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Su, J. ; Brunner, L.* ; Ates Öz, E. ; Sacherl, J. ; Frank, G.* ; Kerth, H.A. ; Thiele, F. ; Wiegand, M. ; Mogler, C.* ; Aguilar, J.C.* ; Knolle, P.A.* ; Collin, N.* ; Kosinska, A. ; Protzer, U.

Activation of CD4 T cells during prime immunization determines the success of a therapeutic hepatitis B vaccine in HBV-carrier mouse models.

J. Hepatol. 78:15 (2022)

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BACKGROUND & AIMS: Therapeutic vaccination represents a promising approach to cure HBV. We employ a heterologous therapeutic vaccination scheme (TherVacB) comprising a particulate protein-prime followed by modified vaccinia-virus Ankara (MVA) vector-boost. The key determinants required to overcome HBV-specific immune tolerance, however, remained unclear. Here, we unravel the essential role of CD4 T-cell activation during the priming phase for antiviral efficacy of TherVacB. METHODS: Recombinant hepatitis B surface (HBsAg) and core antigen (HBcAg) particles were formulated with different liposome-based or oil-in-water emulsion combination adjuvants containing saponin QS21 and monophosphoryl lipid A (MPL) and compared them to STING-agonist c-di-AMP and conventional alum formulation. Immunogenicity and antiviral effects of protein antigen formulations and the vector boost within TherVacB was evaluated in AAV-HBV infected and HBV-transgenic mice. RESULTS: Combination adjuvant formulations preserved HBsAg and HBcAg integrity for ≥ 12 weeks, promoted human and mouse dendritic cell activation and within TherVacB elicited robust HBV-specific antibody and T-cell responses in wild-type and HBV-carrier mice. Combination adjuvants priming a balanced HBV-specific type 1 and 2 T helper response induced high-titer anti-HBs antibodies, cytotoxic T-cell responses and long-term control of HBV. Lack of a T-cell booster by the MVA vector as well selective CD8 T-cell depletion allowed for a drop of HBsAg mediated mainly by anti-HBs antibodies but resulted in a lack of HBV control. Selective CD4 T-cell depletion during the priming phase of TherVacB resulted in a complete loss of vaccine-induced immune responses and its therapeutic anti-viral effect in mice. CONCLUSIONS: Our results identify CD4 T-cell activation during the priming phase as a key determinant for HBV-specific antibody and CD8 T cell immunity using TherVacB as targeted therapeutic vaccine. IMPACT AND IMPLICATIONS: Therapeutic vaccination is a promising, potentially curative treatment for chronic hepatitis B, but the factors essential to break immune tolerance in HBV carriers and determinants of success remain unclear. Our study provides the first direct evidence that correct priming of HBV-specific CD4 T cells preparing a booster of CD8 T-cell responses determines the success of therapeutic hepatitis B vaccination. Understanding how to fine-tune therapeutic vaccines by the selection of appropriate vaccine components proved essential for its antiviral effect in two preclinical HBV-carrier mouse models and may help to guide the clinical development of therapeutic vaccines for chronic hepatitis B. LAY SUMMARY: Therapeutic vaccination is a promising, potentially curative treatment for chronic hepatitis B. Which factors are essential for breaking immune tolerance in HBV carriers and determine a successful outcome of therapeutic vaccination, however, remains unclear. Our study provides the first direct evidence that efficient priming of HBV-specific CD4 T cells determines the success of therapeutic hepatitis B vaccination in two preclinical HBV-carrier mouse models. Applying an optimal formulation of HBV antigens that allows activating CD4 and CD8 T cells during prime immunization provided the foundation for an antiviral effect of therapeutic vaccination, while depletion of CD4 T cells lead to a complete loss of vaccine-induced antiviral efficacy. Boosting CD8 T cells was important to finally control HBV in these mouse models. Our findings provide important insights into the rational design of therapeutic vaccines to cure chronic hepatitis B.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cd4 T Cells ; Chronic Hepatitis B ; Immunotolerance ; Thervacb ; Combination Adjuvant ; Therapeutic Vaccine; Virus-replication; Immunity; Gene

ISSN (print) / ISBN 0168-8278

e-ISSN 1600-0641

Journal Journal of Hepatology

Quellenangaben Volume: 78, Issue: 4, Article Number: 15

Publisher Elsevier

Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Virology (VIRO)

Grants TRR179
Turkish ministry of education (YLSY)
DZIF
Stiftung der Deutschen Wirtschaft" (sdw, German industrial foundation)
Chinese Scholarship Council (CSC)
Bill and Melinda Gates Foundation
PoC initiative via the Helmholtz Association via EURIPRED, 7th FP-European Commission
European Commission
German Research Foundation (DFG)