Integrating genomic surveillance and ecological modelling to maximise pneumococcal vaccine efficacy

肺炎链球菌或肺炎球菌是一种无害的细菌，存在于英国大约一半幼儿的鼻子里。当它们到达身体的其他部位时，肺炎球菌会引起有害的感染，如肺炎、败血症或脑膜炎。这在很大程度上是由于这些细菌有一个胶囊，可以保护它们免受免疫系统的侵害。2010年，英国推出了一种疫苗（称为PCV13），可以预防大约100种已知胶囊类型中的13种。这消除了大多数这13种胶囊类型的疾病和无害的婴儿携带。然而，不受疫苗影响的肺炎链球菌菌株数量增加，以取代丢失的胶囊类型。这些菌株在婴儿中并不经常引起疾病，因此PCV13减少了儿童肺炎球菌疾病的数量。然而，替代菌株似乎更有可能引起成人的疾病，他们从健康的儿童那里感染了细菌。因此，自PCV13以来，成人肺炎球菌疾病的数量有所上升。英国公共卫生部（PHE）在英国领导对PCV13的评估，他们对肺炎球菌疾病的监测意味着他们拥有世界上最大的特征明确的肺炎链球菌集合。该项目将从这些收集中选择分离株，使用全基因组测序进行研究，以了解在引入疫苗（PCV13和类似的早期版本）之前和之后细菌种群的遗传学变化。新的DNA序列分析方法将被用于将英国的数据与世界各地的研究工作数据合并。这将使肺炎链球菌菌株的全球迁移模式得以追踪，确定最近在英国出现的菌株的主要来源。这些遗传数据还将使由PCV13引起的循环菌株变化的数学建模成为可能。我们对疫苗接种后发生变化的基因有具体的假设，但以前这些假设只针对从健康儿童身上收集的细菌进行了测试。这个项目将扩大我们的模型，纳入最有害的菌株，这些菌株在鼻子中很少发现。这对于理解为什么PCV13对英国成人疾病的影响在其他国家并不常见至关重要。随着PHE收集新的监测数据，该项目还将测试这些模型预测肺炎链球菌疾病持续趋势的准确性。这将有助于预测未来几年疾病总体水平的趋势是否可能发生变化。我们会让其他科学家很容易地使用这个模型，这样他们就可以改进和更新它。通过不断改进该模型，我们希望将其作为一种工具，用于识别目前正在开发的每一种下一代肺炎链球菌疫苗的风险。这将有助于确保英国做出正确的选择，以避免像PCV13那样发生意想不到的后果，并最大限度地减少婴儿和成人肺炎链球菌疾病的国家负担。参与该项目的科学家在英国和国际机构服务，就这些疫苗的使用提供建议，因此我们的结果将传达给世界各地的相关机构。我们还将探索我们的模型和方法是否有助于分析其他细菌，特别是那些正在开发新疫苗的细菌。

Streptococcus pneumoniae, or the pneumococcus, is a bacterium found harmlessly living inside the noses of around half of young children in the UK. When they reach other parts of the body, pneumococci can cause harmful infections such as pneumonia, sepsis or meningitis. This is largely attributable to these bacteria having a capsule that protects them from the immune system. In 2010, the UK introduced a vaccine (called PCV13) that protected against 13 of the approximately 100 known capsule types. This eliminated most of these 13 capsule types from both disease and harmless carriage in infants. However, S. pneumoniae strains not affected by the vaccine increased in number to replace the lost capsule types. These strains did not cause disease in infants so frequently, and therefore PCV13 has reduced the amount of childhood pneumococcal disease. However, the replacing strains appear to be more likely to cause disease in adults, who catch the bacteria from healthy children. Hence the amount of adult pneumococcal disease has gone up since PCV13.Public Health England (PHE) lead the evaluation of PCV13 in the UK, and their surveillance of pneumococcal disease means they have the largest collection of well-characterised S. pneumoniae bacteria in the world. This project would select isolates from this collection to study using whole genome sequencing, to understand how the genetics of the bacterial population changed before and after vaccines (PCV13, and similar earlier versions) were introduced. New methods of DNA sequence analysis would be employed to merge UK data with that from research work around the world. These would enable the global migration patterns of S. pneumoniae strains to be traced, identifying the main origins of strains that have recently emerged in the UK.These genetic data will also enable mathematical modelling of the changes in circulating strains caused by PCV13. We have specific hypotheses about the genetics that underlies the changes after vaccination, but previously these have only been tested against bacteria collected from healthy children. This project will expand our models to incorporate the most harmful strains, which are rarely found in the nose. This is critical for understanding why PCV13 had effects on adult disease in the UK that were not common in other countries. This project will also test how accurately these models forecast ongoing trends in S. pneumoniae disease as new surveillance data are collected by PHE. This will help predict whether trends in the overall level of disease are likely to change in the next few years.We would make the model easily accessible to other scientists, such that they could improve and update it. By continually improving the model, we hope to use it as a tool for identifying the risks associated with each of the next generation of vaccines against S. pneumoniae, which are currently being developed. This would help ensure the UK made the right choice to avoid unintended consequences, as occurred with PCV13, and minimise the national burden of S. pneumoniae disease in both infants and adults. Scientists involved in the project serve on UK and international bodies that advise on the use of these vaccines, and therefore our results will be communicated to relevant agencies around the world. We will also explore whether our models and methods could be helpful in analysing other bacteria, particularly focusing on those for which new vaccines are being developed.