Long-TSLP和Short-TSLP佐剂对新冠重组蛋白疫苗免疫应答的影响与作用机制

佐剂对于增强新冠蛋白疫苗免疫应答至关重要。然而，迄今被授权的新冠疫苗候选佐剂仍十分稀缺且存在明显缺陷，寻求安全有效的新型佐剂有助于新冠疫苗的研发。前期我们已报道，TSLP是潜在的新型佐剂，而其亚型长链(Long)和短链(Short)TSLP的佐剂活性及作用机制仍尚不清楚。近期我们发现，Long-TSLP和Short-TSLP可促进新冠重组蛋白疫苗特异性抗体及中和抗体产生。进一步发现，Long-TSLP和Short-TSLP可能通过直接靶向DC细胞而非B细胞，进而增强Tfh和GC B细胞反应发挥其佐剂效应。本项目将以此为基础，利用前沿单细胞测序技术、基因敲除小鼠和不同免疫策略等手段，深入探讨Long-TSLP和Short-TSLP调控“DC-Tfh-GC B细胞”轴增强新冠蛋白疫苗免疫应答的作用与机制，并探究两者与传统佐剂的异同及联合免疫的新路径和新方法，为新冠疫苗的研发提供新思路。

Adjuvant is crucial for enhancing SARS-CoV-2 protein vaccine mediated immune responses. However, the authorized adjuvants of SARS-CoV-2 vaccine are extremely inadequate and have obvious imperfections. It therefore has important implications to explore safe and effective novel adjuvants for the development of SARS-CoV-2 vaccine. Seeking safe and effective novel adjuvants is beneficial to the development of SARS-CoV-2 vaccine. We have previously reported that thymic stromal lymphopoietin (TSLP) is a potential novel adjuvant, but the adjuvanticity and mechanism of two different subtypes of TSLP (Long-TSLP and Short-TSLP) are still unclear. We found in recent pilot experiments that Long-TSLP and Short-TSLP can promote SARS-CoV-2 recombinant protein vaccine specific antibodies and neutralizing antibodies production. Furthermore, we have found that Long-TSLP and Short-TSLP can directly target DC cell but not B cell, which in turn enhance Tfh cell and GC B cell immune responses to exert their adjuvant effects. Based on these results, this project will use advanced Single-cell RNA sequencing technology, multiple gene knockout mice and diverse immunization strategies to explore in depth the role and mechanism of Long-TSLP and Short-TSLP induced SARS-CoV-2 recombinant protein-mediated immune responses by regulating the "DC-Tfh-GC B cells" axis. Furthermore, to explore the similarities and differences between Long-TSLP and Short-TSLP and traditional adjuvants, as well as new pathways and new methods of combined immunization. This study will finally provide new ideas and new strategies for the development of SARS-CoV-2 vaccines.