Whole-Inactivated Influenza Virus Is a Potent Adjuvant for Influenza Peptides Containing CD8+ T Cell Epitopes

Abstract

Influenza peptide antigens coding for conserved T cell epitopes have the capacity to induce cross-protective influenza-specific immunity. Short peptide antigens used as a vaccine, however, often show poor immunogenicity. In this study, we demonstrate that whole-inactivated influenza virus (WIV) acts as an adjuvant for influenza peptide antigens, as shown by the induction of peptide-specific CD8+ T cells in HLA-A2.1 transgenic mice upon vaccination with the influenza-M1-derived GILGFVFTL peptide (GIL), formulated with WIV. By screening various concentrations of GIL and WIV, we found that both components contributed to the GIL-specific T cell response. Whereas co-localization of the peptide antigen and WIV adjuvant was found to be important, neither physical association between peptide and WIV nor fusogenic activity of WIV were relevant for the adjuvant effect of WIV. We furthermore show that WIV may adjuvate T cell responses to a variety of peptides, using pools of either conserved wild-type influenza peptides or chemically altered peptide ligands. This study shows the potential of WIV as an adjuvant for influenza peptides. The simple formulation process and the solid safety record of WIV make this an attractive adjuvant for T cell peptides, and may also be used for non-influenza antigens.

Thioamide Analogues of MHC I Antigen Peptides

“…We selected two well-known HLA-A2-restricted antigens, GILGFVFTL (GIL) and ELAGIGILTV (ELA), for the evaluation of the thio-antigen approach. HLA-A2 is found in ∼50% of the human population. , Both GIL and ELA have been evaluated in vitro or in clinical trials as potential peptide vaccines. ,− Antigens containing 9 or 10 residues appear to be optimal for HLA-A2 presentation, , and we wished to evaluate one antigen of each length. Crystallographic evidence shows that ELA and GIL differ considerably in the presentation of the HLA-A2-bound peptide to cognate TCRs (Figure S1).…”

Backbone Modifications of HLA-A2-Restricted Antigens Induce Diverse Binding and T Cell Activation Outcomes

“…We analyzed a series of GILGFVFTL (GIL hereafter) α/β-peptides derived from the influenza A virus M1 protein. GIL is a highly immunogenic and conserved epitope, , and several recent reports evaluated this epitope for a potential peptide vaccine. ,, In contrast to most pHLA-A2 structures, GIL is considered to be a “featureless” peptide in its complex with HLA-A2 because there are no solvent-exposed side chains in the central region of GIL (p4-p6). ,− For example, the side chain of Phe at p5 points into the HLA-A2 binding groove as opposed to projecting into solvent (Figure S1C).…”

Intranasal Immunization with the Influenza A Virus Encoding Truncated NS1 Protein Protects Mice from Heterologous Challenge by Restraining the Inflammatory Response in the Lungs

“…Modern variations of universal vaccines, such as HA stalk-based constructions [ 19 , 20 , 21 , 22 ], peptide vaccines [ 23 , 24 ], DNA/RNA-vaccines [ 25 , 26 , 27 , 28 , 29 , 30 ], or artificial HA-proteins created using Computationally Optimized Broadly Reactive Antigen (COBRA) technology [ 31 ], are focused on the induction of antibodies and effector T-cells, recognizing the conserved epitopes of the influenza virus. However, the immune response to the restricted set of the conserved epitopes does not prevent the formation of the escape mutants.…”