Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
Virion Therapeutics LLC, 7 Creek Bend Ct, Newark, DE, 19711, USA.
Virol J. 2021 Dec 7;18(1):242. doi: 10.1186/s12985-021-01712-y.
Chronic hepatitis B virus (HBV) infection (CHB) is a significant public health problem that could benefit from treatment with immunomodulators. Here we describe a set of therapeutic HBV vaccines that target the internal viral proteins.
Vaccines are delivered by chimpanzee adenovirus vectors (AdC) of serotype 6 (AdC6) and 7 (AdC7) used in prime only or prime-boost regimens. The HBV antigens are fused into an early T cell checkpoint inhibitor, herpes simplex virus (HSV) glycoprotein D (gD), which enhances and broadens vaccine-induced cluster of differentiation (CD8) T cell responses.
Our results show that the vaccines are immunogenic in mice. They induce potent CD8 T cell responses that recognize multiple epitopes. CD8 T cell responses increase after a boost, although the breadth remains similar. In mice, which carry high sustained loads of HBV particles due to a hepatic infection with an adeno-associated virus (AAV)8 vector expressing the 1.3HBV genome, CD8 T cell responses to the vaccines are attenuated with a marked shift in the CD8 T cells' epitope recognition profile.
Our data show that in different stains of mice including those that carry a human major histocompatibility complex (MHC) class I antigen HBV vaccines adjuvanted with a checkpoint inhibitor induce potent and broad HBV-specific CD8 T cell responses and lower but still detectable CD4 T cell responses. CD8 T cell responses are reduced and their epitope specificity changes in mice that are chronically exposed to HBV antigens. Implications for the design of therapeutic HBV vaccines are discussed.
慢性乙型肝炎病毒（HBV）感染（CHB）是一个重大的公共卫生问题，可以通过免疫调节剂治疗获益。在此，我们描述了一组针对内部病毒蛋白的治疗性 HBV 疫苗。
疫苗通过使用的血清型 6（AdC6）和 7（AdC7）的 chimpanzee 腺病毒载体（AdC）进行传递，仅用作初免或初免-加强方案。HBV 抗原融合到早期 T 细胞检查点抑制剂单纯疱疹病毒（HSV）糖蛋白 D（gD）中，这增强和拓宽了疫苗诱导的分化群（CD8）T 细胞反应。
我们的结果表明，这些疫苗在小鼠中具有免疫原性。它们诱导出针对多种表位的强大 CD8 T 细胞反应。在加强后，CD8 T 细胞反应增加，尽管广度相似。在携带由于表达 1.3HBV 基因组的腺相关病毒（AAV）8 载体而导致肝脏感染的高持续 HBV 颗粒负荷的小鼠中，疫苗对 CD8 T 细胞的反应被削弱，CD8 T 细胞的表位识别谱发生明显改变。
我们的数据表明，在包括携带人类主要组织相容性复合体（MHC）I 类抗原的不同小鼠品系中，用检查点抑制剂佐剂的 HBV 疫苗可诱导出强大且广泛的 HBV 特异性 CD8 T 细胞反应，以及较低但仍可检测到的 CD4 T 细胞反应。在慢性暴露于 HBV 抗原的小鼠中，CD8 T 细胞反应减少，其表位特异性发生变化。讨论了治疗性 HBV 疫苗设计的意义。
