Identification of protective pneumococcal antigens from a surface protein library

描述（由申请方提供）：目前已有抗肺炎链球菌的结合疫苗（与载体蛋白结合的荚膜多糖），但受疫苗中所含血清型的限制;此外，在许多引入结合疫苗的国家中观察到血清型替代。因此，提供物种特异性保护的替代疫苗将代表重要的公共卫生进步。两种类型的获得性免疫，TH 17细胞介导的和抗体介导的，已被证明分别提供针对鼻咽定殖和侵袭性疾病的保护。细菌表面上的蛋白质由于其对抗体的可接近性和促进调理吞噬作用的可能性而成为疫苗开发的有吸引力的靶标。我们将开发一个肺炎球菌物种保守的表面蛋白库，并筛选它的候选疫苗，提供TH 17依赖的保护，防止定植和抗体介导的保护，防止肺炎球菌疾病。筛选TH 17刺激蛋白将首先在小鼠模型中进行，用于诱导IL-17 A，之后在小鼠模型中进行。 肺炎球菌暴露;这些结果将通过检查从儿童获得的腺样细胞的TH 17应答来证实。然后将在小鼠和儿科腺样细胞中引发这些应答的抗原在鼠模型中测试针对定殖和疾病的保护。成功完成这项工作将推动肺炎球菌疫苗研究领域的发展，并为其他病原体（如金黄色葡萄球菌和A组链球菌）的抗原发现提供概念验证策略，其中T和B细胞免疫都发挥着重要的互补作用。

DESCRIPTION (provided by applicant): Conjugate vaccines (capsular polysaccharides conjugated to carrier proteins) against Streptococcus pneumoniae are available but are limited by the serotypes included in the vaccines; furthermore serotype replacement had been observed in many countries that have introduced conjugate vaccines. Therefore, alternative vaccines that provide species-specific protection would represent an important public health advance. Two types of acquired immunity, TH17 cells- and antibody-mediated, have been shown to provide protection against nasopharyngeal colonization and invasive disease, respectively. Proteins on the bacterial surface represent attractive targets for vaccine development due to their accessibility to antibodies and the possibility of promoting opsonophagocytosis. We will develop a pneumococcal species-conserved surface protein library and screen it for vaccine candidates that provide TH17 dependent protection against colonization and antibody-mediated protection against pneumococcal disease. Screens for TH17 stimulatory proteins will be carried out first in mouse models for elicitation of IL-17A after pneumococcal exposure; these results will then be confirmed by examination of the TH17 response from adenoidal cells obtained from children. Antigens that elicit these responses in both mice and pediatric adenoidal cells will then be tested for protection against colonization and disease in murine models. Successful completion of this will both advance the field of pneumococcal vaccine research and provide a proof-of-concept strategy for antigen discovery for other pathogens, such as Staphylococcus aureus and group A streptococcus, in which both T and B cell immunity play important and complementary roles.