A novel therapeutic HBV vaccine candidate induces strong polyfunctional cytotoxic T cell responses in mice

Background & Aims: Current standard-of-care suppresses HBV replication, but does not lead to a functional cure. Treatment aiming to cure chronic hepatitis B (CHB) is believed to require the induction of strong cellular immune responses, such as by therapeutic vaccination. Methods: We designed a therapeutic HBV vaccine candidate (YF17D/HBc-C) using yellow fever vaccine YF17D as a live attenuated vector to express HBV core antigen (HBc). Its ability to induce potent cellular immune responses was assessed in a mouse model that supports flavivirus replication. Results: Following a HBc protein prime, a booster of YF17D/HBc-C was found to induce vigorous cytotoxic T cell responses. In a direct head-to-head comparison, these HBc-specific responses exceeded those elicited by adenovirus-vectored HBc. Target specific T cells were not only more abundant, but also showed a higher degree of polyfunctionality, with HBc-specific CD8+ T cells producing interferon c and tumour necrosis factor a in addition to granzyme B. This immune phenotype translated into a superior cytotoxic effector activity toward HBc-positive cells in YF17D/HBc-C vaccinated animals in vivo. Conclusions: The results presented here show the potential of YF17D/HBc-C as a vaccine candidate to treat CHB, and warrant follow-up studies in preclinical animal models of HBV persistence in which other candidate vaccines have been unable to achieve a sustained virologic response. Lay summary: Resolution of CHB requires the induction of strong cellular immune responses. We used the yellow fever vaccine as a vector for HBV antigens and show that it is capable of inducing high levels of HBV-specific T cells that produce multiple cytokines simultaneously and are cytotoxic in vivo. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).