title: Recombinant, live-attenuated tetravalent dengue virus vaccine formulations induce a balanced, broad, and protective neutralizing antibody response against each of the four serotypes in rhesus monkeys.
abstract: Three tetravalent vaccine (TV) formulations of previously described monovalent dengue (DEN) virus vaccine candidates were compared to a tetravalent formulation of wild-type DEN viruses (T-wt) for replication in SCID mice transplanted with human liver cells (SCID-HuH-7) or for replication and immunogenicity in rhesus monkeys. TV-1 consists of recombinant DEN1, -2, -3, and -4, each with a 30-nucleotide deletion in the 3' untranslated region (Delta30). TV-2 consists of rDEN1Delta30, rDEN4Delta30, and two antigenic chimeric viruses, rDEN2/4Delta30 and rDEN3/4Delta30, both also bearing the Delta30 mutation. TV-3 consists of rDEN1Delta30, rDEN2Delta30, rDEN4Delta30, and a 10-fold higher dose of rDEN3/4Delta30. TV-1 and TV-2 were attenuated in SCID-HuH-7 mice with minimal interference in replication among the virus components. TV-1, -2, and -3 were attenuated in rhesus monkeys as measured by duration and peak of viremia. Each monkey immunized with TV-1 and TV-3 seroconverted to the four DEN components by day 28 with neutralization titers ranging from 1:52 to 1:273 and 1:59 to 1:144 for TV-1 and TV-3, respectively. TV-2 induced low antibody titers to DEN2 and DEN3, but a booster immunization after 4 months increased the neutralizing antibody titers to greater than 1:100 against each serotype and elicited broad neutralizing activity against 19 of 20 DEN subtypes. A single dose of TV-2 induced protection against wild-type DEN1, DEN3, and DEN4 challenge, but not DEN2. However, two doses of TV-2 or TV-3 induced protection against DEN2 challenge. Two tetravalent formulations, TV-2 and TV-3, possess properties of a successful DEN vaccine and can be considered for evaluation in clinical trials.
authors.affiliation: Laboratory of Infectious Diseases, NIH, NIAID, LID Twinbrook III, Room 3W-13, 12735 Twinbrook Parkway, MSC 8133, Bethesda, MD 20892-8133, USA. jblaney@niaid.nih.gov
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Blaney
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Matro
authors.forename: Brian R
authors.initials: BR
authors.lastname: Murphy
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Whitehead
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D003429:Cross Reactions; D003715:Dengue / Q000517:prevention & control*; D003716:Dengue Virus / Q000145:classification / Q000235:genetics / Q000276:immunology*; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007117:Immunization, Secondary; D008253:Macaca mulatta; D051379:Mice; D016513:Mice, SCID; D014611:Vaccination; D017778:Vaccines, Combined / Q000008:administration & dosage / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology; D014762:Viral Interference; D014765:Viral Vaccines / Q000008:administration & dosage / Q000145:classification / Q000276:immunology*; D014779:Virus Replication
chemical_list: D020413:3' Untranslated Regions; D000914:Antibodies, Viral; D017778:Vaccines, Combined; D014614:Vaccines, Synthetic; D014765:Viral Vaccines