Pneumococcal dynamics in the conjugate vaccine era: Addressing unanswered questions

项目摘要/摘要 肺炎链球菌是引起肺炎的最重要的细菌原因之一，是引起肺炎的主要原因之一。 全球幼儿死亡。肺炎球菌结合疫苗(PCV)的广泛使用阻碍了... 减少了PCV中包括的血清型引起的定殖率和疾病。随着这些疫苗的成功， 目前正在努力在许多地区采用减少剂量的PCV计划。然而，突破性的信息- 疫苗血清型引起的感染继续发生，非疫苗血清型的感染正在上升。Alt- 尽管这些变化在很大程度上是用传统培养法记录下来的，但新的分子血清分型法 各种方法正在揭示以前未被认识到的殖民复杂性，包括频繁的共同殖民 有不止一种肺炎链球菌的血清型。然而到目前为止，这种方法在纵向监测中的应用- 兰斯已经受到了限制。在减少PCV剂量和降低其生物压力之前，关键是要不要 了解PCV血清型是否只是被抑制，而不是完全消除。现有的PCV被拆除- 签约针对最具致病性的肺炎球菌血清型，因此揭示了潜在的未被识别的 包含毒力基因的疫苗血清型对于提供信息以防止它们在较小范围内的影响至关重要 致病性的，但现在更普遍的血清型。此外，澄清PCV疫苗接种如何影响 PCV血清型与其他目前流行的肺炎球菌菌株以及其他NP微生物群的作用将 有助于阐明它们在ARI和肺炎链球菌疾病发病机制中的作用。为了解决这些关键的研究 优先事项，Howard博士提出了三个综合的具体目标：1)确定PCV7血清的贡献- 接种后NP肺炎球菌定植的类型，2)确定NP肺炎球菌的决定因素 ARI期间的密度，以及3)确定NP链球菌占主导地位的微生物区系对 阿里。Respira-秘鲁研究旨在评估呼吸道病毒和细菌的流行病学， 尤其是肺炎链球菌，以及它们对秘鲁农村3岁儿童ARI的影响。892名儿童-- 这项研究提供了详细的临床数据和呼吸道样本，将作为数据源 进行拟议的研究。目标1和目标2将描述具有单个或多个Pneu的殖民模式。 儿童接种PCV7前后的肺炎链球菌血清型及其相互关系 呼吸道疾病的定植情况。AIM 3将评估特定的微生物区系分布是否也是如此- 合并急性呼吸窘迫综合征的风险较高。这个项目的目标是利用霍华德博士杰出的 研究环境，她的导师专家团队，以及她成熟的广泛技能集，使她脱颖而出 作为领导一个大型研究项目的独立调查员，该奖项旨在澄清 PCV对肺炎球菌定植和疾病的影响，以提供优化的PCV剂量计划和 改进的肺炎球菌疫苗的开发。

PROJECT SUMMARY/ABSTRACT Streptococcus pneumoniae is one of the most important bacterial causes of pneumonia, a leading cause of death in young children globally. Widespread use of pneumococcal conjugate vaccines (PCVs) has substan- tially reduced colonization and disease caused by serotypes included in PCVs. With these vaccine successes, efforts are underway to employ reduced-dose PCV schedules in many regions. However, breakthrough infec- tions caused by vaccine serotypes continue to occur, and infections by non-vaccine serotypes are rising. Alt- hough these changes have been largely documented using traditional cultures, new molecular serotyping methods are revealing previously unrecognized colonization complexities, including frequent co-colonization with more than one pneumococcal serotype. Yet to date, application of this approach in longitudinal surveil- lance has been limited. Before reducing PCV doses and reducing their biological pressure, it is critical to un- derstand whether PCV serotypes may be just suppressed, but not fully eliminated. Existing PCVs were de- signed to target the most virulent pneumococcal serotypes, so unveiling potentially unrecognized reservoirs of vaccine serotypes containing virulence genes is critical to informing initiatives to prevent their influence in less pathogenic, but now more prevalent, serotypes. Additionally, clarifying how PCV vaccination impacts the inter- action of PCV serotypes with other now prevalent pneumococcal strains, as well as other NP microbiota, will help clarify their role in pathogenesis of ARI and pneumococcal diseases. To address these critical research priorities, Dr. Howard proposes three integrated Specific Aims: 1) Determine the contribution of PCV7 sero- types in NP pneumococcal colonization following vaccination, 2) Define the determinants of NP pneumococcal density during ARI, and 3) Define the contribution of NP Streptococcus-dominated microbiota profiles to risk of ARI. The RESPIRA-Peru study was designed to assess the epidemiology of respiratory viruses and bacteria, especially S. pneumoniae, and their impact on ARI in children <3 years of age in rural Peru. 892 children en- rolled in the study contributed detailed clinical data and respiratory samples that will serve as the data source for the proposed studies. Aims 1 and 2 will characterize patterns of colonization with single or multiple pneu- mococcal serotypes in children over time, before and after vaccination with PCV7, and the association of these colonization profiles with respiratory disease. Aim 3 will evaluate whether specific microbiota profiles are asso- ciated with higher risk of ARI. The goal of this project is to leverage the resources of Dr. Howard’s outstanding research environment, her expert team of mentors, and her established broad skill set so that she emerges from this award as an independent investigator leading a large research program performing work that clarifies the impact of PCVs on pneumococcal colonization and disease to inform optimized PCV dosing schedules and the development of improved pneumococcal vaccines.