Therapeutic vaccine-induced plasma cell differentiation is defective in the presence of persistently high HBsAg levels

• Published in: Journal of hepatology 2024-05, Vol.80 (5), p.714-729
• Main Authors: Qi, Ruoyao, Fu, Rao, Lei, Xing, He, Jinhang, Jiang, Yao, Zhang, Liang, Wu, Yangtao, Wang, Siling, Guo, Xueran, Chen, Feng, Nie, Meifeng, Yang, Man, Chen, Yiyi, Zeng, Jing, Xu, Jingjing, Xiong, Hualong, Fang, Mujin, Que, Yuqiong, Yao, Youliang, Wang, Yingbin, Cao, Jiali, Ye, Huiming, Zhang, Yali, Zheng, Zizheng, Cheng, Tong, Zhang, Jun, Lin, Xu, Yuan, Quan, Zhang, Tianying, Xia, Ningshao
• Format: Article
• Language: English
• Subjects: B cell; chronic infeciton; HBV; humoral reponse; therapeutic vaccine
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2023.12.032

Mechanisms behind the impaired response of antigen-specific B cells to therapeutic vaccination in chronic hepatitis B virus (HBV) infection remain unclear. The development of vaccines or strategies to overcome this obstacle is vital for advancing the management of chronic hepatitis B. A mouse model, denominated as E6F6-B, was engineered to feature a knock-in of a B-cell receptor (BCR) that specifically recognizes HBsAg. This model served as a valuable tool for investigating the temporal and spatial dynamics of humoral responses following therapeutic vaccination under continuous antigen exposure. Using a suite of immunological techniques, we elucidated the differentiation trajectory of HBsAg-specific B cells post-therapeutic vaccination in HBV carrier mice. Utilizing the E6F6-B transfer model, we observed a marked decline in antibody-secreting cells 2 weeks after vaccination. A dysfunctional and atypical pre-plasma cell population (BLIMP-1+ IRF4+ CD40- CD138- BCMA-) emerged, manifested by sustained BCR signaling. By deploying an antibody to purge persistent HBsAg, we effectively prompted the therapeutic vaccine to provoke conventional plasma cell differentiation. This resulted in an enhanced anti-HBs antibody response and facilitated HBsAg clearance. Sustained high levels of HBsAg limit the ability of therapeutic hepatitis B vaccines to induce the canonical plasma cell differentiation necessary for anti-HBs antibody production. Employing a strategy combining antibodies with vaccines can surmount this altered humoral response associated with atypical pre-plasma cells, leading to improved therapeutic efficacy in HBV carrier mice. Therapeutic vaccines aimed at combatting HBV encounter suboptimal humoral responses in clinical settings, and the mechanisms impeding their effectiveness have remained obscure. Our research, utilizing the innovative E6F6-B mouse transfer model, reveals that the persistence of HBsAg can lead to the emergence of an atypical pre-plasma cell population, which proves to be relevant to the potency of therapeutic HBV vaccines. Targeting the aberrant differentiation process of these atypical pre-plasma cells stands out as a critical strategy to amplify the humoral response elicited by HBV therapeutic vaccines in carrier mouse models. This discovery suggests a compelling avenue for further study in the context of human chronic hepatitis B. Encouragingly, our findings indicate that synergistic therapy combining HBV-specific antibodies with vac