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

该项目的重点是研制一种疫苗佐剂BiTar-s3。该项目将开发一种针对许多a型流感病毒株共有的HA茎表位的疫苗，从而解决引发抗流感的异亚型中和抗体（nAb）的困难。具体来说，该项目的目标是构建与BiTar-s3佐剂融合的免疫原，以选择一种主要的候选疫苗；在小鼠实验中测试了s3佐剂候选物的安全性和免疫原性；并在年龄较大的恒河猴中测试了s3佐剂和未佐剂候选疫苗的安全性和免疫原性。方法将包括检测靶向候选免疫原的抗ha抗体的表达和免疫反应性，将选定的免疫原改造成高容量腺载体，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佐剂活性在生发中心的机制。

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.