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

乙型肝炎表面抗原 免疫学 抗体 病毒学 乙型肝炎 接种疫苗 人口 抗原 等离子体电池 B细胞 医学 生物 病毒 乙型肝炎病毒 环境卫生
作者
Ruoyao Qi,Rao Fu,Lei Xing,Jinhang He,Yao Jiang,Liang Zhang,Yangtao Wu,Siling Wang,Xuan Guo,Feng Chen,Meifeng Nie,Man Yang,Yiyi Chen,Jing Zeng,Jingjing Xu,Hualong Xiong,Mujin Fang,Yuqiong Que,Youliang Yao,Ying-Bin Wang,Jiali Cao,Huiming Ye,Yali Zhang,Zizheng Zheng,Tong Cheng,Jun Zhang,Xu Lin,Quan Yuan,Tianying Zhang,Ningshao Xia
出处
期刊:Journal of Hepatology [Elsevier]
被引量:1
标识
DOI:10.1016/j.jhep.2023.12.032
摘要

Background & Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Impact and implications

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 vaccines offers a promising approach that could significantly advance the pursuit of a functional cure for HBV.
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