title: Development of a recombinant, chimeric tetravalent dengue vaccine candidate.
abstract: Dengue is a significant threat to public health worldwide. Currently, there are no licensed vaccines available for dengue. Takeda Vaccines Inc. is developing a live, attenuated tetravalent dengue vaccine candidate (TDV) that consists of an attenuated DENV-2 strain (TDV-2) and three chimeric viruses containing the prM and E protein genes of DENV-1, -3 and -4 expressed in the context of the attenuated TDV-2 genome backbone (TDV-1, TDV-3, and TDV-4, respectively). TDV has been shown to be immunogenic and efficacious in nonclinical animal models. In interferon-receptor deficient mice, the vaccine induces humoral neutralizing antibody responses and cellular immune responses that are sufficient to protect from lethal challenge with DENV-1, DENV-2 or DENV-4. In non-human primates, administration of TDV induces innate immune responses as well as long lasting antibody and cellular immunity. In Phase 1 clinical trials, the safety and immunogenicity of two different formulations were assessed after intradermal or subcutaneous administration to healthy, flavivirus-naïve adults. TDV administration was generally well-tolerated independent of dose and route. The vaccine induced neutralizing antibody responses to all four DENV serotypes: after a single administration of the higher formulation, 24-67%% of the subjects seroconverted to all four DENV and >80% seroconverted to three or more viruses. In addition, TDV induced CD8(+) T cell responses to the non-structural NS1, NS3 and NS5 proteins of DENV. TDV has been also shown to be generally well tolerated and immunogenic in a Phase 2 clinical trial in dengue endemic countries in adults and children as young as 18 months. Additional clinical studies are ongoing in preparation for a Phase 3 safety and efficacy study.
authors.affiliation: Takeda Vaccines Inc., Deerfield, IL, USA. Electronic address: jorge.osorio@wisc.edu.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Osorio
authors.affiliation: Takeda Vaccines Inc., Deerfield, IL, USA.
authors.forename: Charalambos D
authors.initials: CD
authors.lastname: Partidos
authors.affiliation: Takeda Vaccines Inc., Deerfield, IL, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Wallace
authors.affiliation: Takeda Vaccines Inc., Deerfield, IL, USA.
authors.forename: Dan T
authors.initials: DT
authors.lastname: Stinchcomb
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003715:Dengue / Q000453:epidemiology / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000009:adverse effects / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification*; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007271:Injections, Intradermal; D051379:Mice; D011323:Primates; D016019:Survival Analysis; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D014614:Vaccines, Synthetic / Q000009:adverse effects / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053059:Dengue Vaccines; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic
keywords: Dengue fever; Dengue virus; Vaccine development