EBioMedicine. 2019 Nov 1. pii: S2352-3964(19)30713-3. doi: 10.1016/j.ebiom.2019.10.043. [Epub ahead of print]
Evaluation of antiviral-_ passive - active immunization ("sandwich") therapeutic strategy for functional cure of chronic hepatitis B in mice.
Shi B1, Wu Y2, Wang C2, Li X2, Yu F2, Wang B2, Yang Z3, Li J2, Liang M4, Wen Y5, Ying T6, Yuan Z7.
Author information
1
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China; Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Rd, Jinshan District, Shanghai, PR China.
2
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China.
3
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China; Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Xuhui District, Shanghai, PR China.
4
National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China.
5
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China. Electronic address: [email protected].
6
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China. Electronic address: [email protected].
7
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 138 Dong'an Rd, Xuhui District, Shanghai, PR China. Electronic address: [email protected].
Abstract
BACKGROUND:
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.
