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Boosting viral-specific immunotherapy for chronic hepatitis B treatment

Cellular & Molecular Immunology volume 18, pages 2586–2587 (2021)Cite this article

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Hepatitis B virus (HBV)-specific antibody-producing B cells and functional HBV-specific helper and cytotoxic T cells are the primary influence of the clinical outcome of acute or chronic HBV infection. However, patients with chronic hepatitis B (CHB) exhibit a profound defect in both innate and adaptive immunity. Current antiviral treatment efficiently suppresses viral replication and tempers immune-mediated injuries in patients with CHB but cannot directly reduce the hepatitis B e-antigen (HBeAg) or surface antigen (HBsAg) load, of which the latter is closely associated with poor restoration of specific T-cell immunity against HBV [1]. Some immunotherapy  approaches, including therapeutic vaccines, have been tested in proof-of-concept clinical trials for patients with CHB, and evidence-based data have been expected for the past two decades. A recent study published in Hepatology revealed that εPA-44, a new therapeutic vaccine, showed encouraging activity in a phase II trial [2]. Monotherapy with 900-µg εPA-44 achieved a high HBeAg seroconversion rate of up to 38.8% and safety with a finite medication duration in HBeAg-positive patients, and the combinational response rate of HBeAg seroconversion, serum alanine transaminase (ALT) normalization, and HBV DNA < 2000 IU/mL was significantly higher in the vaccine-treated group (18.1%) than in the placebo group (5.0%) in a dose-and-time-dependent manner. Therefore, this trial, led by Dr. Yuzhang Wu, Director of the Institute of Immunology, Army Medical University, provides strong evidence that a well-designed therapeutic vaccine can feasibly evoke clinical benefit in patients with CHB. A Phase III trial (ChiCTR2100043708) is currently ongoing to confirm the potential of this vaccine.

Boosting host adaptive immunity against chronic HBV infection has been demonstrated to be a rational regimen for the treatment of CHB. First, multiple strong adaptive immune responses are closely associated with viral resolution in acute self-limited HBV infection [3]. Second, in chronic HBV infection, spontaneous viral control, as evidenced by HBV DNA suppression and HBsAg seroconversion, occurs in only ~1% of all chronic HBV-infected individuals every year due to the restoration of viral-specific T- and B-cell immune responses against HBV [4]. HBV-specific immunity in acute self-limited individuals and patients with CHB is similar in that it can effectively control viral replication and clear HBsAg. Interestingly, some clinical studies have shown that the transfusion of HBV-specific immunity can cure CHB in recipients with leukemia [5, 6], who received bone marrow transplantation from a hepatitis B surface antibody (HBsAb)-positive donor, suggesting that functional HBV-specific immune responses can be transplanted to eliminate chronic HBV infection. However, it is very difficult to identify human lymphocyte antigen (HLA)-matched donors with HBsAb positivity for the millions of patients with CHB. Therefore, this therapeutic approach is not feasible in practice. Instead, some therapeutic vaccines, including GS-4774 (NCT01943799, NCT02174276), VAC-AND (NCT00536627), NASVAC [7], and YIC [8], have been investigated in phase I, phase II, and phase III clinical trials, but none have achieved a cure for CHB.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81721002 and 82101935).

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  1. Senior Department of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039, China

    Jin Fan, Jun-Liang Fu & Fu-Sheng Wang

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  1. Jin Fan
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Correspondence to Fu-Sheng Wang.

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Fan, J., Fu, JL. & Wang, FS. Boosting viral-specific immunotherapy for chronic hepatitis B treatment. Cell Mol Immunol 18, 2586–2587 (2021). https://doi.org/10.1038/s41423-021-00788-4

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