TY - JOUR
T1 - Immunogenicity and efficacy of flagellin-envelope fusion dengue vaccines in mice and monkeys
AU - Liu, Ge
AU - Song, Langzhou
AU - Beasley, David W.C.
AU - Putnak, Robert
AU - Parent, Jason
AU - Misczak, John
AU - Li, Hong
AU - Reiserova, Lucia
AU - Liu, Xiangyu
AU - Tian, Haijun
AU - Liu, Wenzhe
AU - Labonte, Darlene
AU - Duan, Lihua
AU - Kim, Youngsun
AU - Travalent, Linda
AU - Wigington, Devin
AU - Weaver, Bruce
AU - Tussey, Lynda
N1 - Publisher Copyright:
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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 μgor90 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 μgor48 μg of TDV or a placebo control three times, at 1-month intervals. The animals that received 48-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.
AB - 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 μgor90 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 μgor48 μg of TDV or a placebo control three times, at 1-month intervals. The animals that received 48-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.
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U2 - 10.1128/CVI.00770-14
DO - 10.1128/CVI.00770-14
M3 - Article
C2 - 25761459
AN - SCOPUS:84929092600
SN - 1556-6811
VL - 22
SP - 516
EP - 525
JO - Clinical and Vaccine Immunology
JF - Clinical and Vaccine Immunology
IS - 5
ER -