This new pandemic of COVID-19 has revealed the essential role of the vaccine in preventing infection and controlling the spread of the epidemic. However, the established methods for vaccine production can not achieve a 100% protection effect after vaccination. In addition to ethnic and individual differences, the types of vaccine contribute to the vaccine efficacy significantly. Since the 1980s, recombinant virus-like particle (VLPs) vaccine (such as hepatitis B vaccine and HPV vaccine) has become the leading type of vaccine in the field due to the superior safety, strong immunogenicity and excellent protection rate. However, the VLPs vaccine also has some defects, for example, the antibody level in 5-10% of hepatitis B vaccine recipients was unable to reach the immune protection titer (collectively referred to as vaccine non-responders). These non-responders have a high prevalence of hepatitis B virus infections, which seriously impede the progress of the elimination of hepatitis B.
To overcome this obstacle, PhD students LIN Xinwen and LI Shuran, postdoctoral fellow Trix twelkmeyer supervised by Prof. TANG Hong at Institute Pasteur of Shanghai, the Chinese Academy of Sciences, published an online article entitled "Homeostatic regulation of T follicular helper and antibody response to particle antigens by IL-1Ra of medullary sinus macrophage origin" in PNAS on April 20th 2021 - which provides the key answer.
This study revealed that hepatitis B vaccine and some other particle antigens specifically induce a kind of lymph nodes specific macrophage, medullary sinus macrophages (MSM), to produce a cytokine called interleukin-1 receptor antagonist (IL-1ra), which is the "culprit" of inhibiting B cells to produce high-level antibodies. The characteristic of the virus-like particle vaccine is similar to that of the virus. It will enter an organ called draining lymph nodes once inside the body, where it contacts the subcapsular lymph sinus macrophages (SCS) of the lymph nodes initially, and then spreads to MSM.
Further study identified that IL-1ra was highly expressed in hepatitis B vaccine activated MSM cells. IL-1ra can inhibit the ability of T cells (TFH) in B follicles to stimulate B cells to mature and produce antibodies (also known as germinal center response of draining lymph nodes). Therefore, the antibody response of hepatitis B vaccine was significantly increased after the macrophages were removed or IL-1Ra gene was knocked out from macrophages. Similarly, mice injected with IL-1ra blocking antibody, and then immunized with hepatitis B vaccine, not only improve the antibody titer, but also significantly protect mice from hepatitis B virus infection. Because MSM is responsible for filtering and clearing large particles of foreign substances in lymph nodes, not only the antibody response of hepatitis B vaccine but also that of inactivated vaccines such as hepatitis A vaccine is also regulated by IL-1ra.
The work was completed by the Chinese Academy of Sciences Institute Pasteur of Shanghai,HOU Baidong research group of the Chinese Academy of Sciences Institute of biophysics, and GONG Sitang research group of Guangzhou Women and Children Medical Center. TANG Hong(Institute Pasteur of Shanghai, the Chinese Academy of Sciences), HOU Baidong (Institute of biophysics, the Chinese Academy of Sciences) and LI Shuran are the co-corresponding authors of the paper. LIN Xinwen, the PhD student of TANG Hong’s lab (Institute Pasteur of Shanghai, the Chinese Academy of Sciences), and Trix Twelkmeyer, the postdoctoral fellow of Guangzhou Women and Children’s Medical Center are the co-first authors of the paper.
These findings provide firm evidence that specific macrophages regulate Tfh / antibody response level in the lymph nodes by the production of IL-1ra. The level of IL-1ra may serve as a new diagnostic criteria for the non-responders of Hepatitis B vaccine, and the findings also provide a new basis for the development of vaccine adjuvants to improve the immunogenicity and protection effect of particle vaccines such as hepatitis B vaccine.
Picture Description: working model: HBV vaccine induces macrophages to produce high level of IL-1ra in the draining lymph node, inhibiting Tfh cells activation and antibody production. (Image by IPS).
The work was completed by Chinese Academy of Sciences Institute Pasteur of Shanghai,Baidong Hou research group of Chinese Academy of Sciences Institute of biophysics,and Sitang Gong research group of Guangzhou Women and Children Medical Center. Hong Tang (Institute Pasteur of Shanghai, Chinese Academy of Sciences), Baidong Hou (Institute of biophysics, Chinese Academy of Sciences) and Shuran Li are the co-corresponding authors of the paper. Xinwen Lin, the PhD student of Hong Tang’s lab (Institute Pasteur of Shanghai, Chinese Academy of Sciences), and Trix Twelkmeyer, the postdoctoral fellow of Guangzhou Women and Children’s Medical Center are the co-first authors of the paper.
The research is supported by the Ministry of Science and Technology, the National Natural Science Foundation of China and the Chinese Academy of Sciences.
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