DEVELOPMENT OF SAPONIN DMLT ADJUVANT (SDA)

皂苷DMLT佐剂(SDA)的研制

• 批准号: 10935815
• 负责人: ELIZABETH NORTON
• 金额: $ 160.27万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10935815
• 关键词: ADP ribosylation; Adjuvant; Antigens; Back; Biological Sciences; Campylobacter; Contractor; Cyclic GMP; Development; Dose; Enterotoxins; Evaluation; Food; Formulation; Goals; Human; Human poliovirus; Immunity; Mucosal Immunity; Mucous Membrane; Oral; Phase I Clinical Trials; Phase II Clinical Trials; Poliomyelitis; Poliovirus Vaccines; Preparation; Recording of previous events; Research; Route; Sampling; Saponins; Soapbush; Source; South American; Toxicology; Toxin; Trees; Vaccination; Vaccine Adjuvant; Vaccines; cross reacting material 197; enteric infection; enterotoxigenic Escherichia coli; gastrointestinal; immunogenicity; manufacture; mutant; novel; stability testing; success

Saponins derived from the South-American Tree Quillaja saponaria have a lengthy adjuvant history going back to 1925 and several saponin fractions are currently being utilized in commercial vaccines in humans. These are all injected vaccines and no mucosal saponin adjuvant currently exists. LT(R192G/L211A), or dmLT, is the product of more than 35 years of research on the use of bacterial ADP-ribosylating enterotoxins as adjuvants. dmLT has recently had success in Phase 1 and 2 clinical trials for ETEC and polio virus, though success for oral delivery seems to be dependent upon the immunogenicity of the antigen. Both adjuvants are pursued independently for various vaccines and delivery routes but have not been pursued together. In preliminary studies, we have observed synergistic adjuvant activity when dmLT and saponins are co-administered by oral and sublingual vaccination. In the current project, we propose to evaluate the novel combination saponin dmLT adjuvant (SDA) for oral or sublingual delivery utilizing expertise by both Tulane, Q-Vant Biosciences and PATH. We will optimize SDA in globally relevant vaccines including the U.S. Navy’s adjuvanted subunit ETEC and Campylobacter vaccine (ASEC) targeting bacterial enteric infections and inactivated polio vaccine. We will also explore novel formation preparations specific to gastrointestinal delivery and conduct IND-enabling studies such as GLP and cGMP manufacturing, toxicology, and stability testing. The ultimate goal of these studies is to define the SDA adjuvant platform and formulation that provides potent systemic immunity and/or sustained mucosal immunity.

源自南美树皂树的皂苷具有悠久的佐剂历史，可以追溯到 1925 年，目前有几种皂苷组分被用于人类商业疫苗中。这些都是注射疫苗，目前还没有粘膜皂苷佐剂。 LT(R192G/L211A) 或 dmLT 是使用细菌 ADP 核糖基化肠毒素作为佐剂超过 35 年的研究成果。 dmLT 最近在 ETEC 和脊髓灰质炎病毒的 1 期和 2 期临床试验中取得了成功，尽管口服给药的成功似乎取决于抗原的免疫原性。这两种佐剂都针对不同的疫苗和递送途径独立进行研究，但尚未一起进行研究。在初步研究中，我们观察到当 dmLT 和皂苷通过口服和舌下疫苗接种联合给药时具有协同佐剂活性。在当前的项目中，我们建议利用杜兰大学、Q-Vant Biosciences 和 PATH 的专业知识来评估用于口服或舌下给药的新型组合皂苷 dmLT 佐剂 (SDA)。我们将优化全球相关疫苗中的 SDA，包括美国海军的佐剂亚单位 ETEC 和针对细菌肠道感染的弯曲杆菌疫苗 (ASEC) 和灭活脊髓灰质炎疫苗。我们还将探索针对胃肠道输送的新型制剂，并进行 IND 支持的研究，例如 GLP 和 cGMP 制造、毒理学和稳定性测试。这些研究的最终目标是确定可提供有效的全身免疫和/或持续的粘膜免疫的 SDA 佐剂平台和制剂。