DEVELOPMENT OF VACCINES FOR INFLUENZA USING AN IMMUNO-MODULATOR ADJUVANT AND MULTI-PLATFORM APPROACH

使用免疫调节佐剂和多平台方法开发流感疫苗

• 批准号: 10935797
• 负责人: BRUXANNE EL-KAMMASH
• 金额: $ 196.49万
• 依托单位: UNIVERSITY OF CHICAGO
• 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/10935797
• 关键词: Adjuvant; Agonist; Antibodies; Antibody titer measurement; Antigens; Chemical Structure; Chemistry; Contractor; Contracts; Development; Disease; Emulsions; Ferrets; Fluzone; Formulation; Goals; Good Manufacturing Process; Immune response; Immune system; Immunologic Stimulation; Immunologics; Immunomodulators; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B Virus; Knowledge; Laboratories; Liposomes; Messenger RNA; Modeling; Modification; Molecular; Mus; National Institute of Allergy and Infectious Disease; Oils; Outcome; Parents; Performance; Production; Property; RNA vaccine; Recombinants; Research; Structure; System; TLR7 gene; Testing; Toxicity Tests; Toxicology; Translations; Vaccines; Water; efficacy study; immunogenicity; improved; influenza virus vaccine; inhibitor; lead candidate; manufacture; performance tests; prevent; side effect; vaccine development; vaccine platform

Vaccines are formulated with adjuvants to stimulate the immune system so that the vaccine can be more effective at preventing disease. Our goal is to create an adjuvant formulation that overcomes a limitation in many adjuvants - customization of the immune response for a desired immunological outcome. Specifically, our goal is to reduce inflammation and side effects and to increase antibody levels in vaccines used for influenza. In our previous Adjuvant Discovery Contract, we discovered that when a molecule called Bafetinib was combined with a commercial vaccine or traditional adjuvant, Bafetinib can increase antibody titers or lower inflammation, or both. This new contract with the NIAID is an opportunity to improve Bafetinib’s formulation and yield a better adjuvant. We will partner with Inimmune Corporation to combine our molecule, Bafetinib, with their molecule, INI-4001. INI-4001 is promising due to its strong stimulatory properties, readily altered chemical structure, and because Inimmune has extensive expertise in adjuvant development. Together, we will develop an adjuvant system composed of Bafetinib and INI-4001. We will develop Bafetinib in combination with INI-4001 (a synthetic TLR7/8 agonist) through co-formulation or as a stand-alone adjuvant additive. Using targeted synthetic modifications of Bafetinib, we will improve the formulation, molecular composition, stability, and activity in previously vetted vaccine models. Our expected outcomes include optimized formulations of new molecular compositions of the parent structure of Bafetinib with INI-4001 in new formulations we refer to as “adjuvant systems.” These adjuvant systems will use both liposome and oil-in-water emulsion to localize the components. We will compare the performance of our new system to several existing vaccine platforms. We will iterate the formulations and improve them based on results from repeating the performance and toxicity tests. The purpose is to optimize the most promising formulation to develop a final lead candidate. We will test the lead candidate in Ferret challenge models of influenza. We will also test how well the lead candidate can be produced on a larger scale. This knowledge will improve the translation of our research from the small-scale laboratory to production-scale using standard Good Manufacturing Practices.

疫苗是用佐剂配制而成，可以刺激免疫系统，使疫苗能够更有效地预防疾病。 我们的目标是创造一种佐剂配方，克服许多佐剂的局限性——定制免疫反应以获得所需的免疫学结果。具体来说，我们的目标是减少炎症和副作用，并提高流感疫苗的抗体水平。 在我们之前的佐剂发现合同中，我们发现当一种名为 Bafetinib 的分子与商业疫苗或传统佐剂结合时，Bafetinib 可以增加抗体滴度或降低炎症，或两者兼而有之。与 NIAID 的这份新合同是改进 Bafetinib 配方并生产更好佐剂的机会。我们将与 Inimmune Corporation 合作，将我们的分子 Bafetinib 与他们的分子 INI-4001 结合起来。 INI-4001 因其强大的刺激特性、易于改变的化学结构以及 Inimmune 在佐剂开发方面拥有丰富的专业知识而前景光明。我们将共同开发由 Bafetinib 和 INI-4001 组成的佐剂系统。 我们将通过联合制剂或作为独立的佐剂添加剂来开发 Bafetinib 与 INI-4001（一种合成的 TLR7/8 激动剂）的组合。利用 Bafetinib 的靶向合成修饰，我们将改进先前审查的疫苗模型中的配方、分子组成、稳定性和活性。我们的预期成果包括 Bafetinib 母体结构的新分子组合物与 INI-4001 的优化配方，我们称之为“佐剂系统”。这些佐剂系统将使用脂质体和水包油乳液来定位成分。我们将把新系统的性能与几个现有的疫苗平台进行比较。我们将根据重复性能和毒性测试的结果迭代配方并改进它们。 目的是优化最有希望的配方以开发最终的主要候选药物。 我们将在雪貂流感挑战模型中测试主要候选药物。我们还将测试主要候选药物在更大范围内的生产效果。 这些知识将改善我们的研究从小型实验室到使用标准良好生产规范的生产规模的转化。