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

Robbert Boudewijns; Ji Ma; Johan Neyts; Kai Dallmeier

doi:10.1016/j.jhepr.2021.100295

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

JHEP Rep. 2021 Apr 22;3(4):100295. doi: 10.1016/j.jhepr.2021.100295. eCollection 2021 Aug.

Authors

Robbert Boudewijns¹, Ji Ma¹, Johan Neyts¹, Kai Dallmeier¹

Affiliation

¹ KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium.

Abstract

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 γ and tumour necrosis factor α 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.

Keywords: CAR-T, chimeric antigen receptor T cells; CFSE, carboxy-fluorescein succinimidyl ester; CHB, chronic hepatitis B; CTL, cytotoxic T lymphocyte; Chronic hepatitis B; DCs, dendritic cells; ELISPOT, enzyme-linked ImmunoSpot; GzmB, granzyme B; HBV; HBc, HBV core antigen; HBp, HBV polymerase antigen; HBs, HBV surface antigen; ICS, intracellular cytokine staining; IFNγ, interferon γ; MHC, major histocompatibility complex; NanoLuc, nanoluciferase; STAT2, signal transducer and activator of transcription 2; TNFα, tumour necrosis factor α; Therapeutic vaccination; YF, yellow fever; Yellow fever vaccine; aa, amino acids; cccDNA, covalently closed circular DNA; ifnar, IFN-α/β receptor; pfu, plaque-forming units; rHBc, recombinant HBc; t-SNE, t-stochastic neighbour embedding; wt, wild-type.