title: Safety and efficacy of chimeric yellow Fever-dengue virus tetravalent vaccine formulations in nonhuman primates.
abstract: To construct chimeric YF/DEN viruses (ChimeriVax-DEN), the premembrane (prM) and envelope (E) genes of yellow fever (YF) 17D virus were replaced with those of each wild-type (WT) dengue (DEN) virus representing serotypes 1 to 4. ChimeriVax-DEN1-4 vaccine viruses were prepared by electroporation of Vero cells with RNA transcripts prepared from viral cDNA (F. Guirakhoo, J. Arroyo, K. V. Pugachev, C. Miller, Z.-X. Zhang, R. Weltzin, K. Georgakopoulos, J. Catalan, S. Ocran, K. Soike, M. Ratteree, and T. P. Monath, J. Virol. 75:7290-7304, 2001; F. Guirakhoo, K. Pugachev, J. Arroyo, C. Miller, Z.-X. Zhang, R. Weltzin, K. Georgakopoulos, J. Catalan, S. Ocran, K. Draper, and T. P. Monath, Virology 298:146-159, 2002). Progeny viruses were subjected to three rounds of plaque purifications to produce the Pre-Master Seed viruses at passage 7 (P7). Three further passages were carried out using U.S. current Good Manufacturing Practices (cGMP) to produce the Vaccine Lot (P10) viruses. Preclinical studies demonstrated that the vaccine candidates are replication competent and genetically stable and do not become more neurovirulent upon 20 passages in Vero cells. The safety of a tetravalent vaccine was determined and compared to that of YF-VAX in a formal monkey neurovirulence test. Brain lesions produced by the tetravalent ChimeriVax-DEN vaccine were significantly less severe than those observed with YF-VAX. The immunogenicity and protective efficacy of four different tetravalent formulations were evaluated in cynomolgus monkeys following a single-dose subcutaneous vaccination followed by a virulent virus challenge 6 months later. All monkeys developed low levels of viremia postimmunization, and all the monkeys that had received equal concentrations of either a high-dose (5,5,5,5) or a low-dose (3,3,3,3) formulation seroconverted against all four DEN virus serotypes. Twenty-two (92%) of 24 monkeys were protected as determined by lack of viremia post-challenge. This report is the first to demonstrate the safety of a recombinant DEN virus tetravalent vaccine in a formal neurovirulence test, as well as its protective efficacy in a monkey challenge model.
authors.affiliation: Acambis, Inc., Cambridge, Massachusetts 02139, USA. farshad.guirakhoo@acambis.com
authors.forename: F
authors.initials: F
authors.lastname: Guirakhoo
authors.forename: K
authors.initials: K
authors.lastname: Pugachev
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Myers
authors.forename: I
authors.initials: I
authors.lastname: Levenbook
authors.forename: K
authors.initials: K
authors.lastname: Draper
authors.forename: J
authors.initials: J
authors.lastname: Lang
authors.forename: S
authors.initials: S
authors.lastname: Ocran
authors.forename: F
authors.initials: F
authors.lastname: Mitchell
authors.forename: M
authors.initials: M
authors.lastname: Parsons
authors.forename: N
authors.initials: N
authors.lastname: Brown
authors.forename: S
authors.initials: S
authors.lastname: Brandler
authors.forename: C
authors.initials: C
authors.lastname: Fournier
authors.forename: B
authors.initials: B
authors.lastname: Barrere
authors.forename: F
authors.initials: F
authors.lastname: Rizvi
authors.forename: A
authors.initials: A
authors.lastname: Travassos
authors.forename: R
authors.initials: R
authors.lastname: Nichols
authors.forename: D
authors.initials: D
authors.lastname: Trent
authors.forename: T
authors.initials: T
authors.lastname: Monath
mesh_terms: D000818:Animals; D000833:Animals, Suckling; D003715:Dengue / Q000517:prevention & control* / Q000821:virology; D003716:Dengue Virus / Q000235:genetics*; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D016865:Reassortant Viruses; D011995:Recombination, Genetic; D014765:Viral Vaccines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000235:genetics; D053060:West Nile Virus Vaccines; D015004:Yellow Fever / Q000821:virology; D015005:Yellow fever virus / Q000235:genetics*
chemical_list: C445780:ChimeriVax; D014765:Viral Vaccines; D053060:West Nile Virus Vaccines