Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice

Zhou

Human Vaccines & Immunotherapeutics

et al. 2017

Self Cite

Adjuvants are considered a necessary component for HBV therapeutic vaccines but few are licensed in clinical practice due to concerns about safety or efficiency. In our recent study, we established that a combination protocol of 3-day pretreatments with GM-CSF before a vaccination (3 × GM-CSF+VACCINE) into the same injection site could break immune tolerance and cause over 90% reduction of HBsAg level in the HBsAg transgenic mouse model. Herein, we further investigated the therapeutic potential of the combination in AAV8–1.3HBV-infected mice. After 4 vaccinations, both serum HBeAg and HBsAg were cleared and there was a 95% reduction of HBV-positive hepatocytes, in addition to the presence of large number of infiltrating CD8+ T cells in the livers. Mechanistically, the HBV-specific T-cell responses were elicited via a 3 × GM-CSF+VACCINE-induced conversion of CCR2-dependent CD11b+ Ly6Chi monocytes into CD11b+CD11c+ DCs. Experimental depletion of Ly6Chi monocytes resulted in a defective HBV-specific immune response thereby abrogating HBV eradication. This vaccination strategy could lead to development of an effective therapeutic protocol against chronic HBV in infected patients.

Section: Methodsmentioning

confidence: 99%

“…In contrast, we observed that the 3 × GM-CSF+VACCINE treatment achieved 90% reduction of HBsAg level in the model via the activation of HBsAg specific CD8 + T cells. 18 …”

Section: Introductionmentioning

confidence: 99%

Enrichment of Ly6C^hi monocytes by multiple GM-CSF injections with HBV vaccine contributes to viral clearance in a HBV mouse model

Zhou

Human Vaccines & Immunotherapeutics

et al. 2017

Self Cite

“…Although HBV-transgenic mice, which was reported to persistently express distinct HBV antigens or produce infectious virions (Chisari et al, 1987 ; Wirth et al, 1995 ; Schirmbeck et al, 2000 ), have been used to study HBV immunopathogenesis and test numerous drugs for HBV infection, they are inherently tolerant to transgene products (Araki et al, 1989 ; Moriyama et al, 1990 ; Guidotti et al, 1995 ; Larkin et al, 1999 ; Wang et al, 2016 ). Therefore, the model is not suitable for studying HBV vaccines.…”

Section: Establishment Of Viral Hepatitis Models By Hgdmentioning

confidence: 99%

Technical Improvement and Application of Hydrodynamic Gene Delivery in Study of Liver Diseases

et al. 2017

Development of an safe and efficient in vivo gene delivery method is indispensable for molecular biology research and the progress in the following gene therapy. Over the past few years, hydrodynamic gene delivery (HGD) with naked DNA has drawn increasing interest in both research and potential clinic applications due to its high efficiency and low risk in triggering immune responses and carcinogenesis in comparison to viral vectors. This method, involving intravenous injection (i.v.) of massive DNA in a short duration, gives a transient but high in vivo gene expression especially in the liver of small animals. In addition to DNA, it has also been shown to deliver other substance such as RNA, proteins, synthetic small compounds and even viruses in vivo. Given its ability to robustly mimic in vivo hepatitis B virus (HBV) production in liver, HGD has become a fundamental and important technology on HBV studies in our group and many other groups. Recently, there have been interesting reports about the applications and further improvement of this technology in other liver research. Here, we review the principle, safety, current application and development of hydrodynamic delivery in liver disease studies, and discuss its future prospects, clinical potential and challenges.

“…The undesirable negative impact of GM-CSF as an adjuvant was solved by using our recently published protocol in which 3-day pretreatments with GM-CSF were given before a vaccination into the same site of animals to elicit potent immune responses. This protocol overcame the immune tolerance and over 90% reduction of HBsAg level was observed in the HBsAg transgenic mouse model [ 28 ]. While the outcome remains exciting, the protocol by its original design was too complex for potential use in humans as a therapeutic vaccine.…”

Section: Introductionmentioning

confidence: 99%

Clearance of HBeAg and HBsAg of HBV in mice model by a recombinant HBV vaccine combined with GM-CSF and IFN-α as an effective therapeutic vaccine adjuvant

Zhang

et al. 2018

Oncotarget

Self Cite

Chronic hepatitis B virus (CHB) infection is a significant public threat. Current interferon-α (IFN-α) based therapies and anti-viral drugs have failed to clear the infection in the majority of CHB patients and animal models. In our previous study, we established a combined protocol that employed a 3-day pretreatment with granulocyte-macrophage colony stimulating factor (GM-CSF) prior to a standard HBV vaccine. It achieved a 90% reduction of HBsAg level in the HBsAg transgenic mouse model. This protocol, while effective, remains too complex for clinical use. In this study, we formulated a new regimen by combining GM-CSF, IFN-α and a recombinant HBV vaccine (GM-CSF/IFN-α/VACCINE) into a single preparation and tested its efficacy in a HBV infection model. After four vaccinations, both serum HBeAg and HBsAg were cleared, accompanied by a 95% reduction of HBV+ hepatocytes and the presence of a large number of infiltrating CD8+ T cells in the liver. Mechanistically these robust responses were initiated by a vaccine-induced conversion of CCR2-dependent CD11b+Ly6Chi monocytes into CD11b+CD11c+ DCs. This finding sheds light on the potential mechanism of action of the GM-CSF-based vaccine adjuvant and provides definable markers for clinical assessment during future testing of such highly potent vaccine protocols in HBV patients.