title: Immunogenicity and efficacy of flagellin-envelope fusion dengue vaccines in mice and monkeys.
abstract: The envelope (E) protein of flaviviruses includes three domains, EI, EII, and EIII, and is the major protective antigen. Because EIII is rich in type-specific and subcomplex-specific neutralizing epitopes and is easy to express, it is particularly attractive as a recombinant vaccine antigen. VaxInnate has developed a vaccine platform that genetically links vaccine antigens to bacterial flagellin, a Toll-like receptor 5 ligand. Here we report that tetravalent dengue vaccines (TDVs) consisting of four constructs, each containing two copies of EIII fused to flagellin (R3.2x format), elicited robust and long-lived neutralizing antibodies (geometric mean titers of 200 to 3,000), as measured with a 50% focus reduction neutralization test (FRNT50). In an immunogenicity study, rhesus macaques (n = 2) immunized subcutaneously with 10 μg or 90 μg of TDV three or four times, at 4- to 6-week intervals, developed neutralizing antibodies to four dengue virus (DENV) serotypes (mean post-dose 3 FRNT50 titers of 102 to 601). In an efficacy study, rhesus macaques (n = 4) were immunized intramuscularly with 16 μg or 48 μg of TDV or a placebo control three times, at 1-month intervals. The animals that received 48-μg doses of TDV developed neutralizing antibodies against the four serotypes (geometric mean titers of 49 to 258) and exhibited reduced viremia after DENV-2 challenge, with a group mean viremia duration of 1.25 days and 2 of 4 animals being completely protected, compared to the placebo-treated animals, which all developed viremia, with a mean duration of 4 days. In conclusion, flagellin-EIII fusion vaccines are immunogenic and partially protective in a nonhuman primate model.
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA ge.liu@vaxinnate.com.
authors.forename: Ge
authors.initials: G
authors.lastname: Liu
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Langzhou
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Microbiology and Immunology, Sealy Center for Vaccine Development, and Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: David W C
authors.initials: DW
authors.lastname: Beasley
authors.affiliation: Viral Disease Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Putnak
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Parent
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: John
authors.initials: J
authors.lastname: Misczak
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Reiserova
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Haijun
authors.initials: H
authors.lastname: Tian
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Liu
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Darlene
authors.initials: D
authors.lastname: Labonte
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Duan
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Youngsun
authors.initials: Y
authors.lastname: Kim
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Travalent
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Devin
authors.initials: D
authors.lastname: Wigington
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Weaver
authors.affiliation: VaxInnate Corporation, Cranbury, New Jersey, USA.
authors.forename: Lynda
authors.initials: L
authors.lastname: Tussey
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000097:blood*; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood*; D016207:Cytokines / Q000097:blood / Q000276:immunology; D003715:Dengue / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005408:Flagellin / Q000008:administration & dosage / Q000276:immunology; D007279:Injections, Subcutaneous; D008253:Macaca mulatta / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D051198:Toll-Like Receptor 5 / Q000276:immunology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology*; D014766:Viremia / Q000517:prevention & control
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D016207:Cytokines; D053059:Dengue Vaccines; D051198:Toll-Like Receptor 5; D014613:Vaccines, Attenuated; D022223:Vaccines, Subunit; D005408:Flagellin