I-Corps: A disease-agnostic platform for enhanced vaccine immunogenicity using live microbial vectors

I-Corps这个项目的更广泛影响/商业潜力是开发一个疾病诊断平台，用于研制预防性和治疗性疫苗。对于从癌症到致病菌的各种疾病，弱免疫原性或对抗原的耐受性限制了它们在疫苗中的实际靶向。利用所提出的细菌活疫苗平台和硝化抗原技术，有可能解锁这些抗原作为靶标。所提议的平台可用于开发针对目前缺乏疫苗的疾病的疫苗或具有有限效力的免疫治疗溶液的疾病的疫苗。如果成功，就有可能创造出能够挽救生命并减轻患者和医疗保健负担的商业产品。I-Corps项目的基础是开发一种技术，使自然免疫力较弱的抗原能够接种疫苗。针对免疫原性较弱但高度保守的抗原的免疫疗法或疫苗可能对一些疾病有益。利用代谢工程、化学工程和蛋白质工程，已经开发出细菌载体，通过在所需位点选择性地引入硝基功能化，自主产生蛋白质。研究表明，蛋白质硝化可导致CD4+ T细胞免疫反应扩增，并增强对细菌和癌症相关抗原的免疫反应。该策略采用基于非标准氨基酸（nsAA）的技术。迄今为止，涉及nsAAs的商业努力主要集中在使用生物正交官能团以达到反应性或稳定性的目的。在这里，nsAA技术被用于另一个方向，即改善疫苗的免疫原性反应。此外，所提出的技术结合了nsAAs的代谢合成和蛋白质抗原的掺入，这可能会绕过硝化蛋白质合成（即细胞内合成的运输）和递送（细菌合成）的限制。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the development of a disease agnostic platform for the creation of prophylactic and therapeutic vaccines. For diseases ranging from cancer to pathogenic bacteria, weak immunogenicity or tolerance of antigens limits their practical targeting in vaccines. Using the proposed live bacterial vaccine platform and nitrated antigen technology, it may be possible to unlock these antigens as targets. The proposed platform may be used for developing vaccines against diseases lacking current vaccines or diseases with immunotherapeutic solutions with limited efficacy. If successful, it may be possible to create commercial products that will save lives and reduce patient and health care burden.This I-Corps project is based on the development of a technology to enable the vaccination of antigens with weak natural immunity. Several diseases may benefit from immunotherapies or vaccines that can target weakly immunogenic but highly conserved antigens. Bacterial vectors have been developed that autonomously produce proteins with selective introduction of nitro functionalization at desired sites by using metabolic engineering, chemical engineering, and protein engineering. Studies have demonstrated that protein nitration may result in an amplification of CD4+ T cell immune response with enhancement for both bacterial and cancer-associated antigens. This strategy uses non-standard amino acid (nsAA)-based technology. To date, commercial endeavors involving nsAAs focused on using bio-orthogonal functional groups for purposes of reactivity or stability. Here nsAA technology is used in an alternative direction, the improved immunogenic response in vaccines. In addition, the proposed technology combines metabolic synthesis of nsAAs and incorporation into protein antigens, which may circumvent limitations toward nitrated protein synthesis (namely, transport given the intracellular synthesis) and delivery (given bacterial synthesis).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.