Hepatitis B is a major global health issue caused by the hepatitis B virus (HBV), which attacks the liver and can cause both acute and chronic diseases. It is estimated that 257 million people worldwide are chronic HBV carriers and have a high risk of developing liver disease, cirrhosis and hepatocellular carcinoma (HCC). Approximately one million patients die from these late complications each year. Although conventional HBsAg vaccination has gained great success in prevention of hepatitis B virus infection, a therapeutic vaccine is still lacking. HBV preS1 has been suggested as a unique target for therapeutic vaccine development. However, due to the poor immunogenicity of preS1, a clinically translatable vaccine design that could induce efficient therapeutic antibody response is not available.

Fig. 1 Ferritin NP vaccine coordinately targets lymph node resident SIGNR1+ macrophages and dendritic cells, induces a high-level and persistent antibody response and immune memory. [IMAGE: DR. ZHU MINGZHAO’S GROUP]

Given the crucial role of lymph node (LN) antigen presenting cells (APCs) in the induction of adaptive immune responses, it is not surprising they are quite often targeted for vaccine design. In fact, LN APC-targeting has been frequently considered to be a valuable feature for many nanomaterial-based vaccines. However, given the complex composition of APCs and the diversified functions of different APC subsets, the specific roles of different APC subsets during nanoparticle vaccine immunization appears to be only minimally and vaguely understood. Moreover, it is less clear how to target them in a coordinated manner for an efficient adaptive immune response.

In the current study, the scientists found that ferritin nanoparticle (NP) based vaccine can coordinately target SIGNR1+ resident dendritic cells and lymphatic sinus macrophages in the LNs for effective Tfh response and B cell activation and antibody production, leading to an impressive therapeutic effect against chronic HBV infection.

In naive mice, this ferritin-preS1 NP vaccine induced a robust response that was 150-fold higher and more persistent (235 days) anti-preS1 than the control preS1 vaccine, with a superb memory response upon a boost immunization at day 270. The vaccination led to a significant reduction of HBV load in the peripheral blood upon AAV-HBV1.3 infection. Furthermore, in AAV-HBV1.3 carrier mice, ferritin-preS1 NP vaccine induced a high anti-preS1 response similar to that in naive mice and significantly reduced HBV load in both peripheral blood (HBsAg, HBV DNA) and livers (HBcAg and cccDNA). Moreover, in four out of seven mice in the ferritin NP-preS1 group, sera HBV DNA dropped to undetectable levels. Those mice also showed barely detectable HBsAg and significant amount of anti-HBs, an indicator for functional cure.

Mechanistically, the ferritin NP was first revealed to be able to target distinct SIGNR1+ myeloid cells for antibody response. While resident SIGNR1+ dendritic cells captured and processed NP antigens for Tfh induction, lymphatic sinus associated SIGNR1+ macrophages served as an NP antigen depot and migrated and transferred antigens to follicular regions for B cell activation in a CXCR5-dependent manner, suggesting a novel mode of NP antigen transfer via CXCR5-dependent macrophage migration.

This study uncovers a previously unrecognized mechanism of the coordination of lymph node resident cells for antibody response engaged by ferritin NP vaccine and offers a promising translatable vaccination strategy for the functional cure of chronic hepatitis B. The above research result was published by the research group led by Doctor Zhu Mingzhao from the Institute of Biophysics, Chinese Academy of Sciences in Nature Nanotechnology on March 2, 2020.

Fig. 1 Ferritin NP vaccine coordinately targets lymph node resident SIGNR1+ macrophages and dendritic cells, inducing a high-level and persistent antibody response and immune memory. [IMAGE: DR. ZHU MINGZHA'S GROUP]

For more information, please contact:

Dr. Zhu Mingzhao

Institute of Biophysics, Chinese Academy of Sciences

E-mail: zhumz@ibp.ac.cn

Source: Dr. Zhu Mingzhao’s Group of Key Laboratory of Infection and Immunity Development,

Institute of Biophysics, Chinese Academy of Sciences