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

项目总结/摘要 肺炎链球菌感染的巨大负担的主要问题之一是肺炎链球菌感染的获得。 抗生素耐药性和耐药克隆的全球传播。这个问题得到加强的主要 目前的基于荚膜多糖的疫苗的缺点，如成本、血清型特异性， 造成的不完全覆盖。虽然多糖疫苗，特别是结合疫苗的使用， 显著减少了由Spn引起的侵袭性疾病的数量，它只减少了代表性的 血清型这主要是因为疫苗中不存在的血清型引起的疾病 （>97种胶囊类型中最多有23种，结合疫苗中只有13种）和替换托架。我们 基本原理是开发基于亚单位的疫苗， 与新的聚磷腈（PPZ）佐剂结合，证明诱导适应性免疫将加深 目前的工具包，以防止肺炎球菌疾病没有血清型限制。因此，我们假设， 保守的免疫原性蛋白质的PPZ分子将提供基础的发展， 具有广泛保护性的肺炎球菌亚单位疫苗。我们旨在弥合的知识差距是定义 并表征新的肺炎球菌抗原蛋白和肺炎球菌佐剂制剂， 启动适应性免疫应答并导致以血清型非依赖性方式对疾病的保护。 由于当前多糖的高发生率血清型替换， 基础疫苗容易发生，这导致儿童和老年人对Spn携带的易感性增加 和严重感染（如肺炎、菌血症和脑膜炎）;创新，因为它将使用新的 抗原性和保守性肺炎球菌蛋白的制剂以诱导有效的适应性免疫应答， 不依赖于血清型。

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.