Developing a novel strategy to uncover vaccine targets in bacterial pathogens

 描述(由申请人提供)：目前以胶囊多糖为基础的肺炎链球菌疫苗在世界大多数地区使用过于昂贵，导致只对部分流通菌株产生保护作用，这一点因地域而异。此外，疫苗未涵盖的血清型引起的疾病发病率正在增加，因为这些菌株填补了被消除的血清型的利基，这种现象被称为血清型替换。因此，有必要开发覆盖范围更广、不依赖于血清型的疫苗。以保守的表面蛋白为靶点的蛋白质疫苗有可能以较低的成本提供广泛的覆盖范围。尽管有报道称存在200多种肺炎链球菌表面蛋白，但那些具有理想特性的疫苗，即激发保护性免疫反应、肺炎链球菌菌株之间的高度保守以及对生存和/或毒力至关重要以限制免疫逃逸的那些蛋白的数量要有限得多。我们假设，功能冗余是许多单个表面蛋白可有可无的主要原因。我们最近使用了基于转座子测序的全基因组筛选(TN-SEQ)来鉴定一小部分必需的表面蛋白。在这个项目中，我们将使用TN-SEQ进行遗传交互 鉴定肺炎链球菌表面功能冗余蛋白的图谱。我们将分别测试单价疫苗和多价疫苗中单一必需蛋白质和功能冗余蛋白质的子集。该项目将揭示一套新的保护性肺炎链球菌抗原，并将产生针对病原体的疫苗开发的新战略。

 DESCRIPTION (provided by applicant): Current capsular polysaccharide-based Streptococcus pneumoniae vaccines are too expensive for their use in most of the world and result in protection to only a subset of circulating strains, which varies geographically. In addition, the incidence of disease caused by serotypes not covered in the vaccines is increasing as these strains fill the niche of the eliminated serotypes, a phenomenon referred to as serotype replacement. Thus, there is a need for the development of vaccines with broader, serotype-independent coverage. Protein-based vaccines that target conserved surface proteins have the potential to provide broad coverage at lower cost. Despite reports of the existence of over two hundred S. pneumoniae surface proteins, those that possess desirable characteristics for inclusion in a vaccine, namely eliciting a protective immune response, a high level of conservation among S. pneumoniae strains, and being essential for viability and/or virulence in order to limit immune escape, are much more limited in number. We hypothesize that functional redundancy is a major reason for the dispensability of many individual surface proteins. We recently used a genome-wide screen based on transposon-sequencing (Tn-seq) to identify a small set of essential surface proteins. In this project we will use Tn-seq for genetic interaction mapping to identify S. pneumoniae surface proteins that are functionally redundant. We will test a subset of singly essential and functionally redundant proteins as mono- and multivalent vaccines, respectively. This project will reveal a new set of protective S. pneumoniae antigens and will generate a new strategy of vaccine development against pathogens.