The efficacy of Liposomal Encapsulation of Polysaccharides pneumococcal vaccine in protecting aged hosts against invasive Streptococcus pneumoniae infections in murine models

项目摘要 尽管目前的疫苗，肺炎链球菌（肺炎球菌）仍然是主要的原因， 老年人社区获得性肺炎由于这一脆弱人口预计将达到20亿 到2050年，在全球范围内， needed.背景：Pfeifer小组设计了一种新的疫苗制剂，称为脂质体 多糖包封（LEPS）设计用于解释细菌血清型的广度， 使肺炎球菌疾病的治疗选择复杂化的独特进展特征。这种疫苗 候选人已经匹配并超过了Prevnar-13在年轻小鼠中的能力，这促使了假设 用LEPS颗粒接种老年小鼠将诱导相对于目前的LEPS颗粒的强免疫应答。 肺炎球菌疫苗制剂。这一假设将通过两个具体目标来解决：1）测试 LEPS疫苗接种对抗肺炎球菌肺炎疫苗接种的年轻小鼠与老年小鼠免疫应答的影响 将评估抗体水平和功能;和2）测试LEPS疫苗接种的保护效力， 在原发性肺炎模型中，年轻小鼠与老年小鼠的侵袭性肺炎球菌感染，系统性 感染和流感合并感染后继发性肺炎。宿主存活率，临床疾病评分， 将测量器官特异性细菌负荷和感染严重程度（器官病理学）的其他指标 随着时间的推移，在疫苗和非疫苗肺炎球菌菌株之间， 交叉保护。意义/创新：LEPS配方结合了多糖和 蛋白质抗原，其本身是创新的，并能够提供胶囊特异性 免疫以及针对其他血清型和疾病进展阶段的交叉保护。从 从制造的角度来看，与目前的制剂相比，LEPS构造是成本有效的并且易于制造。 生成.在这里，我们将首次在老年动物模型中测试LEPS疫苗的有效性。 潜在的结果包括超越目前疫苗制剂的治疗有效性（即，PPSV和PCV）， 在这种情况下，我们处于一个理想的状态，以便在以后的时间里对LEPS平台进行更广泛的评估 临床环境。或者，如果目前的LEPS设计不能为老年人提供延长的保护， 通过Bou Ghanem小组的专业知识、免疫学分析和比较提供的评估， 将为改进LEPS飞行器以提高其有效性提供所需的洞察力。下 无论是哪种情况，本R21应用程序中概述的探索性计划中的数据都将为 推进LEPS飞行器（在未来的Bou Ghanem和Pfeifer小组之间的合作工作中）， 老年人肺炎球菌疾病的新选择。

PROJECT SUMMARY Despite current vaccines, Streptococcus pneumoniae (pneumococcus) remains the leading cause of community-acquired pneumonia in the elderly. As this vulnerable population is projected to reach two billion worldwide by 2050, novel preventative approaches that boost resistance to pneumococcal infections are needed. Background: The Pfeifer group engineered a novel vaccine formulation, termed Liposomal Encapsulation of Polysaccharides (LEPS) designed to account for both the breadth of bacterial serotypes and the unique progression profiles that complicate treatment options for pneumococcal disease. This vaccine candidate has matched and exceeded the capabilities of Prevnar-13 in young mice, prompting the Hypothesis that vaccination of elderly mice with the LEPS particle will induce robust immune responses relative to current pneumococcal vaccine formulations. This hypothesis will be addressed through two specific Aims: 1) Test the effect of LEPS vaccination on immune responses in young versus elderly mice where anti-pneumococcal antibody levels and function will be assessed; and 2) Test the protective efficacy of LEPS vaccination against invasive pneumococcal infections in young versus elderly mice in models of primary pneumonia, systemic infection, and secondary pneumonia following influenza co-infection. Host survival, clinical disease score, organ-specific bacterial burden, and other indicators of infection severity (organ pathology) will be measured over time across vaccine and non-vaccine pneumococcal strains to assess serotype-specific protection as well as cross protection. Significance/Innovation: The LEPS formulation combines both polysaccharides and protein antigens within the same vaccine, which by itself is innovative and able to provide capsule specific immunity as well as cross protection against other serotypes and stages of disease progression. From a manufacturing standpoint, in contrast to current formulations, the LEPS construct is cost effective and easy to generate. Here, we will test for the first time the effectiveness of the LEPS vaccine within aged animal models. Potential outcomes include treatment effectiveness beyond current vaccine formulations (i.e., PPSV and PCV), in which case, we are in an ideal situation for more extensive assessment of the LEPS platform in subsequent clinical settings. Alternatively, if the current LEPS design does not provide extended protection in the elderly, with assessment provided through the Bou Ghanem group's expertise, immunological profiling and comparison will provide the insight needed to refine the LEPS vehicle for subsequent improvements in effectiveness. Under either scenario, data from the exploratory plans outlined in this R21 application will provide the foundation to advance the LEPS vehicle (in future collaborative work between the Bou Ghanem and Pfeifer groups) as a new option for pneumococcal disease in aged populations.