한빛사논문
- 조회2,067
Ji Won Han1,∗, Pil Soo Sung1,2,∗, Seon-Hui Hong3,∗, Hoyoung Lee3, June Young Koh1, Hyojin Lee4, Scott White5, Joel N. Maslow4, David B. Weiner6, Su-Hyung Park1,3, Moonsup Jeong4, Jeong Heo7, Sang Hoon Ahn8, Eui-Cheol Shin1,3
1 Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
2 Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
3 Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea
4 GeneOne Life Science, Inc., Seoul 06060, Republic of Korea
5 Inovio Pharmaceuticals, Plymouth Meeting, PA 19462, USA
6 Wistar Institute, Philadelphia, PA 19104, USA
7 Department of Internal Medicine, College of Medicine, Pusan National University, Busan 49241, Republic of Korea
8 Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
Corresponding author: Jeong Heo, Sang Hoon Ahn, Eui-Cheol Shin
*These authors contributed equally to this work.
Abstract
Background & Aims
Although direct-acting antiviral (DAA) treatment results in a sustained virologic response (SVR) in most patients with chronic hepatitis C virus (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 persons with chronic HCV infection (NCT02027116).
Methods
GLS-6150 consists of plasmids encoding HCV non-structural proteins (NS3-NS5A) and adjuvant IFNL3. The vaccine was administered four times at 4-week intervals to three 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 IFN-γ enzyme-linked immunospot assays, intracellular cytokine staining, and 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, 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 PBMCs. Finally, Treg cell frequency inversely correlated with HCV-specific, IFN-γ-producing T-cell responses in the study subjects.
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 subjects with DAA-induced SVR (NCT03674125).
Key words
chronic hepatitis C; DNA vaccine; T cells; regulatory T cell; IFNL3
논문정보
TOP52020년 후보
- Research article
- 2020년 02월 (BRIC 등록일 2020-03-09)
- 국내(교신)+국외 연구진
- 의약학 > 면역의학
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