Evaluation of antiviral - passive - active immunization (“sandwich”) therapeutic strategy for functional cure of chronic hepatitis B in mice

Abstract

a b s t r a c tBackground: Chronic Hepatitis B (CHB) remains a major problem for global public health. Viral persistence and immune defects are the two major reasons for CHB, and it was hypothesized that based on a transient clearance of serum viral DNA and HBsAg "window stage", active immunization against hepatitis B virus (HBV) might initiate effective host immune responses versus HBV to achieve functional cure of CHB. Methods: Two experimental mouse models that mice hydrodynamic injected HBV DNA or infected with recombinant AAV/HBV were used. The "sandwich" therapeutic effect by using a potent human anti-HBsAg neutralizing monoclonal antibody (G12) in combination with antiviral drug tenofovir disoproxil fumarate (TDF), followed by active immunization with HBsAg-HBsAb (mYIC) was evaluated. Findings: A single G12 injection rapidly cleared serum HBsAg in HDI-HBV carrier mice, with a synergistic effect in decreasing viral DNA load when TDF was given orally. When both serum viral DNA and HBsAg load became low or undetectable, mYIC was administered. A more effective clearance of viral DNA and HBsAg was observed and serum HBsAb was developed only in these "sandwich"-treated mice. Efficient intrahepatic anti-HBV immune responses were also observed in these mice, including the formation of aggregates of myeloid cells with CD8 + T cells and increased TNF-α, granzyme B production. Interpretation:The "sandwich" combination therapy not only efficiently decreased HBsAg and HBV DNA levels but also induced effective cellular and humoral immunity, which may result in functional cure of CHB. Research in context section Evidence before this studyPersistence of HBV cccDNA and various host immune defects were shown as the two main obstacles for HBV clearance. Blocking a single target will not be sufficient to achieve functional cure of CHB. A very small percentage of CHB patients could attain "functional cure" by antiviral treatment fol- * Corresponding authors. .cn (Z. Yuan). lowed by interferon therapy. Therapeutic vaccination for CHB showed substantial efficacy. A humanized HBsAb G12 could efficiently block HBV infection and decrease HBsAg level in mice model. Added value of this studyThis research showed that when both serum viral DNA and HB-sAg load became low or undetectable by antiviral and HBsAb treatment, therapeutic vaccine (mYIC) add on induced effective, host humoral and intrahepatic cellular anti-HBV immune responses, with more rapid and efficient clearance of HBV and HBsAg.

Prophylactic Strategy Against De Novo Hepatitis B Virus Infection for Pediatric Recipients Who Receive Hepatitis B Core Antibody–Positive Liver Grafts

“…(15,16) The mechanism relies in the theory that high HBsAb levels would neutralize the potential viral antigen coming from the HBcAb-positive grafts. (17,18) We adopted this strategy and showed similar results that a titer of HBsAb ≥ 1000 IU/L at the time of transplantation delayed the decay of HBsAb titer after transplantation and was associated with lower risk of de novo HBV infection in our pediatric population. However, the blood loss and transfusion during LT and the use of immunosuppressive agents led to the decay of HBsAb titer after transplantation.…”

Restoration of a functional antiviral immune response to chronic HBV infection by reducing viral antigen load: if not sufficient, is it necessary?

“…In agreement with their immune effector functions, several studies have demonstrated that administration of neutralizing HBV antibodies in multiple HBVpersistent infection mouse models significantly reduced or depleted HBV virions and subviral particles in blood (73)(74)(75)(76). In particular, depletion of circulating HBsAg in AAV-HBV transduced mice enabled the induction of HBV-specific B and T cell immune responses by distinct vaccination strategies (57,77). Clinically, several human monoclonal antibodies against HBsAg had been shown to significantly reduce viral load and HBsAg antigenemia (72,78).…”

A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic Hepatitis B Virus Infection

“…The “sandwich” strategy combines an anti-HBsAg neutralizing antibody with an antiviral drug followed by vaccines for specific active immunization ( 36 ). Shi et al have proven that this strategy has the potential to achieve a functional cure for HBV infection ( 26 ). The potential application of mL (G12-IgG) in the combination therapy for HBV infection was underlined by its sustained and progressive effect on reducing HBsAg levels.…”

“…Various therapies targeting innate immunity and HBV-specific immune responses are under clinical investigation ( 24 ). Among these medications, anti-HBsAg antibodies are potent candidates ( 25 – 27 ). Antibody therapies against HBsAg remarkably reduced circulating HBsAg and HBV DNA levels in several mouse models and restored adaptive immunity functionality that was defective due to CHB.…”

“…Antibody therapies against HBsAg remarkably reduced circulating HBsAg and HBV DNA levels in several mouse models and restored adaptive immunity functionality that was defective due to CHB. However, anti-HBsAg antibodies only suppressed HBsAg within a finite duration ( 26 ).…”