IFNL3-adjuvanted HCV DNA vaccine reduces regulatory T cell frequency and increases virus-specific T cell responses

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Background & Aims: Although direct-acting antiviral (DAA) treatment results in a sustained virologic response (SVR) in most patients with chronic HCV infection, they are at risk of reinfection. Moreover, the immune system is not completely normalized even after SVR (e.g. increased regulatory T [Treg] cell frequency). We developed a DNA vaccine, GLS-6150, to prevent re-infection of patients with DAA-induced SVR and evaluated its safety and immunogenicity in individuals with chronic HCV infection. Methods: GLS-6150 consists of plasmids encoding HCV nonstructural proteins (NS3-NS5A) and adjuvant IFNL3. The vaccine was administered 4 times at 4-weekly intervals to 3 groups (1, 3, or 6 mg/vaccination; n = 6 per group), followed by a 6 mg boost at 24 weeks (n = 14). Peripheral blood T cell responses were evaluated by interferon (IFN)-gamma enzyme-linked immunospot assays, intracellular cytokine staining, and major histocompatibility complex class-I (MHC-I) dextramer staining. Treg cell frequency was assessed by flow cytometry. Results: Severe adverse events or vaccine discontinuation were not reported. The IFN-gamma spot-forming cells specific to NS3-NS5A were increased by GLS-6150. Both CD4(+) and CD8(+) T cells produced multiple cytokines. However, the frequency and phenotype of HCV-specific MHC-I dextramer(+)CD8(+) T cells were not changed. Interestingly, the frequency of Treg cells, particularly activated Treg cells, was decreased by GLS-6150, as expected from previous reports that IFNL3 adjuvants decrease Treg cell frequency. Ex vivo IFN-lambda 3 treatment reduced Treg frequency in pre-vaccination peripheral blood mononuclear cells. Finally, Treg cell frequency inversely correlated with HCV-specific, IFN-gamma-producing T cell responses in the study participants. Conclusions: We demonstrate that GLS-6150 decreases Treg cell frequency and enhances HCV-specific T cell responses without significant side effects. A phase I clinical trial of GLS-6150 is currently underway in patients with DAA-induced SVR. Lay summary: Although direct-acting antivirals (DAAs) are successfully used for the treatment of chronic hepatitis C virus (HCV) infection, a prophylactic HCV vaccine needs to be developed, especially for patients who achieve a sustained virologic response. In the current study, we show that a DNA vaccine (GLS-6150) was safe and increased HCV-specific T cell responses. A clinical trial is underway to test this vaccine in patients with a sustained virologic response following DAA therapy.
Publisher
ELSEVIER
Issue Date
2020-07
Language
English
Article Type
Article
Citation

JOURNAL OF HEPATOLOGY, v.73, no.1, pp.72 - 83

ISSN
0168-8278
DOI
10.1016/j.jhep.2020.02.009
URI
http://hdl.handle.net/10203/276098
Appears in Collection
MSE-Journal Papers(저널논문)
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