title: Modified mRNA Vaccines Protect against Zika Virus Infection.
abstract: The emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (∼1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically relevant concern.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Richner
authors.affiliation: Valera LLC, a Moderna Venture, 500 Technology Square, Cambridge, MA, 02139, USA.
authors.forename: Sunny
authors.initials: S
authors.lastname: Himansu
authors.affiliation: Viral Pathogenesis Section, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Dowd
authors.affiliation: Valera LLC, a Moderna Venture, 500 Technology Square, Cambridge, MA, 02139, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Butler
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Salazar
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Fox
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT, 84335 USA.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Julander
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Tang
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta
authors.affiliation: Viral Pathogenesis Section, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Pierson
authors.affiliation: Valera LLC, a Moderna Venture, 500 Technology Square, Cambridge, MA, 02139, USA. Electronic address: Giuseppe.Ciaramella@Valeratx.com.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ciaramella
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: diamond@wusm.wustl.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D000939:Epitopes / Q000276:immunology; D005260:Female; D008055:Lipids / Q000737:chemistry; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000071244:Zika Virus / Q000276:immunology; D000071243:Zika Virus Infection / Q000276:immunology* / Q000517:prevention & control*
chemical_list: D000939:Epitopes; D008055:Lipids; D012333:RNA, Messenger; D014765:Viral Vaccines
keywords: Dengue virus; RNA vaccine; Zika virus; antibody neutralization; flavivirus; immunity; pathogenesis; protection