A therapeutic HBV vaccine containing a checkpoint modifier enhances CD8+ T cell and antiviral responses
Mohadeseh Hasanpourghadi, Mikhail Novikov, Robert Ambrose, Arezki Chekaoui, Dakota Newman, ZhiQuan Xiang, Andrew D. Luber, Sue L. Currie, XiangYang Zhou, Hildegund C.J. Ertl
Mohadeseh Hasanpourghadi, Mikhail Novikov, Robert Ambrose, Arezki Chekaoui, Dakota Newman, ZhiQuan Xiang, Andrew D. Luber, Sue L. Currie, XiangYang Zhou, Hildegund C.J. Ertl
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Research Article Immunology Vaccines

A therapeutic HBV vaccine containing a checkpoint modifier enhances CD8+ T cell and antiviral responses

Abstract

In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8+ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires CD8+ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that augments CD8+ T cell responses. The vaccine is based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, which targets conserved and highly immunogenic regions of the viral polymerase and core antigens fused to HSV gD. The vaccine was tested with and without gD in mice for immunogenicity, and in an AAV8-1.3HBV vector model of antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8+ T cell responses. In a surrogate model of HBV infection, a single intramuscular injection achieved pronounced and sustained declines of circulating HBV DNA copies and HBV surface antigen; both inversely correlated with HBV-specific CD8+ T cell frequencies in spleen and liver.

Authors

Mohadeseh Hasanpourghadi, Mikhail Novikov, Robert Ambrose, Arezki Chekaoui, Dakota Newman, ZhiQuan Xiang, Andrew D. Luber, Sue L. Currie, XiangYang Zhou, Hildegund C.J. Ertl

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Figure 4

Vaccine immunogenicity in AAV8-1.3HBV–infected mice.

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Vaccine immunogenicity in AAV8-1.3HBV–infected mice. (A and B) Experimen...
(A and B) Experimental outline shown in Figure 3A. (A) Frequencies of IFN-γ–producing CD8+ T cells or (B) CD4+ T cells in blood were tested for 5–10 mice 10 weeks after vaccination. Significant differences with P values are displayed on lines above graphs. (C–G) Experimental outline shown in Figure 3C. (C) Frequencies of IFN-γ–producing CD8+ T cells or (D) CD4+ T cells in spleens and livers of 5 experimental mice and 2 control mice 12 weeks after vaccination. P values shown above the lines were calculated by 2-way ANOVA. (E) Frequencies of tetramer+ (tet+) CD8+ T cells in spleens and livers of 5 experimental mice and 2 naive control mice injected with 1 × 1010 vg of AAV8-1.3HBV, vaccinated 4 weeks later with 1 × 1010 vp of the indicated vectors or nothing, and tested 12 weeks later. P values calculated by 2-way ANOVA are shown above the lines. (F) Percentage of tet+CD8+ cells of 5 mice per group expressing PD-1 or LAG-3. Gates were set based on expression on resting CD44–CD8+ cells. P values calculated by 2-way ANOVA are shown above the lines. (G) Spearman’s correlations between frequencies of IFN-γ-producing HBV-specific CD8+ T cells in spleens or livers and viral loads based on intracellular cytokine staining (ICS) of 15 samples. R2 and P values are shown in the upper right corner of the graphs.