# Anti–PD-L1–IFN-α–adjuvanted HBsAg vaccine overcomes HBV immune tolerance through targeting both DCs and macrophages

## TL;DR

A new vaccine adjuvant helps break immune tolerance in chronic hepatitis B by activating both B and T cells, potentially leading to a functional cure.

## Contribution

The study introduces a novel anti–PD-L1–IFN-α fusion protein adjuvant that activates dual immune pathways to overcome HBV tolerance.

## Key findings

- Coimmunization with aPD-L1–IFN-α and rHBsAg activates macrophages and dendritic cells to break immune tolerance.
- The adjuvant induces both anti-HBsAg antibodies and HBsAg-specific CD8+ T cell responses without systemic toxicity.
- Efficacy depends on PD-L1 cis-targeting and IFN-α signaling in antigen-presenting cells.

## Abstract

Recombinant hepatitis B surface antigen (rHBsAg) vaccine with various adjuvants fails to break T and B cell tolerance in hosts with chronic hepatitis B (CHB). This study aims to explore the mechanisms to break immune tolerance that allows the host to respond to rHBsAg, achieving a cure for CHB. We engineered an anti–PD-L1–IFN-α (aPD-L1–IFN-α) heterodimeric fusion protein to allow rHBsAg to rejuvenate T and B cell responses in hepatitis B virus–tolerant (HBV-tolerant) mice. S.c. coimmunization with aPD-L1–IFN-α and rHBsAg significantly enhanced antigen uptake and maturation of both macrophage and dendritic cell (DC) subsets in draining lymph nodes. Macrophages drove early B cell activation, while cDC1s primed CD8+ T cells, breaking tolerance and leading to both B cell and cytotoxic T lymphocyte (CTL) differentiation. This strategy elicited not only anti-HBsAg neutralizing antibodies but also HBsAg-specific CD8+ T cell responses, achieving a functional cure without systemic toxicity. The efficacy of the aPD-L1–IFN-α adjuvant depended on both PD-L1 cis-targeting and IFN-α receptor signaling in antigen-presenting cells. These findings establish aPD-L1–IFN-α as a translatable adjuvant to break the strong tolerance induced by CHB, providing a dual-pathway strategy to induce HBV-specific T and B cell responses.

The aPD-L1-IFNα fusion protein adjuvant, when subcutaneously co-administered with HBsAg vaccine, breaks HBV-induced immune tolerance, activates HBsAg-specific immune responses, and offers the potential for achieving a functional cure in chronic hepatitis B.