Developing a novel strategy to uncover vaccine targets in bacterial pathogens

 描述（由申请人提供）：目前基于荚膜多糖的肺炎链球菌疫苗对于它们在世界上大多数地区的使用来说过于昂贵，并且仅对一部分流行菌株产生保护作用，这在地理上是不同的。此外，由于疫苗中未涵盖的血清型填补了已消除血清型的小生境，因此这些菌株引起的疾病发病率正在增加，这一现象称为血清型替代。因此，需要开发覆盖范围更广、不依赖于疫苗类型的疫苗。靶向保守表面蛋白的基于蛋白质的疫苗具有以较低成本提供广泛覆盖的潜力。尽管有报道称有超过200个S。肺炎链球菌表面蛋白，那些具有包含在疫苗中的所需特征的蛋白，即引发保护性免疫应答，肺炎链球菌中的高水平保守性。肺炎菌株，并且对于生存力和/或毒力是必需的以限制免疫逃逸，在数量上更加有限。我们推测，功能冗余是许多单个表面蛋白的可分配性的主要原因。我们最近使用了基于转座子测序（Tn-seq）的全基因组筛选来识别一小组必需的表面蛋白。在这个项目中，我们将使用Tn-seq进行遗传相互作用 映射以识别S。肺炎表面蛋白的功能冗余。我们将测试一个子集的单一必需和功能冗余的蛋白质作为单价和多价疫苗，分别。该项目将揭示一套新的保护S。肺炎抗原，并将产生针对病原体的疫苗开发的新策略。

 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.