Vaccines to counter emerging antibiotic resistance (R01AI138970)

对抗新出现的抗生素耐药性的疫苗 (R01AI138970)

• 批准号: 10738666
• 负责人: Wendy L Picking
• 金额: $ 125.82万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10738666
• 关键词: Vaccines; counter; emerging; antibiotic; resistance

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针对保守结构，使它们能够跨血清型、菌株和物种边界提供保护。我们已经开发了一种针对重要革兰氏阴性菌的III型分泌系统（T3SS）的保护性抗原策略，无论血清型如何，该策略都应有效，从而跨属（如志贺氏菌）或种（如肠沙门氏菌）边界起作用。通过这种抗原策略，我们已经获得了广泛的血清型独立保护，以抵抗越来越耐抗生素的细菌感染。该策略采用一种佐剂，可在小鼠中提供70-90%的保护，使其免受多种志贺氏菌的致命攻击，并保护6只猴子中的5只在受到索内志贺氏菌攻击后不患严重痢疾。这一平台还对肠道沙门氏菌和其他革兰氏阴性细菌具有血清型不相关的保护作用（70%的保护作用）。

项目成果

Immunogenicity and protective efficacy of nanoparticle formulations of L-SseB against Salmonella infection.

• DOI: 10.3389/fimmu.2023.1208848
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Preformulation Characterization and the Effect of Ionic Excipients on the Stability of a Novel DB Fusion Protein.

• DOI: 10.1016/j.xphs.2020.09.008
• 发表时间: 2021-01
• 期刊: Journal of pharmaceutical sciences
• 影响因子: 3.8
• 作者: Jain A;Hu G;Kumar Ratnakaram SS;Johnson DK;Picking WD;Picking WL;Middaugh CR
• 通讯作者: Middaugh CR

The L-DBF vaccine cross protects mice against different Shigella serotypes after prior exposure to the pathogen.

• DOI: 10.1128/spectrum.00062-23
• 发表时间: 2023-12-12
• 期刊: MICROBIOLOGY SPECTRUM
• 影响因子: 3.7
• 作者: Lu, Ti;Howlader, Debaki R.;Das, Sayan;Dietz, Zackary K.;Nagel, Aaron C.;Whittier, Sean K.;Picking, William D.;Picking, Wendy L.
• 通讯作者: Picking, Wendy L.