundation and WHO).
Collaborator Contribution Aeras, TBVI, BMGF and the WHO provide expertise in vaccine pipeline profiles and potential vaccination strategies to inform the parameterisation of the models under development. Country-level collaborators, such as the China CDC and India RNTCP, help inform country-specific tailoring of the model and calibration targets. All collaborators also provide feedback on the work and link the project with relevant experts.
Impact Interim results have been presented at: - The Union Conference on Lung Health (Hague, October 2018; oral presentation) - To the WHO Global TB programme senior executive - To the China Center for Disease Control TB unit
Start Year 2018
 
Description Memorandum of understanding between LSHTM and Gates Medical Research Institute 
Organisation Bill and Melinda Gates Medical Research Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Providing scientific evidence for GMRI decision making
Collaborator Contribution Expected: - Scientific advice on research project - Training of LSHTM PhD student - Financial support of research projects - Training of high burden country researchers - modelling tools hosting
Impact Expected: - Research evidence and papers - Trained LSHTM PhD student - Financial support of research projects - Training of high burden country researchers - co-creation of methodological platform and consortia; - modelling tools hosted by GMRI
Start Year 2019
 
Description Presentation - TB Vaccine Initiative 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact I presented my work at the 2020 TB Vaccines Initiative at Les Diableret, Switzerland as an invited expert. The audience consisted of a range of stakeholders in the vaccine development process: international academics, trialists, third sector representatives and the pharmaceutical industry.
Year(s) Of Engagement Activity 2020
URL https://www.tbvi.eu/les-diablerets-switzerland-the-tbvi-meeting-accelerating-the-tb-vaccine-pipeline...
 
Description Presentation to WHO TB Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact A presentation on ongoing work regarding the MDRVX project to the head of the WHO Global TB programme and other senior staff. We intended to inform these stakeholders regarding the progress of the work and its anticipated outputs, as well as seek further introductions and links to country level stakeholders, e.g. in Russia.
Year(s) Of Engagement Activity 2019
 
Description Presentation: Country level experts 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Present interim results of MDRVX country model (China) to members of the Chinese Centre for Disease Control for discussion, feedback and further refinement of the model. We use data and assumptions from these country-level experts. To maximise the eventual validity of the work at country level, we presented the interim results to solicit any feedback regarding modifications to the data or assumptions in this work.
Year(s) Of Engagement Activity 2018