The COVID-19 pandemic has revealed the essential role of vaccines in preventing infection and controlling the spread of an infectious disease. However, the established methods for vaccine production cannot achieve a 100 percent protection effect after vaccination. In addition to ethnic and individual differences, the types of vaccine significantly contribute to vaccine efficacy. Since the 1980s, recombinant virus-like particle (VLPs) vaccines (such as the hepatitis B vaccine and the HPV vaccine) have become leaders in the field due to their superior safety, strong immunogenicity and excellent protection rate. However, the VLPs vaccines also have some defects; for example, the antibody level in 5-10 percent of hepatitis B vaccine recipients was unable to reach the immune protection titer (those recipients are collectively referred to as vaccine non-responders). They have a high prevalence of hepatitis B virus infection, which seriously impedes elimination of hepatitis B.

Working model: HBV vaccine induces macrophages to produce high level of IL-1Ra in the draining lymph node, inhibiting Tfh cell activation and antibody production. [Image: IPS]

To overcome this obstacle and provide a key solution, PhD students Lin Xinwen and Li Shuran and postdoctoral fellow Trix Twelkmeyer, who are supervised by Professor Tang Hong at the Institut Pasteur of Shanghai (IPS) of the Chinese Academy of Sciences (CAS), 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 20, 2021.

The study reveals that hepatitis B vaccine and some other particle antigens specifically induce a kind of lymph node specific macrophage, and medullary sinus macrophages (MSM), to produce a cytokine called interleukin-1 receptor antagonist (IL-1Ra), which is the “culprit” 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 the 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 (a process 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 the IL-1Ra gene was knocked out from the macrophages. Similarly, mice injected with IL-1Ra blocking antibody, and then immunized with hepatitis B vaccine, not only improved their antibody titer, but were also significantly protected 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.

These findings provide firm evidence that specific macrophages regulate Tfh/B antibody response levels in the lymph nodes by the production of IL-1Ra. The level of IL-1Ra may serve as new diagnostic criteria for the non-responders of hepatitis B vaccine. 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. 

The work was completed by the IPS, the Hou Baidong research group from the Institute of Biophysics (IBP) of CAS, and the Gong Sitang research group of Guangzhou Women and Children’s Medical Center. Tang Hong (IPS, CAS), Hou Baidong (IBP, CAS) and Li Shuran are the co-corresponding authors of the paper. Lin Xinwen, the PhD student of Tang Hong’s lab (IPS, CAS), and Trix Twelkmeyer, the postdoctoral fellow of the Guangzhou Women and Children’s Medical Center, are the co-first authors of the paper.

For more information, please contact:

Doctor & Professor Tang Hong

E-mail: htang@ips.ac.cn

Institut Pasteur of Shanghai (IPS), Chinese Academy of Sciences

Source: Institut Pasteur of Shanghai (IPS),

Chinese Academy of Sciences