Development of novel protein-based vaccine formulations to prevent pneumococcal colonization and disease

项目摘要/摘要 肺炎链球菌感染负担沉重的主要问题之一是获得 抗菌素耐药性和抗药性克隆的全球传播。这一问题因重大问题而加剧 目前基于壳多糖的疫苗的缺点，如成本、血清型特异性和 由此产生的不完全覆盖。而使用多糖疫苗，特别是结合疫苗， 显著减少了由Spn引起的侵袭性疾病的数量，但它只减少了代表的 血清型。这主要是因为疾病是由疫苗中没有的血清型引起的。 (最多23种&gt；97型胶囊，结合疫苗中只有13种)和替换支架。我们的 基本原理是利用新的保守抗原蛋白开发基于亚单位的疫苗 与新型聚磷腈(PPZ)佐剂结合，被证明可以诱导获得性免疫，将加深 预防肺炎链球菌病的最新工具包，没有血清型限制。因此，我们假设加法 将保守的免疫原性蛋白与PPZ分子结合，将为发展 广泛保护性肺炎链球菌亚单位疫苗。我们致力于弥合的知识差距是为了定义 以及表征新型肺炎球菌抗原蛋白和聚电解质佐剂配方 启动适应性免疫反应，并以不依赖于血清型的方式对疾病进行保护。 这项拟议的工作具有重要意义，因为目前的多糖存在高发的血清型替换 基础疫苗容易感染，导致儿童和老年人对Spn携带者的易感性增加 和严重感染(例如肺炎、菌血症和脑膜炎)；以及创新，因为它将使用新的 抗原性和保守性肺炎球菌蛋白的配方，以诱导强大的适应性免疫反应， 这不会依赖于血清型。

Project Summary/Abstract One of the major problems of the great burden of Streptococcus pneumoniae infections is the acquisition of antimicrobial resistance and the global spread of resistant clones. This problems get enhanced by the major disadvantages of the current capsular polysaccharide based vaccines, such as cost, serotype specificity, and the resulting incomplete coverage. While the use of polysaccharide vaccines, specially the conjugate vaccine, had significantly reduced the amount of invasive disease caused Spn, it only has reduced that of the represented serotypes. This occurs mainly because of disease being caused by serotypes not present in the vaccine (maximum of 23 of the >97 capsule types, only 13 in the conjugate vaccine) and replacement carriage. Our rationale is that development of a subunit based vaccine utilizing novel conserved antigenic proteins in conjunction with novel polyphosphazene (PPZ) adjuvants, proven to induce adaptive immunity will deepen the current toolkit to prevent pneumococcal disease without serotype limitations. Thus, we hypothesize that addition of conserved immunogenic proteins to the PPZ molecule will provide the groundwork for the development of a broadly protective pneumococcal subunit based vaccine. The gaps in knowledge we aim to bridge are to define and characterize novel pneumococcal antigenic proteins and polyelectrolyte adjuvants formulations that will initiate adaptive immune responses and lead to protection against disease in a serotype independent manner. The proposed work is significant due to the high incidence serotype replacement that current polysaccharide based vaccines are prone to, which leads to increase susceptibility of children and the elderly to Spn carriage and severe infections (e.g. pneumonia, bacteremia, and meningitis); and innovative since it will use novel formulations of antigenic and conserved pneumococcal proteins to induce potent adaptive immune responses, that will not be serotype dependent.