title: An alphavirus vector-based tetravalent dengue vaccine induces a rapid and protective immune response in macaques that differs qualitatively from immunity induced by live virus infection.
abstract: Despite many years of research, a dengue vaccine is not available, and the more advanced live attenuated vaccine candidate in clinical trials requires multiple immunizations with long interdose periods and provides low protective efficacy. Here, we report important contributions to the development of a second-generation dengue vaccine. First, we demonstrate that a nonpropagating vaccine vector based on Venezuelan equine encephalitis virus replicon particles (VRP) expressing two configurations of dengue virus E antigen (subviral particles [prME] and soluble E dimers [E85]) successfully immunized and protected macaques against dengue virus, while antivector antibodies did not interfere with a booster immunization. Second, compared to prME-VRP, E85-VRP induced neutralizing antibodies faster, to higher titers, and with improved protective efficacy. Third, this study is the first to map antigenic domains and specificities targeted by vaccination versus natural infection, revealing that, unlike prME-VRP and live virus, E85-VRP induced only serotype-specific antibodies, which predominantly targeted EDIII, suggesting a protective mechanism different from that induced by live virus and possibly live attenuated vaccines. Fourth, a tetravalent E85-VRP dengue vaccine induced a simultaneous and protective response to all 4 serotypes after 2 doses given 6 weeks apart. Balanced responses and protection in macaques provided further support for exploring the immunogenicity and safety of this vaccine candidate in humans.
authors.affiliation: Global Vaccines Inc., Research Triangle Park, NC, USA. steve.rockman@csl.com.au
authors.forename: Laura J
authors.initials: LJ
authors.lastname: White
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Sariol
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Mattocks
authors.forename: Wahala
authors.initials: W
authors.lastname: Wahala M P B
authors.forename: Vorraphun
authors.initials: V
authors.lastname: Yingsiwaphat
authors.forename: Martha L
authors.initials: ML
authors.lastname: Collier
authors.forename: Jill
authors.initials: J
authors.lastname: Whitley
authors.forename: Rochelle
authors.initials: R
authors.lastname: Mikkelsen
authors.forename: Idia V
authors.initials: IV
authors.lastname: Rodriguez
authors.forename: Melween I
authors.initials: MI
authors.lastname: Martinez
authors.forename: Aravinda
authors.initials: A
authors.lastname: de Silva
authors.forename: Robert E
authors.initials: RE
authors.lastname: Johnston
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D003429:Cross Reactions; D003715:Dengue / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004337:Drug Carriers; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics*; D005822:Genetic Vectors; D008251:Macaca; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014766:Viremia / Q000517:prevention & control
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053059:Dengue Vaccines; D004337:Drug Carriers; D014614:Vaccines, Synthetic