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Translation from Cryptic Reading Frames of DNA Vaccines Generates an Extended Repertoire of Immunogenic, MHC Class I-Restricted Epitopes¹

Reinhold Schirmbeck^2,*, Petra Riedl^*, Nicolas Fissolo^*, Francois A. Lemonnier, Antonio Bertoletti and Jörg Reimann^*

^* Institute of Medical Microbiology and Immunology, University of Ulm, Ulm, Germany; Institut Pasteur, Unité d’Immunité Cellulaire Antivirale, Department d‘Immunologie, Paris, France; and Institute of Hepatology, University College London, London, United Kingdom

To test whether simple expression units used in DNA vaccines can generate immunogenic, MHC class I-binding epitopes by translating other than the primary open reading frame (ORF), we constructed a vector (pCI/SX) that encodes the small hepatitis B surface Ag in the primary ORF, and a C-terminal fragment (residue 344–832) of the polymerase (Pol) in an alternative (out-of-frame) reading frame. pCI/SX efficiently primed multispecific, HLA-A2-restricted CD8⁺ T cell responses to epitopes of hepatitis B surface Ag and of Pol (Pol3, Pol_803–811). Pol3-containing products generated from pCI/SX were detected only by T cell assays, but not by biochemical assays. Priming Pol-specific T cell responses to epitopes generated from alternative ORFs depended on promoter sequences that drive transcription in the DNA vaccine (human CMV-derived promoter sequences being more efficient than SV40-derived promoter sequences). Human CMV promoter-driven Pol constructs encoding different Pol fragments in primary or alternative reading frames elicited comparable levels of Pol3-specific T cell responses. We confirmed efficient T cell priming to epitopes from alternative ORFs by constructing DNA vaccines that encode an SV40-derived cT_1–272 protein fused either in frame or out of frame with an immunogenic OVA fragment (OVA_18–385). Similar OVA-specific CD8⁺ T cell responses were primed by both alternative vaccine constructs. Hence, DNA vaccine-stimulated T cell responses to epitopes generated from alternative ORFs seem to be a regular event, although its biological role and risks are largely unexplored.

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