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Forecasting pneumococcal serotype frequencies to develop adult-specific vaccines

预测肺炎球菌血清型频率以开发成人特异性疫苗

基本信息

批准号：
9075526
负责人：
Daniel Martin Weinberger
金额：
$ 42.65万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Pneumococcus causes many clinically-important diseases in adults, including pneumonia and septicemia. Pneumococcal conjugate vaccines administered to children have nearly eliminated both disease and colonization caused by the targeted serotypes not only in children but also in adults because children no longer transmit these serotypes. However, serotypes not targeted by the vaccine have increased and will continue to increase as causes of disease, particularly in adults. As a result, there is a large remaining burden of disease that cannot be effectively prevented with the currently-available conjugate vaccines. Consequently, there is a critical need for a new conjugate vaccine formulation that targets the serotypes that will cause the most disease in adults. The proposed projects will address a major challenge-forecasting which of the remaining 80+ serotypes that are not included in the current conjugate vaccines are most likely to become important causes of disease in adults in the future. To make such forecasts about disease patterns in adults, it is necessary to understand the determinants of serotype frequency among the healthy children who carry pneumococcus in the nasopharynx (the main source of exposure for adults). Likewise, it is critical to understand how changes in the serotype frequency among healthy vaccinated children influence the frequency of serotype-specific disease in adults. To answer these critical questions, we will first use a novel high- throughput in vitro assay of serotype competition (a known correlate of serotype frequency among carriers) in which large numbers of serotypes will be grown in nutrient-limited media. The relative frequency of the serotypes in these competitions will be tracked using targeted Illumina sequencing of the capsular genes. We will fit regression models to compare the in vitro competitiveness of the serotypes with the real world frequency of serotypes colonizing Navajo children in the pre-vaccine years. We will then assess the validity of this model by testing whether serotype competitiveness could have predicted the frequency of serotypes colonizing children after introduction of the first or second generation conjugate vaccines (PCV7 and PCV13). Because serotypes differ in their capacity to cause disease, it is important to know how projected changes in carriage will impact disease rates in adults. Using large clinical databases on carriage and disease from The Navajo Nation and Denmark, we will fit and validate empirical models to determine, for different serotypes, how capacity to cause disease and post-vaccine changes in frequency among pediatric carriers influence disease patterns in adults with or without underlying diseases. Finally, we will combine our projections of changes in carriage (based on the experimental data) with the models linking carriage in children and disease in adults to forecast the serotypes most likely to become important causes of disease in adults. These studies will provide important new information that will inform the selection of which serotypes should be included in a pneumococcal conjugate vaccine for use in adults in the future.

描述（由申请人提供）：肺炎球菌在成人中引起许多临床重要疾病，包括肺炎和败血症。给予儿童的肺炎球菌结合疫苗几乎消除了由目标血清型引起的疾病和定植，不仅在儿童中，而且在成人中，因为儿童不再传播这些血清型。然而，疫苗不针对的血清型已经增加，并将继续增加，特别是在成人中。因此，存在大量剩余的疾病负担，其不能用当前可用的缀合物疫苗有效预防。因此，迫切需要一种新的缀合物疫苗制剂，其靶向将在成人中引起大多数疾病的血清型。拟议的项目将解决一个主要挑战-预测未包括在当前结合疫苗中的剩余80多个血清型中的哪一个最有可能成为未来成人疾病的重要原因。为了对成人的疾病模式做出这样的预测，有必要了解鼻咽部携带肺炎球菌的健康儿童（成人的主要暴露源）中血清型频率的决定因素。同样，了解健康接种疫苗儿童血清型频率的变化如何影响成人中特定型疾病的频率也至关重要。为了回答这些关键问题，我们将首先使用血清型竞争的新型高通量体外测定法（携带者之间血清型频率的已知相关性），其中大量血清型将在营养有限的培养基中生长。将使用荚膜基因的靶向Illumina测序来追踪这些竞争中血清型的相对频率。我们将拟合回归模型，以比较血清型的体外竞争力与接种疫苗前几年纳瓦霍儿童血清型定植的真实的世界频率。然后，我们将通过检测血清型竞争性是否可以预测引入第一代或第二代结合疫苗（PCV 7和PCV 13）后血清型定植儿童的频率来评估该模型的有效性。由于血清型致病能力不同，因此了解预计的携带变化将如何影响成年人的发病率非常重要。使用来自纳瓦霍民族和丹麦的关于携带和疾病的大型临床数据库，我们将拟合和验证经验模型，以确定不同血清型的儿童携带者中引起疾病的能力和疫苗接种后频率的变化如何影响有或无基础疾病的成人的疾病模式。最后，我们将联合收割机结合我们对携带变化的预测（基于实验数据）与儿童携带和成人疾病之间的联系模型，预测最有可能成为成人疾病重要原因的血清型。这些研究将提供重要的新信息，为将来成人使用的肺炎球菌结合疫苗中应包括哪些血清型提供信息。