Conjugate vaccine impact on pneumococcal carriage, disease, and population geneti

描述（由申请人提供）：该竞争性更新申请建立在我们当前项目的成功和生产力基础上，该项目调查了结合疫苗时代肺炎球菌种群的变化，并寻求在引入PCV13期间继续进行监测和分析。迄今为止，我们的工作大大增加了我们对这种病原体如何对疫苗的强选择性压力作出反应的理解。由于PCV7疫苗血清型实际上已从鼻咽中消失，它们已迅速完全被非疫苗血清型所取代。在临床上，这些非疫苗血清型已成为绝大多数侵袭性肺炎球菌疾病的原因。现在，一种新的13价肺炎球菌结合疫苗（PCV13）将于2010年推出，其中包括6种额外的血清型（1,3,5,6a, 7F, 19A）。这项研究将提供必要的数据，以了解使用PCV13的临床意义，测试我们关于细菌适应的特定假设，并作为理解其他病原体进化的模板。鉴于我们的合作团队，社区合作伙伴的持续承诺，以及我们获得最先进的基因测序资源，我们具有独特的优势，可以解决以下具体目标：在引入PCV13之前和之后，研究肺炎球菌定植和侵袭性疾病分离株的趋势，包括血清型和抗生素耐药性、宿主危险因素和侵袭潜力。2. 评估肺炎球菌种群结构的变化（通过MLST），并评估在PCV13引入的背景下，与肺炎球菌克隆在马萨诸塞州成功传播相关的潜在因素。3. 利用全基因组测序确定在选择性疫苗压力下出现的克隆中与血清型转换和侵袭性相关的潜在遗传决定因素。为了实现这些目标，我们将收集来自马萨诸塞州9个不同社区的2250名儿童（2011年和2014年）的新鼻咽标本，并将其与2001年、2004年、2007年和2009年的现有标本进行比较。此外，我们将同时分析从马萨诸塞州儿童身上收集的侵袭性疾病分离物，这是自2001年以来马萨诸塞州加强的全州监测计划的一部分。总的来说，这个持续的项目提供了一个前所未有的机会来实时评估细菌的进化，并将携带的变化与侵袭性疾病的变化联系起来。

DESCRIPTION (provided by applicant): This competing renewal application builds on the success and productivity of our current project investigating changes in the pneumococcal population in the conjugate vaccine era, and seeks to continue surveillance and analysis during the introduction of PCV13. Our work to date has substantially increased our understanding of how this pathogen responds to the potent selective pressure of a vaccine. As PCV7 vaccine serotypes have virtually disappeared from the nasopharynx, they have been quickly and completely replaced by non-vaccine serotypes. Clinically, these non-vaccine serotypes have become responsible for the great majority of invasive pneumococcal disease. Now, a new 13-valent pneumococcal conjugate vaccine (PCV13) that includes 6 additional serotypes (1, 3, 5, 6A, 7F, 19A), will be introduced in 2010. This research will provide data needed to understand the clinical implications of PCV13 use, test specific hypotheses we have developed about bacterial adaptation, and serve as a template for understanding the evolution of other pathogens. Given our team of collaborators, the ongoing commitment of community partners, and our access to state-of-the-art genetic sequencing resources, we are uniquely positioned to address the following specific aims: 1. To examine trends in pneumococcal colonizing and invasive disease isolates, with regard to serotype and antibiotic resistance, host risk factors, and invasive potential, before and after introduction of PCV13. 2. To assess shifts in pneumococcal population structure (by MLST) and evaluate potential factors associated with successful spread of pneumococcal clones in Massachusetts in the context of PCV13 introduction. 3. To use whole genome sequencing to identify potential genetic determinants associated with serotype switching and invasiveness among clones that have emerged under selective vaccine pressure. To achieve these goals, we will collect new nasopharyngeal specimens from 2,250 children as they present for routine pediatric care (in 2011 and 2014) in nine distinct Massachusetts communities, and analyze them in the context of previous collections available for comparison from 2001, 2004, 2007, and 2009. In addition we will simultaneously analyze invasive disease isolates collected from children in Massachusetts as part of an enhanced statewide surveillance program in Massachusetts since 2001. In total, this continuing project provides an unprecedented opportunity to assess bacterial evolution in real time, and connect changes in carriage to those in invasive disease. PUBLIC HEALTH RELEVANCE: Relevance The introduction of PCV13 will allow us to test specific hypotheses about the sequence and mechanisms of bacterial evolution in response to the potent selective pressure of immunization and continuing pressure of high rates of antibiotic use. Specifically, we will better understand the roles of antibiotic resistance, and other specific adaptations (e.g. the presence of pilus), as well as the clinical implications (for invasive disease) of inclusion of 19A, currently the most invasive and rapidly expanding serotype. These results will inform development and implementation of future vaccines, for pneumococcus and other organisms, by providing data on possible responses of bacterial populations that may blunt their intended clinical impact.