title: A rapid immunization strategy with a live-attenuated tetravalent dengue vaccine elicits protective neutralizing antibody responses in non-human primates.
abstract: Dengue viruses (DENVs) cause approximately 390 million cases of DENV infections annually and over 3 billion people worldwide are at risk of infection. No dengue vaccine is currently available nor is there an antiviral therapy for DENV infections. We have developed a tetravalent live-attenuated DENV vaccine tetravalent dengue vaccine (TDV) that consists of a molecularly characterized attenuated DENV-2 strain (TDV-2) and three chimeric viruses containing the pre-membrane and envelope genes of DENV-1, -3, and -4 expressed in the context of the TDV-2 genome. To impact dengue vaccine delivery in endemic areas and immunize travelers, a simple and rapid immunization strategy (RIS) is preferred. We investigated RIS consisting of two full vaccine doses being administered subcutaneously or intradermally on the initial vaccination visit (day 0) at two different anatomical locations with a needle-free disposable syringe jet injection delivery devices (PharmaJet) in non-human primates. This vaccination strategy resulted in efficient priming and induction of neutralizing antibody responses to all four DENV serotypes comparable to those elicited by the traditional prime and boost (2 months later) vaccination schedule. In addition, the vaccine induced CD4(+) and CD8(+) T cells producing IFN-γ, IL-2, and TNF-α, and targeting the DENV-2 NS1, NS3, and NS5 proteins. Moreover, vaccine-specific T cells were cross-reactive with the non-structural NS3 and NS5 proteins of DENV-4. When animals were challenged with DENV-2 they were protected with no detectable viremia, and exhibited sterilizing immunity (no increase of neutralizing titers post-challenge). RIS could decrease vaccination visits and provide quick immune response to all four DENV serotypes. This strategy could increase vaccination compliance and would be especially advantageous for travelers into endemic areas.
authors.affiliation: Takeda Vaccines, Inc. , Madison, WI , USA.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Ambuel
authors.affiliation: Takeda Vaccines, Inc. , Madison, WI , USA.
authors.forename: Ginger
authors.initials: G
authors.lastname: Young
authors.affiliation: Takeda Vaccines, Inc. , Madison, WI , USA.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Brewoo
authors.affiliation: Takeda Vaccines, Inc. , Madison, WI , USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Paykel
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison , Madison, WI , USA.
authors.forename: Kim L
authors.initials: KL
authors.lastname: Weisgrau
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison , Madison, WI , USA.
authors.forename: Eva G
authors.initials: EG
authors.lastname: Rakasz
authors.affiliation: Takeda Vaccines, Inc. , Ft Collins, CO , USA.
authors.forename: Aurelia A
authors.initials: AA
authors.lastname: Haller
authors.affiliation: PharmaJet Inc. , Golden, CO , USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Royals
authors.affiliation: Division of Vector-Borne Diseases, Centers for Disease Control and Prevention , Ft. Collins, CO , USA.
authors.forename: Claire Y-H
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison , Madison, WI , USA.
authors.forename: Saverio
authors.initials: S
authors.lastname: Capuano
authors.affiliation: Takeda Vaccines, Inc. , Ft Collins, CO , USA.
authors.forename: Dan T
authors.initials: DT
authors.lastname: Stinchcomb
authors.affiliation: Takeda Vaccines, Inc. , Madison, WI , USA.
authors.forename: Charalambos D
authors.initials: CD
authors.lastname: Partidos
authors.affiliation: Takeda Vaccines, Inc. , Madison, WI , USA.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Osorio
keywords: T cell responses; dengue; needle-free delivery; neutralizing antibodies; non-human primates; vaccine