DEVELOPMENT OF SAPONIN DMLT ADJUVANT (SDA)

从南美树Quillaja Saponaria中提取的皂苷具有悠久的佐剂历史，可以追溯到1925年，目前有几个皂素组分正在用于人类的商业疫苗。这些都是注射疫苗，目前还不存在粘膜皂素佐剂。LT(R192G/L211A)，或dmLT，是使用细菌ADP核糖化肠毒素作为佐剂的研究超过35年的产物。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。这两种佐剂在不同的疫苗和递送途径中是独立进行的，但没有一起进行。在初步研究中，我们观察到，当dmLT和皂苷通过口服和舌下接种联合给予时，具有协同佐剂活性。在目前的项目中，我们建议利用杜兰、Q-Vant生物科学公司和PATH的专业知识来评估用于口服或舌下给药的新型皂素dmLT佐剂(SDA)。我们将优化全球相关疫苗的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。我们还将探索专门用于胃肠道递送的新型形成制剂，并进行支持IND的研究，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SDA佐剂平台和配方，以提供强大的系统免疫和/或持续的粘膜免疫。

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.