Vaccines to counter emerging antibiotic resistance

对抗新出现的抗生素耐药性的疫苗

基本信息

批准号：
10155392
负责人：
Wendy L Picking
金额：
$ 112.13万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155392
关键词：
Achievement Adjuvant Animal Model Animals Antibiotic Resistance Antibiotics Antigen Presentation Antigen-Presenting Cells Antigens Bacteria Bacterial Infections Bordetella Bordetella bronchiseptica Burkholderia Burkholderia pseudomallei Chimeric Proteins Clinical Complex Cystic Fibrosis Dendritic Cells Development Dose Dysentery Effectiveness Ensure Explosion Exposure to Formulation Gram-Negative Bacteria Hyaluronan Hyaluronic Acid Immune response Infection Infection prevention Lipopolysaccharides Lung Lymphoid Tissue Mediating Microbiology Modeling Monkeys Multi-Drug Resistance Mus Needles Organism Pathogenicity Preventive measure Proteins Pseudomonas Pseudomonas aeruginosa Public Health Rattus Salmonella Salmonella enterica Salmonella typhimurium Serotyping Shigella Shigella Infections Shigella flexneri Shigella sonnei Specialist Structure Surface Technology Testing Time Toxin Type III Secretion System Pathway Vaccinated Vaccination Vaccines Work biophysical properties draining lymph node efficacy study emerging antibiotic resistance enterotoxigenic Escherichia coli experimental study lymph nodes multidrug-resistant Pseudomonas aeruginosa mutant nanoparticle novel novel vaccines particle pathogen pathogen exposure pathogenic bacteria porcine model resistant strain uptake vaccine candidate vaccine delivery vaccine development vaccine efficacy vaccine trial vaccinology

项目摘要

Vaccination may be the greatest public health achievement of our time. With an explosion of antibiotic resistance, developing vaccines against multi-drug resistant (MDR) bacterial pathogens is more important than ever, but most current vaccine strategies fail to target conserved structures that would allow them to protect across serotype, strain and species boundaries. We have developed a protective antigen strategy that targets the type III secretion system (T3SS) of important Gram-negative bacteria and which should be efficacious regardless of serotype, thereby working across genus (e.g. Shigella) or species (e.g. Salmonella enterica) boundaries. With this antigen strategy, we have elicited broad serotype-independent protection against infections by bacteria that are becoming increasingly antibiotic resistant. This strategy employs an adjuvant and provides 70-90% protection in mice against lethal challenge by multiple Shigella species and it protected five of six monkeys from developing severe dysentery after challenge with Shigella sonnei. This same platform has elicits serotype-independent protection against Salmonella enterica challenge (70% protection) as well as other Gram-negative bacteria. To reach complete (100%) protection, we have developed a novel adjuvant carrier platform to create next generation vaccine candidates. With the adjuvant carrier platform, the protective antigen simultaneously enters into antigen presenting cells. This protective antigen will be combined with a carrier to form a multi-protein antigen delivery vehicle to drive uptake by dendritic cells and transport to regional lymph nodes for extended antigen presentation. We hypothesize that the antigen-carrier platform will provide broad serotype-independent protection against all strains of the pathogen including MDR species/strains. The specific aims being proposed are to: 1) Validate cross-strain protection for clinical MDR strains; 2) Optimize the three candidate vaccines using the new particle; 3) Complete the proof-of-concept efficacy studies, including immune response assessment, in appropriate animal models; 4) Assess vaccine efficacy following subclinical pre-exposure to the pathogen as often occurs; 5) Complete biophysical characterization of the top vaccine candidates for subsequent formulation. By the completion of this project, we will have demonstrated that our antigen-carrier platform will prevent infections by MDR Gram negative pathogens.

疫苗接种可能是我们这个时代最伟大的公共卫生成就。随着抗生素耐药性的激增，开发针对多重耐药 (MDR) 细菌病原体的疫苗比以往任何时候都更加重要，但大多数当前的疫苗策略未能针对保守结构，而这些结构使它们能够跨越血清型、菌株和物种界限提供保护。我们开发了一种保护性抗原策略，针对重要革兰氏阴性菌的 III 型分泌系统 (T3SS)，无论血清型如何，该策略都应该有效，从而跨越属（例如志贺氏菌）或种（例如肠沙门氏菌）界限。通过这种抗原策略，我们引发了广泛的、独立于血清型的保护，以防止抗生素耐药性日益增强的细菌感染。该策略采用佐剂，为小鼠提供 70-90% 的保护，使其免受多种志贺氏菌的致命攻击，并保护六只猴子中的五只在受到宋内志贺氏菌攻击后免于患上严重痢疾。该平台可针对肠沙门氏菌攻击（70% 保护）以及其他革兰氏阴性细菌产生独立于血清型的保护。为了达到完全（100%）的保护，我们开发了一种新型佐剂载体平台来创建下一代候选疫苗。通过佐剂载体平台，保护性抗原同时进入抗原呈递细胞。这种保护性抗原将与载体结合形成多蛋白抗原递送载体，以驱动树突状细胞摄取并转运至区域淋巴结以延长抗原呈递时间。我们假设抗原载体平台将为所有病原体菌株（包括 MDR 物种/菌株）提供广泛的、独立于血清型的保护。提出的具体目标是： 1) 验证临床 MDR 菌株的交叉菌株保护； 2）利用新颗粒优化三种候选疫苗； 3）在适当的动物模型中完成概念验证功效研究，包括免疫反应评估； 4) 在经常发生的亚临床预暴露于病原体后评估疫苗功效； 5) 对后续配制的顶级候选疫苗进行完整的生物物理表征。通过该项目的完成，我们将证明我们的抗原载体平台将预防 MDR 革兰氏阴性病原体的感染。