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

项目总结 尽管目前有疫苗，但肺炎链球菌(肺炎球菌)仍然是导致 老年人社区获得性肺炎。由于这一弱势群体预计将达到20亿 到2050年，在全球范围内，提高对肺炎球菌感染抵抗力的新预防方法是 需要的。背景：Pfeifer小组设计了一种新的疫苗配方，称为脂质体 设计用于解释细菌血清型和细菌的广度的多糖类(LEP)的包埋 独特的进展情况使肺炎球菌疾病的治疗选择复杂化。这种疫苗 候选人在幼鼠身上的能力与Prevnar-13相当并超过了Prevnar-13，这促使了这一假设 用LEPS颗粒接种老年小鼠将产生相对于当前的强大免疫反应 肺炎球菌疫苗配方。这一假设将通过两个具体目标来解决：1)测试 LEPS疫苗对抗肺炎球菌感染幼鼠和老年小鼠免疫应答的影响 将评估抗体水平和功能；以及2)测试LEPS疫苗的保护效果 在原发肺炎模型中，幼年和老年小鼠侵袭性肺炎球菌感染 感染，以及流感合并感染后的继发性肺炎。宿主存活率，临床疾病评分， 将测量特定器官的细菌负荷，以及感染严重程度的其他指标(器官病理学) 随着时间的推移，跨疫苗和非疫苗肺炎球菌菌株来评估血清特异性保护 作为交叉保护。意义/创新：LEPS配方结合了多糖和 同一疫苗内的蛋白质抗原，其本身是创新的，并能够提供胶囊特异性 对其他血清型和疾病进展阶段的免疫以及交叉保护。从一个 从制造的角度来看，与目前的配方相比，LEPS结构具有成本效益，并且易于 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。 可能的结果包括目前疫苗配方(即PPSV和PCV)以外的治疗效果， 在这种情况下，我们处于对LEPS平台进行更广泛评估的理想情况下 临床环境。或者，如果当前的LEPS设计不能为老年人提供扩展保护， 通过布加尼姆小组的专业知识、免疫学分析和比较提供评估 将提供改进LEPS工具所需的洞察力，以便随后提高有效性。在……下面 无论哪种情况，此R21应用程序中概述的勘探性计划的数据都将为 推动LEPS工具(在布加尼姆和Pfeifer小组未来的协作工作中)作为 老年人群肺炎球菌病的新选择。

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.