Vaccines to counter emerging antibiotic resistance

接种疫苗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爆炸性增长，开发针对多药耐药(MDR)细菌病原体的疫苗比以往任何时候都更加重要，但目前的大多数疫苗策略都未能针对保守结构，使它们能够跨越血清型、菌株和物种边界进行保护。我们已经开发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)，无论是哪种血清型都应该是有效的，从而跨越属(如志贺氏菌)或种(如肠沙门氏菌)的界限。通过这种抗原策略，我们已经获得了广泛的不依赖于血清型的保护，以抵御细菌感染，这些细菌对抗生素的耐药性越来越强。该策略使用佐剂，可为小鼠提供70%-90%的保护，使其免受多种志贺氏菌的致死攻击，并保护6只猴子中的5只在受到宋内氏志贺氏菌攻击后免于患上严重痢疾。这个相同的平台已经引起了对肠道沙门氏菌挑战(70%的保护)以及其他革兰氏阴性细菌的独立于血清型的保护。 为了达到完全(100%)保护，我们开发了一种新的佐剂载体平台来创造下一代候选疫苗。在佐剂载体平台上，保护性抗原同时进入抗原提呈细胞。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运输到区域淋巴结，以扩大抗原呈递。我们假设抗原载体平台将针对包括MDR物种/菌株在内的所有病原体菌株提供广泛的非血清型保护。建议的具体目标是：1)验证临床MDR毒株的跨毒株保护；2)使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效力研究，包括免疫反应评估；4)评估经常发生的亚临床预暴露病原体后的疫苗效力；5)完成后续配方的首选候选疫苗的生物物理特征。通过这个项目的完成，我们将证明我们的抗原载体平台将防止多药耐药革兰氏阴性病原体的感染。

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.