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Ates Öz, E. ; Su, J. ; Gültan, M. ; Tulessin, M.* ; Müller, N. ; Kerth, H.A. ; Singh, S. ; Mogler, C.* ; Steiger, K.* ; Wettengel, J.M. ; Busch, D.* ; Knolle, P.* ; Protzer, U. ; Kosinska, A.

High HBV antigen levels drive loss of vaccine-induced CD8+ T-cell function in carrier mice over time.

JHEP Rep. 8:102033 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Background & Aims: Chronic HBV infection persists because of the dysfunction of virus-specific CD8+ T cells. High HBV antigen levels impair the success of therapeutic vaccination. The influence of viral titers on vaccine-induced immunity remains to be fully elucidated. We compared the kinetics of vaccine responses in low- and high-titer HBV carrier mice to identify tipping points and dissect the decisive steps determining the outcome of therapeutic vaccination. Methods: We established low- and high-titer persistent HBV replication in the livers of immunocompetent C57BL/6J mice using adeno-associated-virus (AAV)-HBV and administered TherVacB, a heterologous protein prime/modified vaccinia Ankara boost vaccine. Serum and liver samples were collected during vaccination and subsequently longitudinally to analyze HBV-specific immune responses and viral parameters. Results: HBV antigen levels before vaccination did not significantly influence the hepatitis B surface antibody (anti-HBs) response (p >0.9); however, they had a significant effect on the vaccine-induced CD8 T-cell response. TherVacB induced activated core-specific CD8+ T cells that efficiently infiltrated the liver in low- and high-titer HBV carriers. Low-titer HBV carrier mice achieved sustained viral clearance and memory T-cell formation, whereas high-titer mice exhibited only transient viral reduction, followed by CD8+ T-cell dysfunction and failure to clear the infection. The persistence of HBV infection and constant exposure to high antigen levels led to the overexpression of exhaustion markers, such as PD-1 and TOX (p <0.01), as well as the co-stimulatory receptor 4-1BB (p <0.01). Core-specific CD8+ T cells remained trapped in the liver, progressively lost their effector function, and were eventually eliminated. Conclusions: These findings identify critical time points that influence vaccine-induced CD8 T-cell responses, suggesting that early intervention targeting T-cell dysfunction may enhance therapeutic vaccination outcomes in chronic HBV infection. Impact and implications: This study demonstrates that baseline HBV antigen load critically determines the durability of vaccine-induced CD8+ T-cell immunity. Although therapeutic vaccination initially elicited liver-infiltrating, HBV-specific CD8+ T cells irrespective of the viral titer, only low-titer infection permitted sustained viral clearance and memory T-cell formation. In high-titer HBV carriers, persistent antigen exposure drove progressive T-cell exhaustion and deletion, resulting in transient viral control and treatment failure. Importantly, the data identify a critical time window in which early intervention to prevent or reverse T-cell dysfunction may be decisive. Clinically, these findings support combining therapeutic vaccination with antigen-lowering or immunomodulatory strategies applied early to achieve durable immune control in chronic HBV infection.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Antigen-induced T-cell Dysfunction ; Cd8 T-cell Dysfunction ; Chronic Hepatitis B ; Hbv-specific Cd8+ T Cells ; Therapeutic Vaccination ; Thervacb
ISSN (print) / ISBN 2589-5559
e-ISSN 2589-5559
Zeitschrift JHEP Reports
Quellenangaben Band: 8, Heft: 12, Seiten: , Artikelnummer: 102033 Supplement: ,
Verlag Elsevier
Institut(e) Institute of Virology (VIRO)