One of the reasons why chronic hepatitis B is difficult to treat is that the body has developed a certain degree of specific immune tolerance (no immune response to HBV) to the hepatitis B virus (HBV). How to break the immune tolerance, so that the body can produce a normal immune response to clear the virus, is a hot spot in recent hepatitis B research. Prior to 1995 it was generally accepted in the medical community that the purpose of vaccines was to prevent disease. With the development of immunology, a new use of vaccines was discovered – the treatment of some refractory diseases, and in the last decade of the 20th century, theoretical and practical discussions on therapeutic vaccines were conducted. Since then, vaccines have served both preventive and therapeutic purposes. Vaccines with therapeutic effects are called therapeutic vaccines and belong to the category of specific active immunotherapy. Of course, therapeutic vaccines are significantly different from traditional prophylactic vaccines in that prophylactic vaccines mainly act on organisms that have never been infected, and naturally structured pathogen components (e.g., viral proteins) can be used directly as vaccine antigens, whereas therapeutic vaccines act on organisms that have been infected with pathogens and are mostly persistently infected, and naturally structured pathogen components are generally difficult to induce a specific immune response (e.g., hepatitis B). Therefore, the preparation of therapeutic vaccines requires molecular design to reconstitute new immune molecules that are structurally similar to, but different from, the natural pathogenic components. Therapeutic hepatitis B vaccines are specific immunotherapeutic agents for chronic HBV infection, achieved by structural modification of prophylactic vaccines or addition of novel adjuvants. The main strategies currently followed by the global R&D community include: T-cell activation using vaccines against pre-S and S antigens to clear HBV-infected hepatocytes; DNA vaccines; and the use of prophylactic HBV vaccines in combination with anti-HBV immunoglobulin (HBIG). The main ones being tested are protein vaccines, DNA vaccines and peptide vaccines, which can enhance humoral and cellular immunity and facilitate the body’s clearance of the virus. However, the hot spot is also the difficulty, and no mature product has been released so far in the world. In 1988, a research group at Fudan University began to study an immunogenic complex composed of hepatitis B surface antigen (HBsAg) and HBIG, with which to activate the body’s immune response, thereby reducing the virus level or even clearing it. After the completion of the animal model test, the safety clinical trial was passed, and the phase II clinical trial (done on some patients and completed at individual sites, mainly to see the efficacy and drug effectiveness) started from the end of 2003. Now we are ready to start Phase III clinical trials (to further expand the number of cases, determine the dosage and clarify the efficacy). The above-mentioned therapeutic hepatitis B vaccine is the “furthest along” in China to date and is considered to be the most promising vaccine to be developed. However, the medical community is only cautiously optimistic about the prospects for a therapeutic hepatitis B vaccine, because it is still in clinical trials and success and failure are unknown, and the effects and side effects and indications will not be clearly known until the clinical trials are completed. As to when patients can actually use the therapeutic hepatitis B vaccine, I am afraid that it will take time. A trial period should be more than 4 years, and the successful trial should be approved by the state for industrial production before the vaccine becomes available for use. Even the most optimistic estimate of a therapeutic hepatitis B vaccine for clinical use will take at least 5 to 10 years. The therapeutic hepatitis B vaccine has a long way to go to get out of the laboratory. It is also important to note that a therapeutic hepatitis B vaccine should be viewed objectively. Its role is limited, it does not replace antiviral drugs, and there is no scientific basis for the claim that it completely removes HBV. In other words, it is not a panacea for a complete cure for hepatitis B either. But it is, after all, a “new weapon” to be added to the “arsenal” of hepatitis B treatment, and can play a role that is difficult to replace with other drugs. The combination of immunotherapy and antiviral drugs, and the application of effective immunomodulators in antiviral therapy to break immune tolerance, can inhibit or remove the virus more effectively from multiple pathways, achieving high efficiency and low recurrence.