Pneumococcal dynamics in the conjugate vaccine era: Addressing unanswered questions

结合疫苗时代的肺炎球菌动态：解决尚未解答的问题

• 批准号: 10316161
• 负责人: Leigh Meredith Howard
• 金额: $ 18.43万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-17 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316161
• 关键词: 3 year old; Acute; Address; Andean; Award; Bacteria; Biological; Caring; Cause of Death; Child; Childhood; Clinical Data; Collaborations; Conjugate Vaccines; Data Sources; Detection; Developing Countries; Development; Disease; Dose; Ecology; Environment; Epidemiology; Evaluation; Future; Genes; Goals; Household; Infant; Infection; Literature; Longitudinal Studies; Mentors; Methods; Molecular; Morbidity - disease rate; Nose; Pathogenesis; Pathogenicity; Pattern; Peru; Peruvian; Pneumococcal Colonization; Pneumococcal Infections; Pneumococcal conjugate vaccine; Pneumococcal vaccine; Pneumonia; Relative Risks; Reporting; Reproducibility; Research; Research Personnel; Research Priority; Resources; Respiratory Disease; Respiratory Tract Infections; Risk; Role; Rural; Sampling; Schedule; Serotyping; Source; Streptococcus; Streptococcus pneumoniae; Techniques; Testing; Time; Vaccinated; Vaccination; Vaccine Design; Vaccines; Virulence; Virulent; Work; base; breakthrough infection; co-infection; defined contribution; density; design; high risk; improved; microbial; microbiome; microbiota; microbiota profiles; mortality; nasal microbiota; pressure; prevent; programs; respiratory; respiratory virus; skills; success; surveillance study; tool; unvaccinated; uptake; vaccination strategy

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.

项目总结/摘要 肺炎链球菌是肺炎的最重要的细菌原因之一，是肺炎的主要原因。 全球幼儿死亡率。肺炎球菌结合疫苗（PCV）的广泛使用已使 减少PCV中血清型引起的定植和疾病。随着这些疫苗的成功， 在许多地区正在努力采用减少剂量的PCV方案。然而，突破性感染- 疫苗血清型引起的感染继续发生，非疫苗血清型引起的感染正在增加。替代- 尽管这些变化在很大程度上是用传统的培养来记录的，但新的分子血清分型 方法揭示了以前未被认识到的殖民复杂性，包括频繁的共同殖民 不止一种肺炎球菌血清型然而，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 了解PCV血清型是否可能只是被抑制，而不是完全消除。现有的PCV被取消- 签署了针对最致命的肺炎球菌血清型，因此揭示了潜在的未被识别的水库， 含有毒力基因的疫苗血清型对于预防其在更少国家的影响至关重要。 致病的，但现在更普遍的血清型。此外，澄清PCV疫苗接种如何影响间- 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和肺炎球菌疾病发病机制中作用。为了解决这些关键的研究 霍华德博士提出了三个综合的具体目标：1）确定PCV 7血清的贡献， 2）确定NP肺炎球菌定植的决定因素， 3）确定NP链球菌占主导地位的微生物群谱对ARI期间的风险的贡献。 阿里。秘鲁的研究旨在评估呼吸道病毒和细菌的流行病学， 尤指肺炎，以及它们对秘鲁农村<3岁儿童ARI的影响。892名儿童 研究中的Rolled提供了详细的临床数据和呼吸道样本， 对于拟议的研究。目的1和2将描述单个或多个pneu的定殖模式， 儿童在接种PCV 7疫苗前后随时间推移的mococcal血清型，以及这些 与呼吸道疾病的定植概况。目标3将评估特定的微生物群分布是否与 与ARI的高风险有关。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，以及她建立的广泛技能， 从这个奖项作为一个独立的调查员领导一个大型的研究计划执行的工作，澄清 PCV对肺炎球菌定植和疾病的影响，以提供优化的PCV给药方案， 改进的肺炎球菌疫苗的开发。

项目成果

Clinical presentations of adult and pediatric SARS-CoV-2-positive cases in a community cohort, Nashville, Tennessee.

• DOI: 10.1002/jmv.27988
• 发表时间: 2022-11
• 期刊: JOURNAL OF MEDICAL VIROLOGY
• 影响因子: 12.7
• 作者: Rankin, Danielle A.;Yanis, Ahmad;Talj, Rana;Howe, Harrison L.;Bloos, Sean M.;Fernandez, Kailee N.;Amarin, Justin Z.;Bruce, Mercedes;Salib, Seifein;Hargrave, Samarian;Chappell, James D.;Spieker, Andrew J.;Halasa, Natasha B.;Howard, Leigh M.
• 通讯作者: Howard, Leigh M.

COVID-19 and Acute Neurologic Complications in Children.

• DOI: 10.1542/peds.2022-058167
• 发表时间: 2022-11-01
• 期刊: PEDIATRICS
• 影响因子: 8
• 作者: Antoon, James W.;Hall, Matt;Howard, Leigh M.;Herndon, Alison;Freundlich, Katherine L.;Grijalva, Carlos G.;Williams, Derek J.
• 通讯作者: Williams, Derek J.

Variation in antibiotic use among neonatal intensive care units in the United States.

• DOI: 10.1017/ice.2021.379
• 发表时间: 2022-12
• 期刊: INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY
• 影响因子: 4.5
• 作者: Spencer, Hillary J. J.;Dantuluri, Keerti L.;Thurm, Cary;Griffith, Hannah;Grijalva, Carlos G.;Banerjee, Ritu;Howard, Leigh M.
• 通讯作者: Howard, Leigh M.

Rurality of Residence and Inappropriate Antibiotic Use for Acute Respiratory Infections Among Young Tennessee Children.

• DOI: 10.1093/ofid/ofaa587
• 发表时间: 2021-01
• 期刊: Open forum infectious diseases
• 影响因子: 4.2
• 作者: Dantuluri KL;Bruce J;Edwards KM;Banerjee R;Griffith H;Howard LM;Grijalva CG
• 通讯作者: Grijalva CG

Unraveling the Impact of Pneumococcal Conjugate Vaccines on Bacterial Conjunctivitis in Children.

揭示肺炎球菌结合疫苗对儿童细菌性结膜炎的影响。

• DOI: 10.1093/cid/ciaa202
• 发表时间: 2021
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Howard,LeighM;deStMaurice,Annabelle
• 通讯作者: deStMaurice,Annabelle