Forecasting pneumococcal serotype frequencies to develop adult-specific vaccines

项目总结/摘要 给儿童接种肺炎球菌结合疫苗（PCV）几乎消除了 疾病（如肺炎、败血症）和疫苗中血清型引起的定植。该疫苗 不仅在接种疫苗的儿童中，而且在成年人中也降低了发病率，因为儿童不再传播 这些血清型。然而，由非PCV靶向的血清型引起的疾病的频率已经降低。 这一数字正在上升，并将继续上升，特别是在成年人中。因此，迫切需要一个新的 PCV制剂，靶向预期在成人中引起大多数疾病的剩余血清型。 拟议的项目将解决一个主要挑战-预测80多个血清型中哪些不是 包括在当前PCV中的这些物质在未来很可能成为成人疾病的重要原因。到 为了对成人的疾病模式做出这样的预测，有必要知道哪些非疫苗血清型 将出现在健康儿童的鼻咽部，而儿童是成人的主要暴露源。 同样，关键是要了解哪些非疫苗血清型，殖民接种疫苗的儿童可能会 导致成年人患病。为了回答这些问题，我们将首先开发和验证一个统计模型， 根据经验流行病学数据预测哪些血清型将在健康接种疫苗的儿童中定植 和新颖的实验数据。这些模型的实验数据将使用创新的， 血清型竞争（一种已知与定殖频率相关的因素）的高通量体外测定，其中 大量血清型将在营养有限的培养基中生长。血清型的相对丰度 这些竞争将使用Illumina测序进行跟踪。将开发和验证这些模型 使用来自纳瓦霍民族和丹麦的殖民化数据， 儿童PCV。由于血清型在致病能力上各不相同，因此了解它们如何致病是很重要的。 儿童中不同血清型携带的预计变化将影响 成年人的疾病。使用来自纳瓦霍民族和来自印第安纳州的关于携带和疾病的大型临床数据库， 在丹麦，我们将拟合并验证一个经验模型，以确定对于不同的血清型， 致病能力和儿童中特定类型的定植频率相互作用， 患有或不患有基础疾病的成年人的血清型特异性疾病率。最后，我们将使用经过验证的 模型，以预测在引入不同的 儿童中的PCV（例如，计划的PCV 15），并将使用此信息来确定 成人特异性结合疫苗的替代制剂。这些研究将提供重要的新 为新的成人特异性肺炎球菌结合疫苗选择血清型提供信息， 这对成年人的肺炎球菌疾病应该有重大影响。

Project Summary/Abstract Pneumococcal conjugate vaccines (PCVs) administered to children have nearly eliminated both pneumococcal disease (e.g. pneumonia, septicemia) and colonization caused by serotypes in the vaccines. The vaccine has reduced disease rates not only in vaccinated children but also in adults, because children no longer transmit these serotypes. However, the frequency of disease caused by serotypes not targeted by the PCVs has increased and will continue to increase, particularly in adults. Consequently, there is a critical need for a new PCV formulation that targets the remaining serotypes that are expected to cause the most disease in adults. The proposed projects will address a major challenge—predicting which of the 80+ serotypes that are not included in current PCVs are most likely to become important causes of disease in adults in the future. To make such predictions about disease patterns in adults, it is necessary to know which non-vaccine serotypes will emerge to colonize the nasopharynx of healthy children, who are the main source of exposure for adults. Likewise, it is critical to understand which non-vaccine serotypes that colonize vaccinated children are likely to cause disease in adults. To answer these questions, we will first develop and validate a statistical model to predict which serotypes will colonize healthy vaccinated children based on both empirical epidemiologic data and novel experimental data. The experimental data for these models will be collected using an innovative, high-throughput in vitro assay of serotype competition (a known correlate of frequency of colonization) in which large numbers of serotypes will be grown in nutrient-limited media. The relative abundance of the serotypes in these competitions will be tracked using Illumina sequencing. The models will be developed and validated using colonization data from the Navajo Nation and from Denmark from both before and after introduction of PCVs in children. Because serotypes differ in their capacity to cause disease, it is important to know how projected changes in carriage of different serotypes among children will impact serotype-specific rates of disease in adults. Using large clinical databases on carriage and disease from the Navajo Nation and from Denmark, we will fit and validate an empirical model to determine, for different serotypes, how both the capacity to cause disease and serotype-specific frequency of colonization in children interact to influence serotype-specific disease rates in adults with or without underlying diseases. Finally, we will use the validated model to make projections of the serotype-specific rates of disease in adults following introduction of different PCVs in children (e.g., the planned PCV15) and will use this information to determine the potential impacts of alternative formulations of adult-specific conjugate vaccines. These studies will provide important new information that will inform the selection of serotypes for a new adult-specific pneumococcal conjugate vaccine, which should have a major impact on pneumococcal disease in adults.