Abstract
Chronic hepatitis B infection (CHB) is characterized by sub-optimal T cell responses to viral antigens. A therapeutic vaccine capable of restoring these immune responses could potentially improve HBsAg seroconversion rates in the setting of direct acting antiviral therapies. A yeast-based immunotherapy (Tarmogen) platform was used to make a vaccine candidate expressing hepatitis B virus (HBV) X, surface (S), and Core antigens (X-S-Core). Murine and human immunogenicity models were used to evaluate the type and magnitude of HBV-Ag specific T cell responses elicited by the vaccine. C57BL/6J, BALB/c, and HLA-A*0201 transgenic mice immunized with yeast expressing X-S-Core showed T cell responses to X, S and Core when evaluated by lymphocyte proliferation assay, ELISpot, intracellular cytokine staining (ICS), or tumor challenge assays. Both CD4+ and CD8+ T cell responses were observed. Human T cells transduced with HBc18–27 and HBs183–91 specific T cell receptors (TCRs) produced interferon gamma (IFNγ following incubation with X-S-Core-pulsed dendritic cells (DCs). Furthermore, stimulation of peripheral blood mononuclear cells (PBMCs) isolated from CHB patients or from HBV vaccine recipients with autologous DCs pulsed with X-S-Core or a related product (S-Core) resulted in pronounced expansions of HBV Ag-specific T cells possessing a cytolytic phenotype. These data indicate that X-S-Core-expressing yeast elicit functional adaptive immune responses and supports the ongoing evaluation of this therapeutic vaccine in patients with CHB to enhance the induction of HBV-specific T cell responses.
Highlights
Chronic hepatitis B virus infection (CHB) is a major worldwide public health concern
The development of a therapeutic vaccine to induce an immune response in CHB patients that parallels that observed in acute self-resolved infection is likely to be a key requirement of successful immunotherapy for this disease
This study provides evidence for the potential of GS4774 to be used as a hepatitis B virus (HBV)- therapeutic vaccine based on 3 lines of evidence: 1) the induction of HBV Ag-specific CD4+ and CD8+ T cells and anti-tumor responses in multiple mouse models; 2) the activation of T cells that recognize epitopes of known importance in clearance of acute infection, and; 3) the ability to elicit HBV Agspecific T cell responses ex vivo in both healthy and chronicallyinfected human donor cells
Summary
Chronic hepatitis B virus infection (CHB) is a major worldwide public health concern. The nucleos(t)ide analog-based polymerase inhibitors such as entecavir and TDF effectively inhibit HBV genome replication, but result in the loss of HBsAg (HBsAg seroconversion) in less than 10% of subjects after many years of therapy, requiring life-long treatment to maintain viral suppression [4,5,43]. These considerations underscore the need for improved therapies for CHB that are safe and able to provide durable immune control and enhance rates of HBsAg seroconversion with a finite treatment duration
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