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Immunogenicity of adenovirus-vector vaccine targeting hepatitis B virus: non-clinical safety assessment in non-human primates

Zhang, Xuefeng, Wang, Jing, Lu, Jing, Li, Rongrong, Zhao, Shuli
Virology journal 2018 v.15 no.1 pp. 111
Adenoviridae, Hepatitis B virus, Macaca fascicularis, T-lymphocytes, animals, antibodies, body temperature, dose response, epitopes, immunogenicity, immunotherapy, interferon-gamma, interleukin-2, liver, patients, safety assessment, serum albumin, toxicity, vector vaccines, virion, viruses
BACKGROUND: A new promising therapeutic approach has emerged for patients chronically infected by the hepatitis B virus (HBV) with the development of a non-replicative adenovirus vector vaccine candidate (Ad-HBV). The vaccine encodes a fusion protein composed of a truncated HBV core protein, mutated polymerase protein, and two envelope domains. In this study, we assessed the immunogenicity of Ad-HBV administered to cynomolgus monkeys during a non-clinical safety assessment. METHODS: The virus was subcutaneously administered at 1.0 × 10⁹ viral particles (VP)/animal (low-dose group), 1.0 × 10¹⁰ VP/animal (mid-dose group), and 1.0 × 10¹¹ VP/animal (high-dose group); the control groups were administered an Ad5-null virus (1.0 × 10¹¹ VP/animal) and saline only. RESULTS: Except for inflammatory cell infiltration under the skin at the injection sites and transient elevation of body temperature and serum albumin, no Ad-HBV-related toxic effects were noted in any treatment group. Moreover, interferon (IFN)-γ enzyme-linked immunospot assays showed that Ad-HBV induced the targeting of T cells to a broad spectrum of HBV-specific epitopes spanning all three of the selected HBV immunogens (core, polymerase, and envelope domains) in a dose-dependent manner. Although anti-Ad antibody was produced in all groups (except for the saline control), the antibody titers were significantly lower in the high-dose Ad-HBV group than in the group that received the same dose of the Ad-null empty vector. In addition, the IFN-γ and IL-2 expression levels in the liver were significantly improved for the mid-dose, high-dose, and Ad-null control group (p < 0.05), but not for the low-dose group. CONCLUSIONS: Taken together, this safety assessment indicates that the Ad-HBV candidate vaccine is a potent specific immunotherapeutic agent, supporting its further clinical development as an anti-HBV infection vaccine.