title: A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models.
abstract: Zika virus (ZIKV) infection of pregnant women can cause a wide range of congenital abnormalities, including microcephaly, in the infant, a condition now collectively known as congenital ZIKV syndrome. A vaccine to prevent or significantly attenuate viremia in pregnant women who are residents of or travelers to epidemic or endemic regions is needed to avert congenital ZIKV syndrome, and might also help to suppress epidemic transmission. Here we report on a live-attenuated vaccine candidate that contains a 10-nucleotide deletion in the 3' untranslated region of the ZIKV genome (10-del ZIKV). The 10-del ZIKV is highly attenuated, immunogenic, and protective in type 1 interferon receptor-deficient A129 mice. Crucially, a single dose of 10-del ZIKV induced sterilizing immunity with a saturated neutralizing antibody titer, which no longer increased after challenge with an epidemic ZIKV, and completely prevented viremia. The immunized mice also developed a robust T cell response. Intracranial inoculation of 1-d-old immunocompetent CD-1 mice with 1 × 104infectious focus units (IFU) of 10-del ZIKV caused no mortality, whereas infections with 10 IFU of wild-type ZIKV were lethal. Mechanistically, the attenuated virulence of 10-del ZIKV may be due to decreased viral RNA synthesis and increased sensitivity to type-1-interferon inhibition. The attenuated 10-del ZIKV was incapable of infecting mosquitoes after oral feeding of spiked-blood meals, representing an additional safety feature. Collectively, the safety and efficacy results suggest that further development of this promising, live-attenuated ZIKV vaccine candidate is warranted.
authors.affiliation: Department of Biochemistry &Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Shan
authors.affiliation: Institute for Human Infections &Immunity, University of Texas Medical Branch, Galveston, Texas, USA.|Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Antonio E
authors.initials: AE
authors.lastname: Muruato
authors.affiliation: Department of Biochemistry &Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Pará State, Brazil.
authors.forename: Bruno T D
authors.initials: BTD
authors.lastname: Nunes
authors.affiliation: Department of Microbiology &Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Huanle
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Biochemistry &Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Xuping
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Biochemistry &Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Pará State, Brazil.
authors.forename: Daniele B A
authors.initials: DBA
authors.lastname: Medeiros
authors.affiliation: Department of Biochemistry &Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Maki
authors.initials: M
authors.lastname: Wakamiya
authors.affiliation: Institute for Human Infections &Immunity, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pathology and Center for Biodefense &Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Tesh
authors.affiliation: Institute for Human Infections &Immunity, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pathology and Center for Biodefense &Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA.|Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Barrett
authors.affiliation: Department of Microbiology &Immunology, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pathology and Center for Biodefense &Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA.|Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.affiliation: Institute for Human Infections &Immunity, University of Texas Medical Branch, Galveston, Texas, USA.|Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Microbiology &Immunology, University of Texas Medical Branch, Galveston, Texas, USA.|Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA.|Sealy Center for Structural Biology &Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Weaver
authors.affiliation: Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Pará State, Brazil.|Department of Pathology, Pará State University, Belém, Brazil.
authors.forename: Pedro F C
authors.identifier: http://orcid.org/0000-0002-6603-5527
authors.initials: PFC
authors.lastname: Vasconcelos
authors.affiliation: Institute for Human Infections &Immunity, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pathology and Center for Biodefense &Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Shannan L
authors.initials: SL
authors.lastname: Rossi
authors.affiliation: Department of Biochemistry &Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.|Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA.|Sealy Center for Structural Biology &Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Phamarcology &Toxicology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000330:Aedes; D000818:Animals; D057134:Antibodies, Neutralizing / Q000187:drug effects* / Q000276:immunology; D002522:Chlorocebus aethiops; D005455:Fluorescent Antibody Technique; D000071497:Immunogenicity, Vaccine; D007370:Interferon Type I / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D000072138:Mosquito Vectors / Q000821:virology; D009154:Mutation; D012367:RNA, Viral / Q000187:drug effects* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017471:Receptors, Interferon / Q000235:genetics; D014613:Vaccines, Attenuated / Q000494:pharmacology*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*; D000071244:Zika Virus / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D000071243:Zika Virus Infection / Q000517:prevention & control*
chemical_list: D020413:3' Untranslated Regions; D057134:Antibodies, Neutralizing; D007370:Interferon Type I; D012367:RNA, Viral; D017471:Receptors, Interferon; D014613:Vaccines, Attenuated