Developing a novel strategy to uncover vaccine targets in bacterial pathogens

开发一种新策略来发现细菌病原体中的疫苗靶点

• 批准号: 8891081
• 负责人: Andrew Camilli
• 金额: $ 24.75万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891081
• 关键词: Antibodies; Antigens; Bacteria; Carbohydrates; Cells; Characteristics; Disease; Escherichia coli; Genes; Genetic; Goals; Immune; Immune response; Immunity; Immunization; Immunologic Surveillance; In Vitro; Incidence; Individual; Infection; Left; Lung; Maps; Measures; Mediating; Membrane Proteins; Methods; Modeling; Mono-S; Mus; Mutation; Nasopharynx; Pneumococcal vaccine; Polysaccharides; Proteins; Proteolysis; Reporting; Role; Serotyping; Serum; Streptococcus pneumoniae; Testing; Vaccine Antigen; Vaccines; Virulence; base; cost; fitness; genome editing; genome-wide; genome-wide analysis; high throughput screening; immunogenic; in vivo; mutant; novel strategies; pathogen; protein expression; public health relevance; vaccine development; vaccine evaluation

 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.

 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在世界大部分地区使用而言过于昂贵，并且只能对一小部分流行菌株提供保护，而这些菌株因地理位置而异。此外，由于疫苗未涵盖的血清型所引起的疾病的发病率正在增加，因为这些菌株填补了已消除的血清型的空位，这种现象称为血清型替代。因此，需要开发具有更广泛的、与血清型无关的覆盖范围的疫苗。针对保守表面蛋白的蛋白质疫苗有可能以较低的成本提供广泛的覆盖范围。尽管有报道称存在超过 200 种肺炎链球菌表面蛋白，但那些具有包含在疫苗中的所需特征的蛋白（即引发保护性免疫反应、肺炎链球菌菌株之间的高度保守性以及对于生存力和/或毒力以限制免疫逃逸至关重要）的数量却非常有限。我们假设功能冗余是许多单独表面蛋白可有可无的主要原因。我们最近使用基于转座子测序 (Tn-seq) 的全基因组筛选来鉴定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 映射以识别功能冗余的肺炎链球菌表面蛋白。我们将分别测试单必需蛋白和功能冗余蛋白的子集作为单价疫苗和多价疫苗。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新策略。