title: Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax-DEN2) vaccine: Phase I clinical trial for safety and immunogenicity: effect of yellow fever pre-immunity in induction of cross neutralizing antibody responses to all 4 dengue serotypes.
abstract: A randomized double-blind Phase I Trial was conducted to evaluate safety, tolerability, and immunogenicity of a yellow fever (YF)-dengue 2 (DEN2) chimera (ChimeriVax-DEN2) in comparison to that of YF vaccine (YF-VAX). Forty-two healthy YF naïve adults randomly received a single dose of either ChimeriVax-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAX by the subcutaneous route (SC). To determine the effect of YF preimmunity on the ChimeriVax-DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naïve subjects inoculated with 5.0 and 3.0 log10 PFU of ChimeriVax-DEN2, respectively, seroconverted to wt DEN2 (strain 16681); 92% of subjects inoculated with YF-VAX seroconverted to YF 17D virus but none of YF naïve subjects inoculated with ChimeriVax-DEN2 seroconverted to YF 17D virus. Low seroconversion rates to heterologous DEN serotypes 1, 3 and 4 were observed in YF naïve subjects inoculated with either ChimeriVax-DEN2 or YF-VAX. In contrast, 100% of YF immune subjects inoculated with ChimeriVax-DEN2 seroconverted to all 4 DEN serotypes. Surprisingly, levels of neutralizing antibodies to DEN 1, 2 and 3 viruses in YF immune subjects persisted after 1 year. These data demonstrated that (1) the safety and immunogenicity profile of the ChimeriVax-DEN2 vaccine is consistent with that of YF-VAX, and (2) preimmunity to YF virus does not interfere with ChimeriVax-DEN2 immunization, but induces a long lasting and cross neutralizing antibody response to all 4 DEN serotypes. The latter observation can have practical implications toward development of a dengue vaccine.
authors.affiliation: Acambis, Inc., Cambridge, Massachusetts 02139, USA. Farshad.Guirakhoo@acambis.com
authors.forename: Farshad
authors.initials: F
authors.lastname: Guirakhoo
authors.forename: Scott
authors.initials: S
authors.lastname: Kitchener
authors.forename: Dennis
authors.initials: D
authors.lastname: Morrison
authors.forename: Remi
authors.initials: R
authors.lastname: Forrat
authors.forename: Karen
authors.initials: K
authors.lastname: McCarthy
authors.forename: Richard
authors.initials: R
authors.lastname: Nichols
authors.forename: Sutee
authors.initials: S
authors.lastname: Yoksan
authors.forename: Xiaochu
authors.initials: X
authors.lastname: Duan
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Ermak
authors.forename: Niranjan
authors.initials: N
authors.lastname: Kanesa-Thasan
authors.forename: Philip
authors.initials: P
authors.lastname: Bedford
authors.forename: Jean
authors.initials: J
authors.lastname: Lang
authors.forename: Marie-Jose
authors.initials: MJ
authors.lastname: Quentin-Millet
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Monath
mesh_terms: D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000032:analysis / Q000096:biosynthesis; D003429:Cross Reactions; D003715:Dengue / Q000276:immunology* / Q000517:prevention & control*; D003716:Dengue Virus / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000276:immunology; D014765:Viral Vaccines / Q000009:adverse effects* / Q000276:immunology*; D014766:Viremia / Q000097:blood / Q000276:immunology; D022341:Yellow Fever Vaccine / Q000009:adverse effects* / Q000276:immunology*; D015005:Yellow fever virus / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D014613:Vaccines, Attenuated; D014765:Viral Vaccines; D022341:Yellow Fever Vaccine