Sequential mRNA vaccine-enabled quadruple therapy induces functional cure of HBV in rAAV8-1.3HBV carrier mice
4
Issued Date
2026-01-01
Resource Type
ISSN
22113835
eISSN
22113843
Scopus ID
2-s2.0-105042592857
Journal Title
Acta Pharmaceutica Sinica B
Rights Holder(s)
SCOPUS
Bibliographic Citation
Acta Pharmaceutica Sinica B (2026)
Suggested Citation
Dong S., Dai J., Hong Y., Guo X., Ji W., Zhang Y., Hu H., Zhang Z., Yan H., Liu J., Deng M., Yu Y., Ying S., Zhang Q., You J., Manonai J., Zou Y., Qiu Y., Lou Y. Sequential mRNA vaccine-enabled quadruple therapy induces functional cure of HBV in rAAV8-1.3HBV carrier mice. Acta Pharmaceutica Sinica B (2026). doi:10.1016/j.apsb.2026.06.013 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/117581
Title
Sequential mRNA vaccine-enabled quadruple therapy induces functional cure of HBV in rAAV8-1.3HBV carrier mice
Corresponding Author(s)
Other Contributor(s)
Abstract
Chronic hepatitis B (CHB) functional cure remains difficult to achieve with current treatments, primarily due to hepatitis B virus (HBV)-induced multilayered immune tolerance. We proposed a sequential strategy to gradually reduce viral antigen load, enhance antigen presentation, and promote cytotoxic T-cell memory formation to overcome this immune barrier: (1) viral suppression with antisense oligonucleotides (ASO) and entecavir (ETV); (2) dendritic cell (DC) priming with interferon α (IFNα); and (3) induction of cytotoxic memory T cell responses with a codon-optimized messenger RNA (mRNA) vaccine (encoding full-length HBV large S protein) delivered via chitosan nanoemulsion (CNE). In recombinant adeno-associated virus serotype 8 with 1.3 copies of the hepatitis B virus genome (rAAV8-1.3HBV) carrier mice, this regimen induced durable functional cure in 50% of mice for 17 weeks. A key finding was that functional cure depended on achieving hepatitis B surface antigen (HBsAg) levels below 100 IU/mL before IFNα administration. This threshold was necessary to permit IFNα-mediated DC activation, which enabled vaccine-expanded and functionally restored HBV-specific CD8<sup>+</sup> T cells, alongside dissolution of immunosuppressive networks. Non-responders (pre-IFNα HBsAg >100 IU/mL) displayed impaired DC–T cell interactions. These results provide a mechanistic and staged pharmacological strategy to overcome HBV immune tolerance and advance toward functional cure.