title: Evaluation of protection induced by a dengue virus serotype 2 envelope domain III protein scaffold/DNA vaccine in non-human primates.
abstract: We describe the preclinical development of a dengue virus vaccine targeting the dengue virus serotype 2 (DENV2) envelope domain III (EDIII). This study provides proof-of-principle that a dengue EDIII protein scaffold/DNA vaccine can protect against dengue challenge. The dengue vaccine (EDIII-E2) is composed of both a protein particle and a DNA expression plasmid delivered simultaneously via intramuscular injection (protein) and gene gun (DNA) into rhesus macaques. The protein component can contain a maximum of 60 copies of EDIII presented on a multimeric scaffold of Geobacillus stearothermophilus E2 proteins. The DNA component is composed of the EDIII portion of the envelope gene cloned into an expression plasmid. The EDIII-E2 vaccine elicited robust antibody responses to DENV2, with neutralizing antibody responses detectable following the first boost and reaching titers of greater than 1:100,000 following the second and final boost. Vaccinated and naïve groups of macaques were challenged with DENV2. All vaccinated macaques were protected from detectable viremia by infectious assay, while naïve animals had detectable viremia for 2-7 days post-challenge. All naïve macaques had detectable viral RNA from day 2-10 post-challenge. In the EDIII-E2 group, three macaques were negative for viral RNA and three were found to have detectable viral RNA post challenge. Viremia onset was delayed and the duration was shortened relative to naïve controls. The presence of viral RNA post-challenge corresponded to a 10-30-fold boost in neutralization titers 28 days post challenge, whereas no boost was observed in the fully protected animals. Based on these results, we determine that pre-challenge 50% neutralization titers of >1:6000 correlated with sterilizing protection against DENV2 challenge in EDIII-E2 vaccinated macaques. Identification of the critical correlate of protection for the EDIII-E2 platform in the robust non-human primate model lays the groundwork for further development of a tetravalent EDIII-E2 dengue vaccine.
authors.affiliation: Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: McBurney
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.
authors.forename: Justine E
authors.initials: JE
authors.lastname: Sunshine
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Huynh
authors.affiliation: Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Sutton
authors.affiliation: Department of Microbiology, University of Washington School of Medicine, 1705 NE Pacific St., Seattle, WA 98195, USA.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Fuller
authors.affiliation: Division of Pathobiology & Immunology, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Haigwood
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA; Division of Infectious Diseases, Department of Medicine, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA. Electronic address: messer@ohsu.edu.
authors.forename: William B
authors.initials: WB
authors.lastname: Messer
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D019470:Biolistics; D003715:Dengue / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000276:immunology*; D003716:Dengue Virus / Q000145:classification*; D008253:Macaca mulatta; D012367:RNA, Viral / Q000097:blood; D011993:Recombinant Fusion Proteins / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology; D014766:Viremia / Q000517:prevention & control
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053059:Dengue Vaccines; D012367:RNA, Viral; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic
keywords: DNA vaccine; Dengue; Dengue envelope domain III vaccine; Dengue subunit vaccine; Dengue vaccine; Protein scaffold vaccine