In a dose escalation trial, 17 patients were vaccinated with viral vectors encoding hepatitis C virus (HCV) NS antigens fused to the MHC-II-associated invariant chain (Ii). The vaccine was well tolerated and did not induce Ii-specific immunity. Ii increased the magnitude and breadth of NS-specific T cell responses, along with effector memory markers, cytokine secretion, and proliferative capacity. NS-specific CD8+ T cells responded more robustly than CD4+ T cells, likely due to a 21-amino acid Ii sequence that acted as a degron and promoted ubiquitination of the fused antigen, increasing proteasomal degradation and MHC-I presentation.
Contributed by Alex Najibi
ABSTRACT: Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. Major histocompatibility complex (MHC) class II-associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4(+) T cell responses. Preclinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding human Ii fused to the nonstructural (NS) antigens of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV-specific CD8(+) and CD4(+) responses were induced with up to 30% of CD3(+)CD8(+) cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti-Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets and paves the way for developing class II Ii vaccines against cancer and other infections.
Author Info: (1) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. (2) The Jenner Institute Laboratories, Nuffield Department of Medicine, University of Oxford, Oxford
Author Info: (1) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. (2) The Jenner Institute Laboratories, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK. (3) ReiThera s.r.l., 00128 Rome, Italy. (4) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. (5) ReiThera s.r.l., 00128 Rome, Italy. (6) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. (7) Center for Medical Parasitology, University of Copenhagen, DK-2200 Copenhagen, Denmark. Department of Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark. InProTher ApS, BioInnovation Institute, 2200 Copenhagen, Denmark. (8) Center for Medical Parasitology, University of Copenhagen, DK-2200 Copenhagen, Denmark. (9) Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy. (10) ReiThera s.r.l., 00128 Rome, Italy. (11) GSK Vaccines, 1330 Rixensart, Belgium. (12) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. (13) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. (14) Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy. (15) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. (16) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. (17) ReiThera s.r.l., 00128 Rome, Italy. (18) ReiThera s.r.l., 00128 Rome, Italy. (19) ReiThera s.r.l., 00128 Rome, Italy. (20) ReiThera s.r.l., 00128 Rome, Italy. (21) Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy. (22) Department of Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark. (23) Department of Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark. (24) ReiThera s.r.l., 00128 Rome, Italy. (25) ReiThera s.r.l., 00128 Rome, Italy. (26) ReiThera s.r.l., 00128 Rome, Italy. (27) ReiThera s.r.l., 00128 Rome, Italy. (28) ReiThera s.r.l., 00128 Rome, Italy. (29) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. The Jenner Institute Laboratories, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK. (30) Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy. CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy. Keires AG, 4051 Basel, Switzerland. (31) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. Oxford NIHR Biomedical Research Centre, Headington OX3 9DU, UK. (32) ReiThera s.r.l., 00128 Rome, Italy. (33) ReiThera s.r.l., 00128 Rome, Italy. (34) Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. ellie.barnes@ndm.ox.ac.uk. The Jenner Institute Laboratories, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
