Vaccines to counter emerging antibiotic resistance

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爆发，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，但目前大多数疫苗策略未能靶向保守结构，使它们能够跨越血清型，菌株和物种界限提供保护。我们已经开发了一种保护性抗原策略，其靶向重要革兰氏阴性菌的III型分泌系统（T3 SS），并且无论血清型如何都应该是有效的，从而跨属（例如志贺氏菌）或种（例如肠道沙门氏菌）边界起作用。通过这种抗原策略，我们已经引起了广泛的非依赖于细菌类型的保护，以对抗越来越耐抗生素的细菌的感染。该策略采用佐剂，并在小鼠中提供70-90%的保护以对抗多种志贺氏菌属的致死性攻击，并且在用宋内志贺氏菌攻击后，其保护六只猴子中的五只免于发展严重的痢疾。该相同平台具有针对肠道沙门氏菌挑战（70%保护）以及其他革兰氏阴性细菌的不依赖于细菌类型的保护。 为了达到完全（100%）保护，我们开发了一种新型佐剂载体平台，以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。该保护性抗原将与载体组合以形成多蛋白抗原递送载体，以驱动树突细胞的摄取并运输至区域淋巴结以延长抗原呈递。我们假设抗原载体平台将提供针对所有病原体菌株（包括MDR种/株）的广泛的非型别依赖性保护。 提出的具体目标是：1）临床MDR菌株的交叉菌株保护; 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有效性研究，包括免疫应答评估; 4）评估经常发生的亚临床预暴露于病原体后的疫苗有效性; 5）完成最佳疫苗候选物的生物物理表征以用于随后的配制。 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。

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.