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

@article{oz2026high,
  title = {{High HBV antigen levels drive loss of vaccine-induced CD8+ T-cell function in carrier mice over time}},
  author = {Edanur Ates Öz and Jinpeng Su and Merve Gültan and Margaret Tulessin and Nikolas Müller and Hélène Anne Kerth and Swati Singh and Carolin Mogler and Katja Steiger and Jochen Wettengel and Dirk Busch and Percy Knolle and Ulrike Protzer and Anna Kosinska},
  journal = {JHEP Reports},
  year = {2026},
  month = sep,
  doi = {10.1016/j.jhepr.2026.102033},
  url = {https://doi.org/10.1016/j.jhepr.2026.102033},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - High HBV antigen levels drive loss of vaccine-induced CD8+ T-cell function in carrier mice over time
AU  - Edanur Ates Öz
AU  - Jinpeng Su
AU  - Merve Gültan
AU  - Margaret Tulessin
AU  - Nikolas Müller
AU  - Hélène Anne Kerth
AU  - Swati Singh
AU  - Carolin Mogler
AU  - Katja Steiger
AU  - Jochen Wettengel
AU  - Dirk Busch
AU  - Percy Knolle
AU  - Ulrike Protzer
AU  - Anna Kosinska
PY  - 2026
DA  - 2026/09/10
JO  - JHEP Reports
DO  - 10.1016/j.jhepr.2026.102033
UR  - https://doi.org/10.1016/j.jhepr.2026.102033
AB  - 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.
SN  - 2589-5559
ER  -