PMID- 37781393 OWN - NLM STAT- MEDLINE DCOM- 20231003 LR - 20231003 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Induction of broad multifunctional CD8+ and CD4+ T cells by hepatitis B virus antigen-based synthetic long peptides ex vivo. PG - 1163118 LID - 10.3389/fimmu.2023.1163118 [doi] LID - 1163118 AB - INTRODUCTION: Therapeutic vaccination based on synthetic long peptides (SLP((R))) containing both CD4+ and CD8+ T cell epitopes is a promising treatment strategy for chronic hepatitis B infection (cHBV). METHODS: We designed SLPs for three HBV proteins, HBcAg and the non-secreted proteins polymerase and X, and investigated their ability to induce T cell responses ex vivo. A set of 17 SLPs was constructed based on viral protein conservation, functionality, predicted and validated binders for prevalent human leukocyte antigen (HLA) supertypes, validated HLA I epitopes, and chemical producibility. RESULTS: All 17 SLPs were capable of inducing interferon gamma (IFNɣ) production in samples from four or more donors that had resolved an HBV infection in the past (resolver). Further analysis of the best performing SLPs demonstrated activation of both CD8+ and CD4+ multi-functional T cells in one or more resolver and patient sample(s). When investigating which SLP could activate HBV-specific T cells, the responses could be traced back to different peptides for each patient or resolver. DISCUSSION: This indicates that a large population of subjects with different HLA types can be covered by selecting a suitable mix of SLPs for therapeutic vaccine design. In conclusion, we designed a set of SLPs capable of inducing multifunctional CD8+ and CD4+ T cells ex vivo that create important components for a novel therapeutic vaccine to cure cHBV. CI - Copyright (c) 2023 Jansen, de Beijer, Luijten, Kwappenberg, Wiekmeijer, Kessler, Pieterman, Bouzid, Krebber, de Man, Melief and Buschow. FAU - Jansen, Diahann T S L AU - Jansen DTSL AD - Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. FAU - de Beijer, Monique T A AU - de Beijer MTA AD - Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. FAU - Luijten, Robbie J AU - Luijten RJ AD - Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. FAU - Kwappenberg, Kitty AU - Kwappenberg K AD - ISA Pharmaceuticals B.V., Oegstgeest, Netherlands. FAU - Wiekmeijer, Anna-Sophia AU - Wiekmeijer AS AD - ISA Pharmaceuticals B.V., Oegstgeest, Netherlands. FAU - Kessler, Amy L AU - Kessler AL AD - Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. FAU - Pieterman, Roel F A AU - Pieterman RFA AD - Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. FAU - Bouzid, Rachid AU - Bouzid R AD - Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. FAU - Krebber, Willem-Jan AU - Krebber WJ AD - ISA Pharmaceuticals B.V., Oegstgeest, Netherlands. FAU - de Man, Robert A AU - de Man RA AD - Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. FAU - Melief, Cornelis J M AU - Melief CJM AD - ISA Pharmaceuticals B.V., Oegstgeest, Netherlands. FAU - Buschow, Sonja I AU - Buschow SI AD - Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230913 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 82115-62-6 (Interferon-gamma) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Histocompatibility Antigens Class II) RN - 0 (Peptides) RN - 0 (HLA Antigens) RN - 0 (Epitopes, T-Lymphocyte) SB - IM MH - Humans MH - *Hepatitis B virus MH - *CD4-Positive T-Lymphocytes MH - Interferon-gamma/metabolism MH - Histocompatibility Antigens Class I/metabolism MH - CD8-Positive T-Lymphocytes MH - Histocompatibility Antigens Class II/metabolism MH - Peptides MH - HLA Antigens/metabolism MH - Epitopes, T-Lymphocyte PMC - PMC10534072 OTO - NOTNLM OT - HBV OT - HLA OT - T cell OT - chronic hepatitis B OT - synthetic long peptide OT - therapeutic vaccination COIS- Author CM, WK, AW and KK were employed by the company ISA Pharmacuticals B.V. SB, DJ, MB, AW, WK and CM are listed as inventors on a patent application related to the work in this manuscript on novel long peptide antigens for treatment of hepatitis B related disease, filled by ISA Pharmaceuticals B.V. CM and WK have a stock appreciation right in the issued share capital of ISA Pharmaceuticals B.V. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from ISA Pharmaceuticals B.V. The funder had the following involvement in the study: study concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, statistical analysis, obtained funding. EDAT- 2023/10/02 06:42 MHDA- 2023/10/03 06:47 PMCR- 2023/01/01 CRDT- 2023/10/02 04:44 PHST- 2023/02/10 00:00 [received] PHST- 2023/08/18 00:00 [accepted] PHST- 2023/10/03 06:47 [medline] PHST- 2023/10/02 06:42 [pubmed] PHST- 2023/10/02 04:44 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1163118 [doi] PST - epublish SO - Front Immunol. 2023 Sep 13;14:1163118. doi: 10.3389/fimmu.2023.1163118. eCollection 2023.