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

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.

Design and Immunological Validation of Macaca fascicularis Papillomavirus Type 3 Based Vaccine Candidates in Outbred Mice: Basis for Future Testing of a Therapeutic Papillomavirus Vaccine in NHPs

“…Lower molecular weight signals are indicative of degradation products. This effect was not observed for E1 without Ii, which suggested that Ii induced an accelerated proteasomal degradation, as also reported by Esposito et al (27).…”

“…The molecular basis of the T cell adjuvant effect of Ii has not been fully clarified yet (43), but one of the suggested mechanisms of action is Ii mediated ubiquitination leading to proteasomal degradation of the linked antigen and thereby enhanced MHC-I presentation (Figure 2C) (27). To investigate if this mechanism could also account for the enhanced CD8 + T-cell responses against the Ii-linked MfPV3 antigens, Ii-E1E2E6E7-and E1E2E6E7transfected cells were cultivated in absence or presence of the proteasome inhibitor MG132.…”

“…To develop such a therapeutic vaccine, vectors expressing antigen candidates comprising E1, E2, E6 and E7 of MfPV3 were generated and characterized. The antigens are genetically linked to the intrinsic T cell adjuvant MHC-II-associated invariant chain (Ii) that has been shown to increase viral-vector-induced T cell responses in mice, cynomolgus macaques and humans (25)(26)(27). The antigens were designed in different configurations as artificial fusion proteins and initially characterized via DNA vaccination of outbred CD1 mice.…”

Adaptive Immune Response against Hepatitis C Virus

“…This interpretation is also in line with the finding that the epitope repertoire between HCV genotype 1 and genotype 3 or 4, respectively, display little overlap [145,146]. Thus, current research addresses novel adjuvant formulations such as the use of MHC class II invariant chain-adjuvanted viral vectors, enhancing the peak magnitude, breath, and proliferative capacity of HCV-specific T cells induced by the ChAd3-HCV1b-NS prime/MVA-HCV-1b-NS boost vaccine in healthy volunteers [147]. In addition, the team of Eleanor Barnes further optimized the vaccine strategy to generate pan-genotypic T cell responses to conserved subdominant epitopes [148].…”

Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial

“…If immunogenicity in this population is found to be muted, whether due to opioid use or previous sub-infectious exposures, the addition and use of novel adjuvants or vaccine platforms to enhance immunogenicity in PWID may be required. For example, the inclusion of MHC class II-associated invariant chain in a viral vectored HCV vaccine broadly enhanced CD4 + and CD8 + T cell responses over the original vaccine in recently conducted human clinical trials [ 156 ].…”