Elimination of Immunodominant Epitopes from Multispecific DNA-Based Vaccines Allows Induction of CD8 T Cells That Have a Striking Antiviral Potential

Immunodominance limits the TCR diversity of specific antiviral CD8 T cell responses elicited by vaccination or infection. To prime multispecific T cell responses, we constructed DNA vaccines that coexpress chimeric, multidomain Ags (with CD8 T cell-defined epitopes of the hepatitis B virus (HBV) surface (S), core (C), and polymerase (Pol) proteins and/or the OVA Ag as stress protein-capturing fusion proteins. Priming of mono- or multispecific, HLA-A*0201- or K-b-restricted CD8 T cell responses by these DNA vaccines differed. K-b/OVA(257-264)- and K-190-197(b)-specific CD8 T cell responses did not allow priming of a K-b/C93-100-specific CD8 T cell response in mice immunized with multidomain vaccines. Tolerance to the S- Ag in transgenic Alb/HBs mice (that express large amounts of transgene-encoded S- Ag in the liver) facilitated priming of subdominant, K-b/C93-100-specific CD8 T cell immunity by multidomain Ags. The weak (i.e., easily suppressed) K-b/C93-100-specific CD8 T cell response was efficiently elicited by a HBV core Ag-encoding vector in 1.4HBV-S-mut tg mice (that harbor a replicating HBV genome that produces HBV surface, core, and precore Ag in the liver). K-b/C93-100-specific CD8 T cells accumulated in the liver of vaccinated 1.4HBV-S-mut transgenic mice where they suppressed HBV replication. Subdominant epitopes in vaccines can hence prime specific CD8 T cell immunity in a tolerogenic milieu that delivers specific antiviral effects to HBV-expressing hepatocytes. The Journal of Immunology, 2009, 183: 370-380.