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Michler, T. ; Kosinska, A. ; Merdan, O. ; Hagen, P. ; Bunse, T. ; Öz, E.A. ; Su, J. ; Busch, D.H.* ; Mogler, C.* ; Protzer, U.

Long-term antigen reduction does not achieve durable HBV control in mice but enhances therapeutic vaccine efficacy.

JHEP Rep. 8:101943 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Background & Aims: Chronic HBV infection has an increasing death toll, but curative therapies are lacking. The study aimed to determine whether long-term suppression of viral antigens using RNA-interference restores HBV-specific immunity and achieves durable virus control, and how long HBV antigens must be suppressed to enable therapeutic vaccination to restore immunity. Methods: HBV-transgenic or AAV-HBV-infected, HBV-carrier mice were treated for up to 7 months with liver-directed small interfering RNAs (siRNAs) or short-hairpin RNAs (shRNAs) that target all HBV transcripts. The antiviral effect and development of B- and T-cell immunity were evaluated. A subcohort of mice received the heterologous prime/boost therapeutic vaccine, TherVacB, before cessation of siRNA. Results: Continuous siRNA therapy reduced HBsAg by up to 4 log10, but a threshold effect was observed after 12–16 weeks. Suppression of viral antigens for up to 7 months did not lead to spontaneous reconstitution of T-cell immunity; this required stimulation by therapeutic vaccination. Without vaccination, HBV replication rebounded after discontinuation of siRNA therapy, even though HBsAg and HBeAg seroconversion had occurred. However, a longer duration of siRNA pretreatment correlated with increasing interferon type I signaling in the liver. siRNA pretreatment for 8 instead of 3.5 weeks improved the ability of therapeutic vaccination to activate functional antiviral T cells, fully control HBV replication, and significantly reduce the number of HBV-positive hepatocytes (p <0.01 to p <0.001). Conclusions: Our data show that, in addition to suppressing viral antigens, immune stimulation is necessary to achieve long-lasting HBV control after treatment discontinuation. These results will help design clinical trials that can ultimately achieve HBV control. Impact and implications: Drug entities in development to cure chronic hepatitis B include direct-acting antivirals, nucleic acid-based therapeutics, immunotherapies, and combinations thereof. In our study, long-term suppression of HBV in HBV-carrier mice using siRNAs targeting all HBV antigens neither allowed spontaneous reconstitution of T-cell immunity nor sustained HBV control, even when accompanied by anti-HBs seroconversion. However, prolonged viral antigen suppression by siRNA enhanced the efficacy of therapeutic vaccination. Our study highlights that achieving loss of viral parameters from serum, or even anti-HBe/HBs seroconversion, should not represent the ultimate goal of curative therapy, but rather be viewed as a prerequisite that empowers immunostimulatory drugs to induce curative T-cell responses.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Chronic Hepatitis B ; Combination Therapy ; Hbv Cure ; Immunotolerance ; Sirna ; Therapeutic Vaccination
ISSN (print) / ISBN 2589-5559
e-ISSN 2589-5559
Zeitschrift JHEP Reports
Quellenangaben Band: 8, Heft: 10, Seiten: , Artikelnummer: 101943 Supplement: ,
Verlag Elsevier
Institut(e) Institute of Virology (VIRO)