Engineered therapeutic nanovaccine against chronic hepatitis B virus infection

Chronic hepatitis B (CHB), caused by persistent hepatitis B virus (HBV) infection, significantly increases the risk of leading to liver diseases. Despite the successful development and implementation of HBV prophylactic vaccines for several decades, the development of therapeutic vaccine, a substantially potential strategy to eradicate HBV and achieve CHB cure, remains a great challenge. Herein, we applied flash nanocomplexation (FNC) technology to prepare nanovaccines with narrow size distribution and high encapsulation via the charge complexation between chitosan and heparin to encapsulate recombinant hepatitis B virus surface antigen (rHBsAg) or core antigen (rHBcAg), with CpG as adjuvant. The two nanovaccines enhanced the uptake of antigen and adjuvant into Raw264.7 cells and their co-administration further promoted maturation and activation of bone marrow-derived dendritic cells (BMDCs). Meanwhile, they exhibited excellent lymph nodes (LNs) targeting ability, draining to proximal and distal LNs with prolonged retention time, following subcutaneous injection. Co-administered nanovaccines could break immune tolerance and restore HBV-specific immune responses. In a mouse model of CHB, 90% and 80% of mice achieved hepatitis B virus surface antigen (HBsAg) seroclearance and hepatitis B virus surface antibody (HBsAb) seroconversion, respectively. Moreover, the vaccines induced long-term immune memory in HBV-cured mice to protect them from HBV reinfection. Thus, this work offers a promising and translational alternative for therapeutic CHB vaccine.