Mathematical modelling to accelerate development of critical new Tuberculosis vaccines

结核病是全世界单一传染病导致死亡的主要原因。2015年有1040万例病例，其中大多数在印度、印度尼西亚、中国、尼日利亚、巴基斯坦和南非，导致140万人死亡。另有40万结核病死亡与艾滋病毒/艾滋病有关。新出现的结核病耐药流行加剧了这一局面，2015年约有48万例耐多药结核病（MDR-TB）新病例。世卫组织终止结核病战略描绘了2015-2035年的路线图，旨在到2050年消除结核病这一公共卫生问题。针对成人和青少年的新型感染后疫苗可能对实现这些目标至关重要，这一观点得到建模研究的支持，并得到世卫组织的认可。模型还预测了疫苗在低收入和中等收入国家的成本效益。除了疫苗之外，现有的干预措施正在扩大，新的结核病诊断和药物治疗已进入开发管道的后期阶段。2017年将评估四种新的诊断检测方法。9种新药也处于后期临床试验阶段。通过减少结核病的全球负担，这些新的干预措施可能会自相矛盾地降低新疫苗的预期成本效益。此外，预计耐药结核病病例和相关费用都将上升，因此有必要估计新型疫苗对耐药结核病的影响和成本效益。这些发展汇集在一起，造成了一个关键的知识缺口：在预计推出新药物和诊断方法的背景下，新型结核病疫苗的首选特征是什么，以及它们对药物敏感和耐药结核病的可能影响是什么？迫切需要更新国家一级的流行病学和卫生经济模型来估计这些影响。该项目旨在解决这些问题，从而支持全球结核病疫苗开发战略和决策。这个博士研究生的目的是产生一个流行病学和卫生经济学知识体系，以支持结核病候选疫苗的选择。它将在预计推出新的诊断和药物干预措施以及世卫组织2035年和2050年结核病目标的背景下，定量模拟疫苗接种对药敏（DS-）和耐药（DR-）结核病的影响。我们将扩展现有的年龄结构结核分枝杆菌传播动态数学模型，根据三个不同背景（中国、印度和南非）的当前和历史流行病学特征进行校准，以包括DR层和健康经济评估。最初，我们将对选定的可能的基线情景进行建模，其中没有新疫苗，但包括可能的新药和诊断方法。在这些研究中，我们将模拟具有不同特征的潜在结核候选疫苗的影响。这将提供对新的潜在结核候选疫苗对DS- TB和DR-TB的直接和间接影响以及成本效益的估计。概述的项目解决了疫苗利益攸关方未满足的需求。它旨在为目标产品概况的开发、候选疫苗的选择和部署以及其他结核病控制措施提供信息。它与MRC LID方案的“全球传染病”主题及其在疫苗研究、数学建模和卫生政策影响分析方面的战略重点有关。它适用于更广泛的MRC 2014-2019更新战略计划（“研究改变生活”）的所有优先领域，包括目标1（“选择有价值的研究”）和目标3（“走向全球”）。此外，它与MRC高级定量技能和跨学科工作的技能重点密切相关，因为它需要培训先进的定量方法和跨学科方法，包括疫苗学、数学建模和卫生经济学。

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, reducethe 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.