Objective This study aimed to develop a novel therapeutic vaccine based on a unique B cell epitope and investigate its therapeutic potential against chronic hepatitis B (CHB) in animal models. Methods A series of peptides and carrier proteins were evaluated in HBV-tolerant mice to obtain an optimised therapeutic molecule. The immunogenicity, therapeutic efficacy and mechanism of the candidate were investigated systematically. Results Among the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immunoenhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming candidate molecule CR-T3-SEQ13. Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent anti-HBs antibody response in mice, rabbits and cynomolgus monkeys. Sera and purified polyclonal IgG from the immunised animals neutralised HBV infection in vitro and mediated efficient HBV/hepatitis B virus surface antigen (HBsAg) clearance in the mice. CR-T3-SEQ13-based vaccination induced long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice. The suppressive effects on HBsAg were strongly correlated with the anti-HBs level after vaccination, suggesting that the main mechanism of CR-T3-SEQ13 vaccination therapy was the induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance. Conclusions The novel particulate protein CR-T3-SEQ13 suppressed HBsAg effectively through induction of a humoural immune response in HBV-tolerant mice. This B cell epitope-based therapeutic vaccine may provide a novel immunotherapeutic agent against chronic HBV infection in humans.

中文翻译：

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一种独特的基于 B 细胞表位的颗粒疫苗显示出对小鼠乙型肝炎表面抗原的有效抑制

目的 本研究旨在开发一种基于独特 B 细胞表位的新型治疗性疫苗，并研究其在动物模型中对慢性乙型肝炎 (CHB) 的治疗潜力。方法 在 HBV 耐受小鼠中评估一系列肽和载体蛋白以获得优化的治疗分子。系统地研究了候选物的免疫原性、治疗效果和机制。结果 在本研究评估的含 HBsAg-aa119-125 的肽中，HBsAg-aa113-135（SEQ13）表现出最显着的治疗效果。创造了一种源自圆叶蝙蝠 HBV 核心抗原 (RBHBcAg) 的新型免疫增强病毒样颗粒载体 (CR-T3) 并用于展示 SEQ13，形成候选分子 CR-T3-SEQ13。在这种微粒抗原表面上展示的多拷贝 SEQ13 促进了在小鼠、兔和食蟹猴中诱导有效的抗 HBs 抗体反应。来自免疫动物的血清和纯化的多克隆 IgG 在体外中和了 HBV 感染，并介导了小鼠体内 HBV/乙型肝炎病毒表面抗原 (HBsAg) 的有效清除。基于 CR-T3-SEQ13 的疫苗接种在 HBV 转基因小鼠中诱导了 HBsAg 和 HBV DNA 的长期抑制，并在基于流体动力学的 HBV 携带者小鼠中完全根除病毒。对 HBsAg 的抑制作用与疫苗接种后的抗 HBs 水平密切相关，表明 CR-T3-SEQ13 疫苗接种治疗的主要机制是诱导介导 HBV/HBsAg 清除的 SEQ13 特异性抗体反应。结论 新型颗粒蛋白 CR-T3-SEQ13 通过诱导 HBV 耐受小鼠的体液免疫反应有效抑制 HBsAg。这种基于 B 细胞表位的治疗性疫苗可以提供一种新型的免疫治疗剂来对抗人类慢性 HBV 感染。