title: An intact signal peptide on dengue virus E protein enhances immunogenicity for CD8(+) T cells and antibody when expressed from modified vaccinia Ankara.
abstract: Dengue is a global public health concern and this is aggravated by a lack of vaccines or antiviral therapies. Despite the well-known role of CD8(+) T cells in the immunopathogenesis of Dengue virus (DENV), only recent studies have highlighted the importance of this arm of the immune response in protection against the disease. Thus, the majority of DENV vaccine candidates are designed to achieve protective titers of neutralizing antibodies, with less regard for cellular responses. Here, we used a mouse model to investigate CD8(+) T cell and humoral responses to a set of potential DENV vaccines based on recombinant modified vaccinia virus Ankara (rMVA). To enable this study, we identified two CD8(+) T cell epitopes in the DENV-3 E protein in C57BL/6 mice. Using these we found that all the rMVA vaccines elicited DENV-specific CD8(+) T cells that were cytotoxic in vivo and polyfunctional in vitro. Moreover, vaccines expressing the E protein with an intact signal peptide sequence elicited more DENV-specific CD8(+) T cells than those expressing E proteins in the cytoplasm. Significantly, it was these same ER-targeted E protein vaccines that elicited antibody responses. Our results support the further development of rMVA vaccines expressing DENV E proteins and add to the tools available for dengue vaccine development.
authors.affiliation: Laboratory of Basic and Applied Virology, Department of Microbiology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Campus Pampulha, CEP: 31270-901, Belo Horizonte, MG, Brazil; Division of Biomedical Science and Biochemistry, Research School of Biology, Bldg. 134 Linnaeus Way, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Bárbara R
authors.initials: BR
authors.lastname: Quinan
authors.affiliation: Division of Biomedical Science and Biochemistry, Research School of Biology, Bldg. 134 Linnaeus Way, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Inge E A
authors.initials: IE
authors.lastname: Flesch
authors.affiliation: Laboratory of Basic and Applied Virology, Department of Microbiology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Campus Pampulha, CEP: 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Tânia M G
authors.initials: TM
authors.lastname: Pinho
authors.affiliation: Laboratory of Basic and Applied Virology, Department of Microbiology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Campus Pampulha, CEP: 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Fabiana M
authors.initials: FM
authors.lastname: Coelho
authors.affiliation: Division of Biomedical Science and Biochemistry, Research School of Biology, Bldg. 134 Linnaeus Way, The Australian National University, Canberra, ACT 0200, Australia. Electronic address: david.tscharke@anu.edu.au.
authors.forename: David C
authors.initials: DC
authors.lastname: Tscharke
authors.affiliation: Laboratory of Basic and Applied Virology, Department of Microbiology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Campus Pampulha, CEP: 31270-901, Belo Horizonte, MG, Brazil; Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil. Electronic address: dafonseca@cpqrr.fiocruz.br.
authors.forename: Flávio G
authors.initials: FG
authors.lastname: da Fonseca
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003715:Dengue / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000276:immunology*; D003716:Dengue Virus; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D021382:Protein Sorting Signals; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D053059:Dengue Vaccines; C084188:E protein, Dengue virus type 3; D018984:Epitopes, T-Lymphocyte; D021382:Protein Sorting Signals; D014759:Viral Envelope Proteins
keywords: CD8(+) T cells; CTL; Cytotoxic T cells; Dengue virus; MVA; Recombinant MVA