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Elimination of Immunodominant Epitopes from Multispecific DNA-Based Vaccines Allows Induction of CD8 T Cells That Have a Striking Antiviral Potential¹

Petra Riedl^2,*, Andreas Wieland^2,*, Kasper Lamberth, Soren Buus, Francois Lemonnier, Kurt Reifenberg, Jörg Reimann^* and Reinhold Schirmbeck^3,*

^* Department of Internal Medicine I, University of Ulm, Germany; Laboratory of Experimental Immunology, University of Copenhagen, Denmark; Institute Pasteur, Unite d'Immunite Cellulaire Antivirale, Paris, France; and Central Laboratory Animal Facility, University of Mainz, Germany

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^b/S_190–197-specific CD8 T cell responses did not allow priming of a K^b/C_93–100-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/C_93–100-specific CD8 T cell immunity by multidomain Ags. The "weak" (i.e., easily suppressed) K^b/C_93–100-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/C_93–100-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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Deutsche Forschungsgemeinschaft (Ri 1297/1-1 to P.R. and Schi 505/2H4 to R.S.).

² P.R. and A.W. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Reinhold Schirmbeck, Department of Internal Medicine I, University of Ulm, Albert Einstein Allee 23, D-89081 Ulm, Germany. E-mail address: reinhold.schirmbeck{at}uniklinik-ulm.de

⁴ Abbreviations used in this paper: HBV, hepatitis B virus; HBsAg or S, HBV surface Ag; HBcAg, or C, HBV core Ag; HBeAg, HBV e Ag; Pol, polymerase; tg, transgenic; Hsp, heat shock protein.

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