New advances in the therapeutic hepatitis B vaccine in Nat Nanotech, Zhu Mingzhao group reveal editing new mechanisms for the targeting of nano-vaccine immunization in lymph nodes.

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 [1].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.on March 2, 2020, Zhu Mingzhao, Key Laboratory of infection and immunology, Institute of Biophysics, Chinese Academy of Sciences, published a long article "dual targeting nanoparticle vaccine elicits a therapeutic antibody response against chronic diseases B" in Nature Nanotechnology.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.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 a new immunological mechanism of targeted delivery, transport, and induction of TFH and B cell activation response by nanoparticles antigen, which has important theoretical value of immunity and medical application prospect. the study was completed by the Institute of Biophysics, Chinese Academy of Sciences. researcher Zhu Mingzhao is the corresponding author. He is a graduate of Zhu Mingzhao's research group. Wang Wenjun, an assistant researcher, is the first author. this work has been greatly assisted by many experts in related fields, including Professor Fu Yangxin of Southwest Medical Center, researcher Li Wenhui of Beijing Institute of life sciences, academician Yan Xiyun, researcher Zhu Ping and researcher Peng Hua from Institute of Biophysics, and Wang Shan, director of Oncology Department of children's Hospital Affiliated to Chongqing Medical University. in addition, a number of partners provided experimental materials or technical support, including Professor Qi Hai of Tsinghua University, researcher Hou Baidong and researcher fan Kelong of Institute of Biophysics, and Senior Laboratory Engineer of animal center of Institute of biophysics. 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 [2-4], and also developed a simple and rapid construction technology of Click vaccine [5]. 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 1: ferritin nanoparticle vaccine synergistically targets lymph node macrophages and dendritic cells to induce high-level antibody response and persistent immune memory. recruitment notice of Zhu Mingzhao group, Institute of Biophysics, Chinese Academy of Sciences, carried out relevant research on "microenvironment of lymphoid tissue and development and function of T lymphocytes". the specific research directions include: (1) the development and function of lymphoid tissue microenvironment; (2) epigenetic regulation of T cell development and function; (3) vaccine immunology based on lymphoid tissue microenvironment. for the basic information of the research group, we are now recruiting a postdoctoral / specially appointed research assistant. 1. Basic requirements: 1. Be interested in scientific research and devote himself to scientific research; 2. Obtain a doctor's degree in related fields recently or soon, have basic experimental skills in cell biology, molecular biology and biochemistry, and have rich experience in epigenetics and bioinformatics; 3. Publish high-level papers as the first author in related majors; 4 Good Chinese and English writing skills and scientific research communication skills; 5, integrity, practical work, love and dedication, rigorous style of study, active, innovative, good at communication, cooperative spirit. 2. Job responsibilities: 1. Undertake scientific research tasks (epigenetic regulation of T cells by microenvironment signals of lymphoid tissue); 2. Assist the project leader in guiding postgraduates and interns; 3. Independently or assisting the project leader in applying for the project. 3. Welfare benefits: 1. According to the regulations of the Academy of Sciences and research institutes, salary and welfare benefits are provided according to the individual's research background and experience; 2. Competitive performance salary is provided according to the actual contribution; 3. Excellent talents can apply for "special research assistant subsidy project of Chinese Academy of Sciences". IV. application methods and requirements: applicants should provide the following materials: resume, research work experience, representative papers and other relevant materials that can prove their ability level, and the names and contact information of the two referees. as of the date of this notice, those who meet the requirements of the post can apply for the job until they are suitable. please send relevant materials to: ibpzhulab@126.com 。 please indicate "application name" in the subject of the email. original link: plate maker: xiaoxianzi references 1. 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