title: Induction of broad cytotoxic T cells by protective DNA vaccination against Marburg and Ebola.
abstract: Marburg and Ebola hemorrhagic fevers have been described as the most virulent viral diseases known to man due to associative lethality rates of up to 90%. Death can occur within days to weeks of exposure and there is currently no licensed vaccine or therapeutic. Recent evidence suggests an important role for antiviral T cells in conferring protection, but little detailed analysis of this response as driven by a protective vaccine has been reported. We developed a synthetic polyvalent-filovirus DNA vaccine against Marburg marburgvirus (MARV), Zaire ebolavirus (ZEBOV), and Sudan ebolavirus (SUDV). Preclinical efficacy studies were performed in guinea pigs and mice using rodent-adapted viruses, whereas murine T-cell responses were extensively analyzed using a novel modified assay described herein. Vaccination was highly potent, elicited robust neutralizing antibodies, and completely protected against MARV and ZEBOV challenge. Comprehensive T-cell analysis revealed cytotoxic T lymphocytes (CTLs) of great magnitude, epitopic breadth, and Th1-type marker expression. This model provides an important preclinical tool for studying protective immune correlates that could be applied to existing platforms. Data herein support further evaluation of this enhanced gene-based approach in nonhuman primate studies for in depth analyses of T-cell epitopes in understanding protective efficacy.
authors.affiliation: Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Devon J
authors.initials: DJ
authors.lastname: Shedlock
authors.forename: Jenna
authors.initials: J
authors.lastname: Aviles
authors.forename: Kendra T
authors.initials: KT
authors.lastname: Talbott
authors.forename: Gary
authors.initials: G
authors.lastname: Wong
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Wu
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Villarreal
authors.forename: Devin Jf
authors.initials: DJ
authors.lastname: Myles
authors.forename: Maria A
authors.initials: MA
authors.lastname: Croyle
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.forename: Gary P
authors.initials: GP
authors.lastname: Kobinger
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000818:Animals; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008379:Marburg Virus Disease / Q000276:immunology* / Q000517:prevention & control*; D029024:Marburgvirus / Q000276:immunology / Q000472:pathogenicity; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology* / Q000627:therapeutic use; D014765:Viral Vaccines / Q000276:immunology / Q000627:therapeutic use
chemical_list: D019444:Vaccines, DNA; D014765:Viral Vaccines