title: Investigating the efficacy of monovalent and tetravalent dengue vaccine formulations against DENV-4 challenge in AG129 mice.
abstract: Dengue (DEN) is the most important mosquito-borne viral disease, with a major impact on global health and economics, caused by four serologically and distinct viruses termed DENV-1 to DENV-4. Currently, there is no licensed vaccine to prevent DEN. We have developed a live attenuated tetravalent DENV vaccine candidate (TDV) (formally known as DENVax) that has shown promise in preclinical and clinical studies and elicits neutralizing antibody responses to all four DENVs. As these responses are lowest to DENV-4 we have used the AG129 mouse model to investigate the immunogenicity of monovalent TDV-4 or tetravalent TDV vaccines, and their efficacy against lethal DENV-4 challenge. Since the common backbone of TDV is based on an attenuated DENV-2 strain (TDV-2) we also tested the efficacy of TDV-2 against DENV-4 challenge. Single doses of the tetravalent or monovalent vaccines elicited neutralizing antibodies, anti-NS1 antibodies, and cellular responses to both envelope and nonstructural proteins. All vaccinated animals were protected against challenge at 60 days post-immunization, whereas all control animals died. Investigation of DENV-4 viremias post-challenge showed that only the control animals had high viremias on day 3 post-challenge, whereas vaccinated mice had no detectable viremia. Overall, these data highlight the excellent immunogenicity and efficacy profile of our candidate dengue vaccine in AG129 mice.
authors.affiliation: Takeda Vaccines, Inc., Madison, WI, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fuchs
authors.affiliation: Takeda Vaccines, Inc., Madison, WI, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chu
authors.affiliation: Takeda Vaccines, Inc., Madison, WI, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Day
authors.affiliation: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555-0436, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Pyles
authors.affiliation: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555-0436, USA.
authors.forename: Nigel
authors.initials: N
authors.lastname: Bourne
authors.affiliation: Takeda Vaccines, Inc., Madison, WI, USA.
authors.forename: Subash C
authors.initials: SC
authors.lastname: Das
authors.affiliation: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555-0436, USA.
authors.forename: Gregg N
authors.initials: GN
authors.lastname: Milligan
authors.affiliation: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555-0436, USA.
authors.forename: Alan D T
authors.initials: AD
authors.lastname: Barrett
authors.affiliation: Takeda Vaccines, Inc., Madison, WI, USA. Electronic address: harry.partidos@takeda.com.
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
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation; D003715:Dengue / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000737:chemistry / Q000276:immunology*; D003716:Dengue Virus / Q000145:classification; D004195:Disease Models, Animal; D007111:Immunity, Cellular; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology; D014766:Viremia / Q000517:prevention & control
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053059:Dengue Vaccines
keywords: AG129 mice; Dengue; Dengue 4; Immune protection; Vaccines