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

Abstract

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 re-infection. 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 non-structural 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)-γ 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-γ 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-λ3 treatment reduced Treg frequency in pre-vaccination peripheral blood mononuclear cells. Finally, Treg cell frequency inversely correlated with HCV-specific, IFN-γ-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.

CLINICAL TRIAL NUMBER:

NCT02027116.

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.

• Authors: Ji Won Han, Pil Soo Sung, Seon-Hui Hong, Hoyoung Lee, June Young Koh, Hyojin Lee, Scott White, Joel N Maslow, David B Weiner, Su-Hyung Park, Moonsup Jeong, Jeong Heo, Sang Hoon Ahn, Eui-Cheol Shin
• Journal: Journal of hepatology (J Hepatol) Vol. 73 Issue 1 Pg. 72-83 (07 2020) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 32088322 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Adjuvants, Immunologic
• Antiviral Agents
• interferon-lambda, human
• Vaccines, DNA
• Interferons

Topics

• Adjuvants, Immunologic (pharmacology)
• Antiviral Agents (therapeutic use)
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Drug Monitoring (methods)
• Female
• Hepacivirus (genetics, immunology, isolation & purification)
• Hepatitis C, Chronic (blood, drug therapy, immunology)
• Humans
• Interferons (pharmacology)
• Male
• Middle Aged
• Monitoring, Immunologic (methods)
• Secondary Prevention (methods)
• Sustained Virologic Response
• T-Lymphocytes, Regulatory (immunology)
• Vaccines, DNA (administration & dosage, adverse effects, immunology)
• Virus Activation (drug effects, immunology)