MHC class II invariant chain–adjuvanted viral vectored vaccines enhances T cell responses in humans

Originally published on SCIENCE TRANSLATIONAL MEDICINE • 17 Jun 2020 • Vol 12, Issue 548.

  • Ilaria Esposito, Paola Cicconi, Anna Morena D’Alise, Anthony Brown, Marialuisa Esposito, Leo Swadling, Peter Johannes Holst, Maria Rosaria Bassi, Mariano Stornaiuolo, Federica Mori, Ventzislav Vassilev, Wenqin Li, Timothy Donnison, Chiara Gentile, Bethany Turner, Annette von Delft, Mariarosaria Del Sorbo, Federica Barra, Alessandra Maria Contino, Adele Abbate, Ettore Novellino, Allan Randrup Thomsen, Jan Pravsgaard Christensen, Armin Lahm, Fabiana Grazioli, Virginia Ammendola, Loredana Siani, Stefano Colloca, Paul Klenerman, Alfredo Nicosia, Lucy Dorrell, Antonella Folgori, Stefania Capone, Eleanor Barnes, PEACHI Consortium

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  eveloped 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.