title: Immunogenicity and efficacy of chimeric dengue vaccine (DENVax) formulations in interferon-deficient AG129 mice.
abstract: Formulations of chimeric dengue vaccine (DENVax) viruses containing the pre-membrane (prM) and envelope (E) genes of serotypes 1-4 expressed in the context of the attenuated DENV-2 PDK-53 genome were tested for safety, immunogenicity and efficacy in interferon receptor knock-out mice (AG129). Monovalent formulations were safe and elicited robust neutralizing antibody responses to the homologous virus and only limited cross-reactivity to other serotypes. A single dose of monovalent DENVax-1, -2, or -3 vaccine provided eighty or greater percent protection against both wild-type (wt) DENV-1 (Mochizuki strain) and DENV-2 (New Guinea C strain) challenge viruses. A single dose of monovalent DENVax-4 also provided complete protection against wt DENV-1 challenge and significantly increased the survival times after challenge with wt DENV-2. In studies using tetravalent mixtures, DENVax ratios were identified that: (i) caused limited viremia, (ii) induced serotype-specific neutralizing antibodies to all four DENV serotypes with different hierarchies, and (iii) conferred full protection against clinical signs of disease following challenge with either wt DENV-1 or DENV-2 viruses. Overall, these data highlight the immunogenic profile of DENVax, a novel candidate tetravalent dengue vaccine and the advantage of sharing a common attenuated genomic backbone among the DENVax monovalent vaccines that confer protection against homologous or heterologous virus challenge.
authors.affiliation: Inviragen, Inc., Madison, WI, United States.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Brewoo
authors.forename: Richard M
authors.initials: RM
authors.lastname: Kinney
authors.forename: Tim D
authors.initials: TD
authors.lastname: Powell
authors.forename: John J
authors.initials: JJ
authors.lastname: Arguello
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Silengo
authors.forename: Charalambos D
authors.initials: CD
authors.lastname: Partidos
authors.forename: Claire Y-H
authors.initials: CY
authors.lastname: Huang
authors.forename: Dan T
authors.initials: DT
authors.lastname: Stinchcomb
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Osorio
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D001831:Body Temperature; D001835:Body Weight; D003715:Dengue / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D053059:Dengue Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D004195:Disease Models, Animal; D007372:Interferons / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D016019:Survival Analysis; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D019562:Viral Load; D014766:Viremia / Q000517:prevention & control
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053059:Dengue Vaccines; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D007372:Interferons