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

该项目的重点是研发疫苗佐剂Bitar-S3。该项目将开发一种针对许多流感病毒株共有的HA干细胞表位的疫苗，从而解决诱导针对流感的异亚型中和抗体(NAB)的困难。具体地说，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；在小鼠身上测试S3佐剂候选疫苗的安全性和免疫原性；以及在老年恒河猴身上测试S3佐剂和非佐剂疫苗候选疫苗的安全性和免疫原性。方法将包括测试目标候选免疫原的抗HA抗体的表达和免疫反应性，将选定的免疫原工程化为高容量的腺载体，测试S3驱动抗HA干细胞Tfh和抗体反应的能力，测试S3佐剂和非佐剂疫苗在老年恒河猴中的安全性，评估适应性免疫反应，以及研究S3佐剂在生发中心的作用机制。

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.