Forecasting pneumococcal serotype frequencies to develop adult-specific vaccines

项目摘要/摘要 接种给儿童的肺炎球菌结合疫苗(PCV)几乎消除了两种肺炎球菌 疫苗中的血清型引起的疾病(如肺炎、败血症)和定植。疫苗已经有了 不仅在接种疫苗的儿童中，而且在成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PCV没有针对的血清型引起的疾病的频率 增加了，并将继续增加，特别是在成年人中。因此，迫切需要一种新的 PCV配方，针对预计会在成年人中引起最多疾病的剩余血清型。 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 包括在目前的PCV中的病毒最有可能成为未来成人疾病的重要原因。至 要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，他们是成年人接触的主要来源。 同样，了解在接种疫苗的儿童中定居的非疫苗血清型可能会导致 在成年人身上引发疾病。为了回答这些问题，我们将首先开发和验证一个统计模型来 根据两个经验流行病学数据预测哪些血清型将在健康接种的儿童中定居 和新奇的实验数据。这些模型的实验数据将使用创新的、 高通量的血清型竞争的体外分析(已知的定植频率的相关性) 大量的血清型将在营养有限的培养基中生长。日本血吸虫血清型的相对丰度 这些比赛将使用Illumina测序进行跟踪。这些模型将被开发和验证 使用纳瓦霍民族和丹麦在引入之前和之后的殖民数据 儿童中的PCV。因为血清型致病的能力不同，所以知道它们是如何致病的是很重要的。 儿童中不同血清型携带率的预测变化将影响特定血清型的发病率 成人的疾病。使用来自纳瓦霍民族的关于携带者和疾病的大型临床数据库 丹麦，我们将拟合和验证一个经验模型，以确定对于不同的血清型，两者是如何 儿童的致病能力和特定血清型的定植频率相互影响 在有或没有潜在疾病的成年人中，血清型特定疾病的发病率。最后，我们将使用经过验证的 模型预测成人在引入不同类型的疾病后的特定血清型发病率 儿童的PCV(例如，计划的PCV15)，并将利用这一信息来确定 成人特异性结合疫苗的替代配方。这些研究将提供重要的新的 将为选择一种新的成人特异性肺炎球菌结合疫苗的血清型提供信息， 这应该会对成人的肺炎球菌疾病产生重大影响。

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.