siRNA plus nanovaccine achieves stable functional cure for chronic hepatitis B

Chronic hepatitis B (CHB) remains a significant global health burden, with existing therapies including nucleos(t)ide analogs, interferon, siRNA, and therapeutic vaccines demonstrating limited success in achieving functional cure and often resulting in viral rebound after treatment discontinuation. Addressing this challenge, Professor Zhu's research team at the Institute of Microbiology, Chinese Academy of Sciences has developed an innovative combination therapy. Their approach synergistically combines their proprietary ferritin nanoparticle-preS1 (Ferritin-NP-preS1) therapeutic vaccine with a preclinically validated HBV-specific siRNA. This dual-targeted strategy represents a significant advancement in the pursuit of durable CHB functional cure.

The research team employed an AAV-HBV1.3-infected HBV-carrier mouse model to evaluate their therapeutic strategy. A siRNA agent AD-66810 was administered biweekly for three doses, and the Ferritin-NP-preS1 vaccine was administered biweekly from day 14 for four doses. Serum samples were collected and analyzed until day 393.

HBsAg serum clearance: Ferritin-NP-preS1 monotherapy resulted in HBsAg serum clearance in about 62.5% of mice at the end point; siRNA monotherapy induced transient antigen reduction but rapid rebound post-cessation. Combination therapy achieved HBsAg serum clearance in 100% of mice, which was sustained for 11 months by the end of the study.

​​

HBsAb generation: Ferritin-NP-preS1 monotherapy generated HBsAb in about 37.5% of mice at the end point; siRNA rarely induced HBsAb. Combination therapy generated HBsAb in 80% of mice, with HBsAb levels sustained for at least 11 months until the end of the study.

In addition, this study also showed that combination therapy resulted in efficient seroconversion from preS1 to anti-preS1, and approximately 70% clearance rates for serum HBV DNA and liver HBcAg.

These compelling results reported in this study set the foundation for a promising strategy for CHB functional cure, encouraging researchers to pursue further clinical validation.

About Author:

Dr. Mingzhao Zhu is currently a tenured Professor at the Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences. His research interests mainly include lymphoid tissue microenvironment, T cell development and response, and vaccine immunology. His recent research has been published in Nature, Nature Nanotechnology, Nature Communications, Journal of Clinical Investigation, eLife, Cellular & Molecular Immunology, Journal of Immunology, etc. His achievement has been selected as one of the Top Ten Advances in Chinese Science (2020), has won CAS Outstanding Science and Technology Achievement Prize (2022). Dr. Zhu is a recipient of 'National Science Fund for Distinguished Young Scholars', and a recipient of the 'Scholar Award' of the WuXi AppTec Life Chemistry Research Award. He is currently the secretary-general of the Infection and Immunity Branch of the Chinese Biophysical Society, member of the Standing Committee of the Tumor Immunology and Biotherapy Branch of the Chinese Society of Immunology, and member of the Immunology Committee of the Chinese Pathophysiological Society. He serves as an Editorial Board Member of Science Bulletin.