TFH-TARGETING GENETIC ADJUVANTS TO PROMOTE DURABLE ANTI-INFLUENZA STEM ANTIBODIES IN OLDER ADULTS.

靶向 TFH 的基因佐剂可促进老年人产生持久的抗流感干抗体。

• 批准号: 10933286
• 负责人: KENTNER SINGLETON
• 金额: $ 60万
• 依托单位: TENDEL THERAPIES INC.
• 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 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10933286
• 关键词: Address; Adenovirus Vector; Adenoviruses; Adjuvant; Antibodies; Antibody Response; Antigens; CD3 Antigens; Contractor; Elderly; Engineering; Epitopes; Genetic; Hemagglutinin; Human; Influenza; Lead; Licensing; Macaca mulatta; Messenger RNA; Methods; Mus; NIH Vaccine Research Center; Safety; Serotyping; Structure of germinal center of lymph node; Testing; Transfer Agreement; Vaccine Adjuvant; Vaccine Research; Vaccines; Validation; adaptive immune response; aged; anti-influenza; data exchange; flu; immunogenicity; immunoreactivity; influenza virus vaccine; lipid nanoparticle; neutralizing antibody; safety testing; stem; vaccine candidate; vaccine development; vaccine platform; vector

The project is focused on progressing BiTar-s3, a vaccine adjuvant agent. The project will develop a vaccine that targets HA stem epitopes shared across many flu-A strains, thereby addressing the difficulty of eliciting heterosubtypic neutralizing antibodies (nAb) against influenza. Specifically, the project’s aims are constructing immunogens fused to the BiTar-s3 adjuvant, to select a lead vaccine candidate; test safety and immunogenicity of the s3-adjuvanted candidate in mice; and test safety and immunogenicity of the s3-adjuvanted and unadjuvanted vaccine candidate in aged rhesus macaques. Methods will include testing expression and immunoreactivity with anti-HA antibodies of targeted candidate immunogens, engineering the selected immunogen into a high-capacity adenovector, testing the ability of s3 to drive anti-HA stem Tfh and antibody responses, testing safety of the s3-adjuvanted and unadjuvanted vaccines in aged rhesus macaques, evaluating adaptive immune responses, and examining the mechanisms of s3 adjuvant activity in germinal centers.

该项目的重点是开发疫苗佐剂BiTar-s3。该项目将开发一种针对许多甲型流感病毒株共有的HA干细胞表位的疫苗，从而解决引发针对流感的异亚型中和抗体（nAb）的困难。具体而言，该项目的目标是构建与BiTar-s3佐剂融合的免疫原，以选择领先的候选疫苗;在小鼠中测试s3佐剂候选疫苗的安全性和免疫原性;并在老年恒河猴中测试s3佐剂和无佐剂候选疫苗的安全性和免疫原性。方法将包括测试靶向候选免疫原的表达和与抗HA抗体的免疫反应性，将选择的免疫原工程化到高容量腺载体中，测试s3驱动抗HA茎Tfh和抗体应答的能力，测试s3佐剂化和无佐剂化疫苗在老年恒河猴中的安全性，评估适应性免疫应答，并检查S3佐剂活性在生发中心的机制。