Vaccines to counter emerging antibiotic resistance

对抗新出现的抗生素耐药性的疫苗

• 批准号: 9918856
• 负责人: Wendy L Picking
• 金额: $ 112.14万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 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/9918856
• 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; Family suidae; 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; resistant strain; uptake; vaccine candidate; vaccine delivery; vaccine development; vaccine efficacy; vaccine trial; vaccinology

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时代最大的公共健康成就。随着抗生素耐药性的爆炸，开发抗多药耐药（MDR）细菌病原体的疫苗比以往任何时候都更为重要，但是大多数当前的疫苗策略无法靶向保守的结构，这些结构可以使它们跨血清型，菌株和物种边界保护。我们制定了一种保护性抗原策略，该策略针对重要的革兰氏阴性细菌的III型分泌系统（T3SS），无论血清型如何，都应有效，从而跨越属（例如Shigella）或物种（例如Salmonella enterica）边界。采用这种抗原策略，我们引起了广泛的血清型独立的保护，以防止细菌越来越多地抗生素抗生素。该策略采用辅助药，并在小鼠中提供70-90％的保护，以防止多种志贺氏菌物种进行致命的挑战，并且它保护了六只猴子中的五只猴子在与Shigella Sonnei挑战后不受严重的痢疾。该平台具有针对沙门氏菌肠挑战（70％保护）以及其他革兰氏阴性细菌的血清型无关的保护。 为了获得完整的（100％）保护，我们开发了一种新型的辅助载体平台来创建下一代疫苗候选者。使用佐剂载体平台，保护性抗原同时进入抗原呈递细胞。该保护性抗原将与载体结合使用，形成多蛋白抗原递送车，以驱动树突状细胞的吸收，并运输到区域淋巴结以进行扩展抗原呈递。我们假设抗原载体平台将对包括MDR物种/菌株在内的所有病原体的所有菌株提供广泛的非依赖性保护。 提出的具体目的是：1）验证临床MDR菌株的跨压力保护； 2）使用新粒子优化三种候选疫苗； 3）在适当的动物模型中完成概念验证疗效研究，包括免疫反应评估； 4）评估疫苗在接触病原体后经常发生的疫苗功效； 5）顶部疫苗候选物的完整生物物理表征，以进行后续配方。 通过该项目完成，我们将证明我们的抗原载体平台将防止MDR革兰氏阴性病原体感染。