The study reveals a new mechanism of immune to the targeting of lymph nodes.

On March 2, Zhu Mingzhao, Key Laboratory of infection and immunity, Institute of Biophysics, Chinese Academy of Sciences, published an article paper in Nature Nanotechnology: dual targeting nanoparticle vaccine elicits a therapeutic antibody response against chronic diseases B.in this study, we designed a hepatitis B virus (HBV) PreS1 nano vaccine based on ferritin nanoparticles. In the mouse model, it induced high-level, high affinity, persistent antibody response and immune memory, which not only had excellent preventive effect, but also achieved functional cure and HBsAg seroconversion in the treatment model, and significantly reduced HBV cccDNA.this study further revealed the new immunological mechanism of ferritin nanoparticles antigen actively targeted recognition, transport, and induction of TFH and B cell activation response by lymph node signr1 + antigen-presenting cells.HBV infection is one of the major global public health problems.there are about 260 million people with chronic hepatitis B virus infection in the world, and nearly one million people die of liver failure, liver cirrhosis and hepatocellular carcinoma caused by chronic hepatitis B every year.although the preventive hepatitis B vaccine has achieved remarkable results in clinical application, so far, there is no effective therapeutic hepatitis B vaccine on the market.among them, the most challenging problem is how to break through the long-term established immune tolerance in patients with chronic hepatitis B infection, induce effective and sustained immune response, obtain functional cure, and even completely eliminate cccDNA.as a new functional target of therapeutic hepatitis B vaccine, HBV PreS1 has recently obtained conceptual validation.however, PreS1 is a weak immunogenic functional epitope. How to fully and reasonably mobilize the body's immune system and induce high-efficiency antibody response against the weak immunogenic epitopes is still a key problem at present, and also a common problem in the field of vaccine immunology.virus like particles (as well as ferritin which has been paid more and more attention in recent years) and other nano particle carriers have been widely valued and recognized for improving the immunogenicity and antibody response of antigens.but its immunological mechanism is not very clear. For a long time, traditional cognition such as lymph node targeted delivery, ideal antigen display density and so on, as well as the trimer conformation antigen display of ferritin particle carrier have restricted the improvement and optimization of this kind of vaccine.in this study, the researchers designed ferritin np-pres1 nano vaccine by using the ferritin nano click vaccine technology established by the research group.in the mouse model, the antibody response was induced 150 times higher than that in the control group after two times of immunization, and lasted for at least 8 months, and the antibody response level was about 600 times higher than that of the control group at the second immunization.in aav-hbv1.3 infected mice model, the vaccine not only has excellent preventive and protective effect, but also has excellent therapeutic effect. It significantly reduces the levels of HBV DNA and HBsAg in peripheral blood, and decreases the levels of HBcAg and cccDNA in liver. Some mice get functional cure and HBsAg seroconversion (negative for HBsAg and DNA in peripheral blood and positive for anti HBS).further studies on immunological mechanism showed that ferritin nanoparticles actively targeted signr1 + macrophages and signr1 + dendritic cells resident in mouse lymph nodes, respectively, which promoted the activation of B cells and TFH cells, and synergistically induced antibody production.this targeting property of signr1 + cells was also verified by clinical samples of human lymph nodes (human DC-SIGN is the homologous molecule of mouse signr1).interestingly, the researchers also found that signr1 + macrophages located in the lymphatic sinuses can carry ferritin nanoantigen, migrate to the lymph follicles (B cell area), transfer the antigen to B cells, and promote the activation of B cells; CXCR5 gene knockout macrophages can not migrate to lymphatic follicles and can not effectively activate B cells. this is completely different from the long-standing hypothesis that lymphatic sinus macrophages transfer nanoparticle antigen to B cells through endocytosis / exocytosis or cell membrane flow. therefore, this study not only reported a therapeutic hepatitis B vaccine with significant effect and clinical transformation potential, but also revealed the new immunological mechanism of nanoparticle antigen targeted delivery, transport, induction of TFH and B cell activation response, which has important immunologic theoretical value and medical application prospect. the study was completed by the Institute of biophysics. researcher Zhu Mingzhao is the corresponding author, Zhu Mingzhao is a graduate of master's degree and doctoral program, and now assistant researcher Wang Wenjun is the first author. this work has been greatly assisted by many experts in related fields, including Professor Fu Yangxin of Southwest Medical Center of the United States, Li Wenhui, researcher of Beijing Institute of life sciences, Yan Xiyun, researcher Zhu Ping and Peng Hua, academician of Chinese Academy of Sciences and researcher of Institute of Biophysics, and Wang Shan, director of oncology surgery of children's Hospital Affiliated to Chongqing Medical University. in addition, a number of partners provided experimental materials or technical support, including Qi Hai, Professor of Tsinghua University, Hou Baidong and fan Kelong, researchers of the Institute of biophysics. Senior Laboratory Technician Shi Xiang of animal center of Institute of Biophysics provided organization and coordination guarantee at the critical moment of project progress. this work is supported by the Chinese Academy of Sciences, the National Natural Science Foundation of China, and the Ministry of science and technology. ZHU Mingzhao's research group has been committed to the research of vaccine immunology based on the immune microenvironment of lymphoid tissue, and has developed a variety of nano vaccines targeting lymph nodes and antigen-presenting cells, and also developed a simple and rapid construction technology of click vaccine. these studies have improved the level and effect of vaccine immune response, revealed the new mechanism of vaccine immunology, and provided new ideas for vaccine research and development. figure: ferritin nanoparticles vaccine synergistically targets lymph node macrophages and dendritic cells, inducing high-level antibody response and lasting immune memory. source: Institute of Biophysics, Chinese Academy of Sciences