Integrating genomic surveillance and ecological modelling to maximise pneumococcal vaccine efficacy

肺炎链球菌，或肺炎球菌，是一种在英国大约一半的幼儿鼻子里发现的无害细菌。当肺炎球菌到达身体的其他部位时，会引起肺炎、败血症或脑膜炎等有害感染。这在很大程度上是因为这些细菌有一个保护它们免受免疫系统攻击的胶囊。2010年，英国推出了一种疫苗(称为PCV13)，可以预防约100种已知胶囊类型中的13种。这消除了这13种胶囊中的大部分，既不会导致婴儿患病，也不会对婴儿造成伤害。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。这些菌株不会如此频繁地在婴儿中引起疾病，因此PCV13减少了儿童肺炎球菌疾病的数量。然而，替换的菌株似乎更有可能在成年人身上引发疾病，他们从健康的儿童那里感染了这种细菌。因此，自PCV13以来，成人肺炎球菌疾病的数量有所上升。英国公共卫生署(PHE)领导了对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良好的肺炎链球菌细菌集合。该项目将从这个集合中选择分离物进行研究，使用全基因组测序，以了解疫苗(PCV13和类似的早期版本)引入前后细菌群体的遗传学是如何变化的。新的DNA序列分析方法将被用来将英国的数据与世界各地的研究工作的数据合并。这些基因数据将使人们能够追踪肺炎链球菌菌株的全球迁移模式，确定最近在英国出现的菌株的主要来源。这些基因数据还将使人们能够对PCV13引起的循环菌株的变化进行数学建模。我们对疫苗接种后的变化背后的遗传学有具体的假设，但在此之前，这些假设只针对从健康儿童身上收集的细菌进行测试。该项目将扩展我们的模型，以纳入最有害的菌株，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是至关重要的。该项目还将测试随着PHE收集新的监测数据，这些模型预测肺炎链球菌疾病持续趋势的准确性。这将有助于预测疾病总水平的趋势在未来几年是否可能发生变化。我们将使其他科学家很容易地访问该模型，以便他们可以改进和更新它。通过不断改进该模型，我们希望将其用作一种工具，用于识别与目前正在开发的每一种下一代肺炎链球菌疫苗相关的风险。这将有助于确保英国做出正确的选择，以避免像PCV13那样出现意想不到的后果，并将全国范围内肺炎链球菌疾病对婴儿和成年人的负担降至最低。参与该项目的科学家为英国和国际机构提供有关使用这些疫苗的建议，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.