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Enhanced Priming of Multispecific, Murine CD8⁺ T Cell Responses by DNA Vaccines Expressing Stress Protein-Binding Polytope Peptides¹

Reinhold Schirmbeck^*, Nicolas Fissolo^*, Paul Chaplin and Jörg Reimann^2,*

^* Institute of Medical Microbiology and Immunology, University of Ulm, Ulm, Germany; and Bavarian-Nordic GmbH, Copenhagen, Denmark

A polytope DNA vaccine (pCI/pt10) was used that encodes within a 106-residue sequence 10-well characterized epitopes binding MHC class I molecules encoded by the K, D, or L locus (of H-2^d, H-2^b, and H-2^k haplotype mice). The pCI/pt10 DNA vaccine efficiently primed all four K^b/D^b-restricted CD8⁺ T cell responses in H-2^b mice, but was deficient in stimulating most CD8⁺ T cell responses in H-2^d mice. Comparing CD8⁺ T cell responses elicited with the pCI/pt10 DNA vaccine in L^d+ BALB/c and L^d- BALB/c^dm2 (dm2) mice revealed that L^d-restricted CD8⁺ T cell responses down-regulated copriming of CD8⁺ T cell responses to other epitopes regardless of their restriction or epitope specificity. Although the pt10 vaccine could thus efficiently co prime multispecific CD8⁺ T cell responses, this priming was impaired by copriming L^d-restricted CD8⁺ T cell responses. When the pt10 sequence was fused to a 77-residue DnaJ-homologous, heat shock protein 73-binding domain (to generate a 183-residue cT₇₇-pt10 fusion protein), expression and immunogenicity (for CD8⁺ T cells) of the chimeric Ag were greatly enhanced. Furthermore, priming of multispecific CD8⁺ T cell responses was readily elicited even under conditions in which the suppressive, L^d-dependent immunodominance operated. The expression of polytope vaccines as chimeric peptides that endogenously capture stress proteins during in situ production thus facilitates copriming of CD8⁺ T cell populations with a diverse repertoire.

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